CONTENTS

INTRODUCTION TO PATHOPHYSIOLOGY, xxi

Part One BASIC CONCEPTS OF PATHOPHYSIOLOGY

UNIT 1 THE CELL

1 Cellular Biology, 1
2 Genes and Genetic Diseases, 34
3 Altered Cellular and Tissue Biology, 59
4 Fluids and Electrolytes, Acids and Bases, 98

UNIT 2 MECHANISMS OF SELF-DEFENSE

5 Innate Immunity: Inflammation and Wound Healing, 118
6 Adaptive Immunity, 142
7 Infection and Defects in Mechanisms of Defense, 165
8 Stress and Disease, 204

UNIT 3 CELLULAR PROLIFERATION: CANCER

9 Biology, Clinical Manifestations, and Treatment of Cancer, 222
10 Cancer Epidemiology, 253
11 Cancer in Children, 288

Part Two BODY SYSTEMS AND DISEASES

UNIT 4 THE NEUROLOGIC SYSTEM

12 Structure and Function of the Neurologic System, 293
13 Pain, Temperature, Sleep, and Sensory Function, 324
14 Alterations in Cognitive Systems, Cerebral Hemodynamics, and Motor Function, 347
15 Disorders of the Central and Peripheral Nervous Systems and Neuromuscular Junction, 377
16 Alterations of Neurologic Function in Children, 409

UNIT 5 THE ENDOCRINE SYSTEM

17 Mechanisms of Hormonal Regulation, 426
18 Alterations of Hormonal Regulation, 447

UNIT 6 THE HEMATOLOGIC SYSTEM

19 Structure and Function of the Hematologic System, 477
20 Alterations of Hematologic Function, 500
21 Alterations of Hematologic Function in Children, 535

UNIT 7 THE CARDIOVASCULAR AND LYMPHATIC SYSTEMS

22 Structure and Function of the Cardiovascular and Lymphatic Systems, 551
23 Alterations of Cardiovascular Function, 585
24 Alterations of Cardiovascular Function in Children, 643

UNIT 8 THE PULMONARY SYSTEM

25 Structure and Function of the Pulmonary System, 659
26 Alterations of Pulmonary Function, 678
27 Alterations of Pulmonary Function in Children, 707

UNIT 9 THE RENAL AND UROLOGIC SYSTEMS

28 Structure and Function of the Renal and Urologic Systems, 724
29 Alterations of Renal and Urinary Tract Function, 741
30 Alterations of Renal and Urinary Tract Function in Children, 764
UNIT 10 THE REPRODUCTIVE SYSTEMS
31 Structure and Function of the Reproductive Systems, 774
32 Alterations of the Reproductive Systems, Including Sexually Transmitted Infections, 799

UNIT 11 THE DIGESTIVE SYSTEM

33 Structure and Function of the Digestive System, 871
34 Alterations of Digestive Function, 894
35 Alterations of Digestive Function in Children, 938

UNIT 12 THE MUSCULOSKELETAL AND INTEGUMENTARY SYSTEMS

36 Structure and Function of the Musculoskeletal System, 954
37 Alterations of Musculoskeletal Function, 978
38 Alterations of Musculoskeletal Function in Children, 1022
39 Structure, Function, and Disorders of the Integument, 1038
40 Alterations of the Integument in Children, 1070

APPENDIX, 1083
GLOSSARY, 1085

HEALTH ALERTS
Gene Therapy, 54 Vitamin D, 437 Genetic and Immunologic Advancements in Lung
Whole Food Antioxidants, 66 Hormones from Adipose Tissue—The Adipokines, 439 Cancer Treatment, 703
Unintentional Injury Errors in Healthcare, 75 Subclinical Thyroid Dysfunction, 453 Exercise-Induced Bronchoconstriction, 718
Decline in Life Expectancy in Some U.S. Counties, 92 Incretin Hormones for Type 2 Diabetes Mellitus Newborn Screening for Cystic Fibrosis, 720
Breast-Feeding and Hypernatremia, 105 Therapy, 463 Gene Therapies for Cystic Fibrosis, 720
Increase in United States of “Tropical Diseases,” 166 Sticky Platelets, Genetic Variations, and Cranberry Juice and Urinary Tract Infection, 735
The Continued Rise of Antibiotic-Resistant Cardiovascular Complications, 490 Urinary Tract Infection and Antibiotic Resistance,
Microorganisms, 177 Dark Chocolate, Wine, and Platelet-Inhibitory 748
Risk of HIV Transmission Associated With Sexual Functions, 526 Childhood Urinary Tract Infections, 768
Practices, 184 Vaccine-Associated ITP in Early Childhood, 545 Male Hormone Contraception, 794
AIDS Vaccine Trials, 188 Dasatinib: A Promising Agent to Treat Refractory Symptoms of Menopause and Breast Cancer Risk,
Psychosocial Stress and Progression to Coronary Chronic Myeloid Leukemia, 547 795
Heart Disease, 210 Multiple Effects of the Renin-Angiotensin- Dietary Interventions and Lifestyle Changes for
Glucocorticoids, Insulin, Inflammation, and Aldosterone System, 577 Pelvic Prolapse, 811
Obesity, 212 Adrenomedullin, 578 Cervical Cancer Primary Prevention, 815
Acute Emotional Stress and Adverse Heart Effects, 217 The Renin-Angiotensin-Aldosterone System and Recovery After Cancer Treatment, 818
Partner’s Survival and Spouse’s Hospitalizations Cardiovascular Disease, 588 Iodine and Breast Diseases Including Breast Cancer,
and/or Death, 217 Obesity and Hypertension, 589 841
Screening Mammograms: Far From Perfect, 243 The Basics on Fats, 598 Bacterial Vaginosis, 857
Snapshot of Foods as Therapeutic Nutrients, 265 Inflammatory Markers for Cardiovascular Risk, 600 Anti-Infective Treatment for Victims of Sexual
Radiation and Vulnerable Populations: Pregnant Women and Coronary Artery Disease, 602 Assault, 857
Women, Embryos, Fetus, and Children, 269 Metabolic Changes in Heart Failure, 625 Helicobacter Pylori and Gastric Cancer, 882
Increasing Use of Computed Tomography Scans The Role of Nitric Oxide in Severe Sepsis, 634 Paracetamol (Acetaminophen) and Acute Liver
and Risks, 270 The Role of Activated Protein C in Sepsis and DIC, Failure, 887
Rising Incidence of HIV-Associated Oropharyngeal 634 Refeeding Syndrome, 914
Cancers, 277 Nutritional Support to Prevent and Treat MODS, Childhood Obesity and Nonalcoholic Fatty Liver
Magnetic Fields and Development of Pediatric 637 Disease, 950
Cancer, 291 Endocarditis Risk, 646 Tendon and Ligament Repair, 974
Neuroplasticity, 299 U.S. Childhood Obesity and Its Association With Managing Tendinopathy, 984
Attention-Deficit Hyperactivity Disorder (ADHD): Cardiovascular Disease, 655 Osteoporosis Facts and Figures at a Glance, 989
Not Just a Childhood Disorder, 353 Changes in the Chemical Control of Breathing Calcium, Vitamin D, and Bone Health, 992
Biomarkers and Neurodegenerative Dementia, 360 During Sleep, 666 New Treatment for Osteoporosis, 993
Tourette Syndrome, 369 Pharmacogenetics and Beta Agonists in the Body Weight and Osteoarthritis, 999
West Nile Virus, 396 Treatment of Asthma, 692 Musculoskeletal Molecular Imaging, 1002
Stem Cells: Neuroprotection and Restoration, 398 Ventilator-Associated Pneumonia (VAP), 695 Psoriasis and Comorbidities, 1050
Stereotactic Radioneurosurgery, 403 Serum Biomarkers for the Diagnosis of Pneumonia, Skin Photoprotection from the Inside Out, 1058
Iron and Cognitive Function, 410 697 Hidradenitis Suppurativa (Inverse Acne), 1071
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Sue E. Huether, MSN, PhD
Professor Emeritus
College of Nursing
University of Utah
Salt Lake City, Utah

Kathryn L. McCance, MSN, PhD

Professor
College of Nursing
University of Utah
Salt Lake City, Utah

Section Editors
Valentina L. Brashers, MD
Professor of Nursing and Attending Physician in Internal Medicine
University of Virginia Health System
Charlottesville, Virginia

Neal S. Rote, PhD

Academic Vice-Chair and Director of Research
Department of Obstetrics and Gynecology
University Hospitals of Cleveland;
Professor of Reproductive Biology and Pathology
Case School of Medicine
Case Western Reserve University
Cleveland, Ohio

with 1,000 illustrations


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UNDERSTANDING PATHOPHYSIOLOGY ISBN: 978-0-323-07891-7

Copyright © 2012 by Mosby, Inc., an imprint of Elsevier Inc.

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our understanding, changes in research methods, professional practices, or medical treatment may become
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Library of Congress Cataloging-in-Publication Data

Understanding pathophysiology / [edited by] Sue E. Huether, Kathryn L. McCance;
section editors, Valentina L. Brashers, Neal S. Rote. — 5th ed.
p. ; cm.

Includes bibliographical references and index. ABOUT
ISBN 978-0-323-07891-7 (pbk. : alk. paper) THE COVER
I. Huether, Sue E. II. McCance, Kathryn L.
[DNLM: 1. Pathology—Nurses’ Instruction. 2. Disease—Nurses’ Instruction.
3. Physiology—Nurses’ Instruction. QZ 4]
616.07—dc23 2011039731

Image of white blood cells and inflammation: B lymphocytes

Vice President and Publisher: Loren S. Wilson (orange) communicate via cytokines with other inflammatory cells,
Senior Editor: Sandra Clark such as T lymphocytes (purple) and monocytes/macrophages (pur-
Senior Developmental Editor: Charlene Ketchum ple in bag), to maintain and amplify the cycle of inflammation.
Editorial Assistant: Brooke Kannady
Publishing Services Manager: Jeffrey Patterson
Project Manager: Jeanne Genz
Designer: Paula Catalano
Multimedia Producer: Lisa Godoski

Printed in the United States of America

Last digit is the print number: 9  8  7  6  5  4  3  2

 CONTRIBUTORS*

Jan Belden, MSN, RN-BC, FNP-BC Kristi K. Gott, MSN, RN, CPNP Vinodh Narayanan, MD
Pain Management Nurse Practitioner Pediatric Pulmonary Nurse Practitioner Child Neurologist
Loma Linda University Medical Center University of Virginia School of Nursing St. Joseph’s Hospital and Medical Center
Linda, California Charlottesville, Virginia Professor of Clinical Pediatrics and
­Neurology
Barbara J. Boss, PhD, RN, CFNP, CANP Todd C. Grey, MD University of Arizona College of Medicine
Director of DNP Program and Professor of Chief Medical Examiner Phoenix, Arizona
Nursing State of Utah
School of Nursing Associate Clinical Professor of Pathology Noreen Heer Nicol, PhD,
University of Mississippi Medical Center University of Utah School of Medicine RN, FNP, NEA-BC
Jackson, Mississippi Salt Lake City, Utah Director, Professional Development
The Children’s Hospital
Kristen Lee Carroll, MD Robert E. Jones, MD, FACP, FACE Clinical Senior Instructor
Associate Professor of Orthopedics Professor of Medicine University of Colorado
Assistant Professor of Pediatric Neurology University of Utah School of Medicine Affiliate Associate Professor
University of Utah Medical Center Salt Lake City, Utah University of Northern Colorado
Shriner’s Intermountain Unit
Salt Lake City, Utah Lynn B. Jorde, PhD Patricia Ring, RN, PNP-BC
H.A. and Edna Benning Presidential Pediatric Nephrology Nurse Practitioner
Margaret F. Clayton, PhD, APRN-BC Professor and Chair Children’s Hospital of Wisconsin
Assistant Professor Department of Human Genetics Milwaukee, Wisconsin
College of Nursing University of Utah School of Medicine
University of Utah Salt Lake City, Utah Anna L. Schwartz, PhD, FNP, FAAN
Salt Lake City, Utah Associate Professor, School of Nursing
Lynne M. Kerr, MD, PhD Idaho State University
Christy L. Crowther-Radulewicz, Associate Professor Oncology Nurse Practitioner
RN, MS, CRNP Pediatric Neurology Wilson Medical
Nurse Practitioner Primary Children’s Medical Center Jackson, Wyoming
Anne Arundel Orthopaedic Surgeons Salt Lake City, Utah
Annapolis, Maryland Richard A. Sugerman, PhD
Adjunct Faculty Nancy E. Kline, PhD, RN, CPNP, FAAN Professor of Anatomy
Johns Hopkins School of Nursing Director, Research and Evidence-Based College of Osteopathic Medicine
Department of Community-Public Health Practice Western University of Health Sciences
Baltimore, Maryland Department of Nursing Pomona, California
Memorial Sloan-Kettering Cancer Center
Curtis DeFriez, MD New York, New York David Virshup, MD
Professor Professor and Director
Department of Health Sciences Gwen Latendresse, PhD, CNM Program in Cancer and Stem Cell Biology
Weber State University Assistant Professor Duke-NUS Graduate Medical School
Ogden, Utah University of Utah College of Nursing Singapore
Salt Lake City, Utah Professor of Pediatrics
Angela Deneris, PhD, CNM Duke University School of Medicine
Associate Professor, Clinical Nancy L. McDaniel, MD Durham, North Carolina
University of Utah College of Nursing Associate Professor of Pediatrics
Salt Lake City, Utah University of Virginia Jo Voss, PhD, RN, CNS
Charlottesville, Virginia Associate Professor
Sharon Dudley-Brown, PhD, FNP-BC South Dakota State University
Assistant Professor Rapid City, South Dakota
Schools of Medicine and Nursing
Johns Hopkins University
Baltimore, Maryland

*The authors would also like to thank the previous edition contributors.

v
This page intentionally left blank

     
 REVIEWERS

Mandi Counters, RN, MSN, CNRC Bruce S. McEwen, PhD Louise Suit, EdD, RN, CNS, CAS
Assistant Professor Alfred E. Mirsky Professor Assistant Professor
Mercy College of Health Sciences Head, Harold and Margaret Milliken Hatch Regis University
Des Moines, Iowa Laboratory of Neuroendocrinology Denver, Colorado
The Rockefeller University
April N. Hart, RN, MSN, FNP-BC, CNE New York, New York Jo Voss, PhD, RN, CNS
Assistant Professor Associate Professor
Bethel College Charles Preston Molsbee, West River Department of Nursing
Mishawaka, Indiana EdD, MSN, RN, CNE South Dakota State University
Assistant Professor Rapid City, South Dakota
Stephen D. Krau, PhD, RN, CNE, CT University of Arkansas
Associate Professor Little Rock, Arkansas Kim Lee Webb, RN, MN
Vanderbilt University Medical Center Nursing Department Chair
Nashville, Tennessee Judith L. Myers, MSN, RN Northern Oklahoma College
Assistant Professor of Nursing Tonkawa, Oklahoma
Grand View University
Des Moines, Iowa

vii
This page intentionally left blank

     
 PREFACE

This edition, like the previous one, has been rigorously updated and • Updated and revised content on alterations of immunity and
revised, with many sections completely rewritten to reflect recent inflammation (Chapter 7)
findings. The pace of advances in areas such as immunity, inflamma- • Extensive revisions and reorganization of stress and disease
tion, cancer, genetics, and cardiovascular disease is astounding. And ­(Chapter 8)
although some of this progress already has been translated into clinical • Extensive revisions and reorganization of tumor biology (Chapter 9)
practice, many challenges remain on just how to use this new informa- • Extensive entire chapter revisions and reorganization of epidemiol-
tion to help improve diagnostic and disease management and caring ogy of cancer (Chapter 10)
practices. Nonetheless, we believe students should be exposed to these
emerging understandings as they unfold and be encouraged to follow Part Two: Body Systems and Diseases
these developments throughout their professional lives. Part Two presents the pathophysiology of the most common altera-
A major goal of this edition of Understanding Pathophysiology was tions according to body system. To guarantee readability and com-
to make it even more understandable. Toward that end, we have edited prehension, we have used a logical sequence and uniform approach in
the book to improve clarity by defining more of the terms used, by presenting the content of the units and chapters. Each unit focuses on
explaining some concepts more fully, by simplifying the more diffi- a specific organ system and contains chapters related to anatomy and
cult content, by reorganizing the sequence of some content, and by physiology, the pathophysiology of the most common diseases, and
revising and adding more color illustrations and photos. For example, common alterations in children. The anatomy and physiology content
the chapters on altered cellular and tissue biology, inflammation, and is presented as a review to enhance the learner’s understanding of the
immunity were rewritten entirely for simplification. We believe we structural and functional changes inherent in pathophysiology. A brief
have met our challenge without deleting any key information. summary of normal aging effects is included at the end of these review
Although the primary focus of the text is pathophysiology, we con- chapters. The general organization of each disease/disorder discussion
tinue to include discussions of the following interconnected topics to includes an introductory paragraph on relevant risk factors and epide-
highlight their importance for clinical practice: miology, then related pathophysiology, clinical manifestations, and a
• A life span approach that includes special sections on aging and brief review of evaluation and treatment. Significant revisions to Part
separate chapters on children Two include new and/or updated information on the following topics:
• Epidemiology and incidence rates showing dramatic, worldwide • The blood-brain barrier (Chapter 12)
differences that reflect the importance of environmental and life- • Mechanisms of pain and pain syndromes and sleep disorders
style factors on disease initiation and progression including restless legs syndrome (Chapter 13)
• Clinical manifestations and summaries of treatment • Alterations in levels of arousal, seizure disorders, and delirium.
• Gender differences that affect epidemiology and pathophysiology Pathogenesis of degenerative brain diseases, the dementias, motor
• Molecular biology—mechanisms of normal cell function and how neuron syndromes, traumatic brain and spinal cord injury, stroke
their alteration leads to disease syndromes, and headache (Chapters 14, 15, 16)
• Health promotion/risk reduction • Mechanisms of hormone receptors and hormone action
(Chapter 17)
ORGANIZATION AND CONTENT: WHAT’S • Thyroid disorders, insulin resistance and inflammatory cytokines,
and diabetes mellitus (Chapter 18)
NEW IN THE FIFTH EDITION • Platelet function and coagulation; alterations of leukocyte function
The book is organized into two parts: Part One, Basic Concepts of and myeloid tumors (Chapters 19 and 20)
Pathophysiology, and Part Two, Body Systems and Diseases. • Mechanisms of cardiac workload, cardiac muscle remodeling,
angiogenesis and growth factors, endothelial function (Chapter 22)
Part One: Basic Concepts of Pathophysiology • Mechanisms of atherosclerosis, hypertension, coronary artery dis-
Part One introduces basic principles and processes. The concepts ease, heart failure, and shock (Chapter 23)
include descriptions of cellular communication; genes and genetic • Pediatric valvular disorders, heart failure, hypertension, obesity,
disease; forms of cell injury; fluid and electrolytes and acid and base and heart disease (Chapter 24)
balance; immunity and inflammation; mechanisms of infection; stress, • Clinical manifestations of respiratory disease, acute respiratory
coping, and illness; and tumor biology. Knowledge of these principles distress syndrome, asthma, and respiratory tract infections
and processes is essential to gaining a contemporary understanding of (Chapter 26)
the pathophysiology of common diseases. • Croup, respiratory distress in the newborn, asthma, cystic fibrosis
Significant revisions to Part One include new or updated informa- (Chapter 27)
tion on the following topics: • Urinary tract obstruction, urinary tract infection, glomerulone-
• Updated content on cell communication, membrane transport, phritis, acute and chronic kidney injury (Chapter 29)
fluids and solute transportation (Chapter 1) • Polycystic kidney disease and pediatric glomerular disorders
• Updated content on oxidative stress, types of cell death, and aging (Chapter 30)
(Chapter 3) • Female and male reproductive disorders, prostate cancer, breast
• Extensive entire chapter revisions of mechanisms of human diseases and mechanisms of breast cancer, male breast cancer,
defense—characteristics of innate and adaptive immunity and sexually transmitted infections (Chapter 32)
(Chapters 5 and 6) • Peptic ulcer disease, obesity, liver disease, pancreatitis (Chapter 34)

ix
x Preface

• Gluten-sensitive enteropathy, necrotizing enterocolitis, and neona- discussions, and critical thinking exercises with answers; a Test Bank
tal jaundice (Chapter 35) of approximately 1,400 items (available as text files or in ExamView
• Bone cells, bone remodeling, joint and tendon diseases, osteoporo- computerized testing software); a PowerPoint Presentation of more
sis, rheumatoid and osteoarthritis (Chapters 36 and 37) than 2,000 lecture slides; an Image Collection of approximately 800 key
• Congenital and acquired musculoskeletal disorders, and muscular figures from the text; and Audience Response Questions for use with
dystrophies in children (Chapter 38) i>clicker and other systems.
• Psoriasis, discoid lupus erythematosus, and scleroderma (Chapter 39) All of these teaching resources are also available to instructors on
• Acne vulgaris and impetigo (Chapter 40) the book’s Evolve site, along with access to the WebLinks and other
Cancer of the various organ systems was updated for all of the student learning resources. Plus the Evolve Learning System provides a
chapters. comprehensive suite of course communication and organization tools
that allow you to upload your class calendar and syllabus, post scores
and announcements, and more. Go to http://evolve.elsevier.com/
FEATURES TO PROMOTE LEARNING Huether.
A number of features are incorporated into this text that guide and The newest and most exciting part of the package is Pathophysiol-
support learning and understanding, including: ogy Online, a complete set of online modules that provide thoroughly
• A Glossary of more than 850 terms related to pathophysiology developed lessons on the most important and difficult topics in patho-
• Chapter Outlines including page numbers for easy reference physiology supplemented with illustrations, animations, interactive
• Quick Check questions strategically placed throughout each chap- activities, interactive algorithms, self-assessment reviews, and exams.
ter to help readers confirm their understanding of the material; Instructors can use it to enhance traditional classroom lecture courses
answers are included on the textbook’s Evolve website or for distance and online-only courses. Students can use it as a self-
• Health Alerts with concise discussions of the latest research guided study tool.
• Risk Factors boxes for selected diseases
• End-of-chapter Did You Understand? summaries that condense the
major concepts of each chapter into an easy-to-review list format
ACKNOWLEDGMENTS
• Key Terms set in boldface in text and listed, with page numbers, at Although we can never really thank our contributors adequately, we
the end of each chapter would like to try by expressing our enormous gratitude for their gener-
• Special headings for Aging and Pediatrics content that highlight dis- ous contributions of time, knowledge, and talent. With today’s major
cussions of life span alterations emphasis on evidence-based practice, the challenges to read, interpret,
synthesize, and clearly communicate are notable. Times are changing,
with enormous amounts of published literature in many major fields
ART PROGRAM creating unique opportunities to “get it right”— increase patient-
The art program was carefully considered. This edition features more centered quality care, safety, and satisfaction. So quite simply, without
than 100 new and revised illustrations and photographs. The art program our contributors’ expertise, we would not have a textbook tending to
received as much attention as the narrative with a total of 900 images. With establish rigorous and robust facts or evidence.
new biologic understandings many new spectacular figures were designed For this edition Tina Brashers, MD, and Neal Rote, PhD, con-
to help students visually understand sometimes difficult and complex tinued to serve as Section Editors and contributing authors. Tina is
material. Hundreds of high-quality photographs show clinical manifesta- a distinguished teacher and has received numerous awards for her
tions, pathologic specimens, and clinical imaging techniques. Numerous work with nursing and medical students and faculty. She is nation-
micrographs show normal and abnormal cellular structure. The combi- ally known for contributions in promoting and teaching interprofes-
nation of illustrations, algorithms, photographs, and use of color for tables sional collaboration. Tina brings innovation and clarity to the subject
and boxes allows keen understanding of essential information. of pathophysiology. Her work on Pathophysiology Online continues
to be intensive and creative, and a significant learning enhancement
TEACHING/LEARNING PACKAGE for students. Thank you Tina for your writing, guidance of authors,
review of manuscript, and foresight about the overall scope of this
For Students project. Neal has major expertise, passion, and hard-to-find precision
The free Student Learning Resources on Evolve include review ques- in the topics of immunity and human defenses. He is a top-notch and
tions and answers, numerous animations, answers to the Quick Check successful researcher and has received numerous awards and recogni-
questions in the book, algorithm completion exercises, key term/defi- tion for his teaching. Neal has a gift for creating images that bring
nition matching exercises, critical thinking questions with answers, clarity to the complex content of immunology. Thank you Neal for
and WebLinks. These electronic resources enhance learning options your persistence in promoting understanding and your continuing
for students. Go to http://evolve.elsevier.com/Huether. devotion to students.
The Study Guide includes learning objectives, “Memory Check!” As always we are deeply indebted to Sue Meeks. She has worked
anatomy and physiology reviews, concise summaries of key chapter with us on this project for 30 years, orchestrating the various stages
concepts, a practice examination for each chapter, and case studies with of manuscript preparation. She single-handedly word-processes the
critical thinking questions. Answers to the practice examinations and a entire revision of the manuscript and continues to amaze us with her
discussion of each case study can be found in the back of the Study Guide. sincere level of enthusiasm for attention to detail. We are grateful for
the extraordinary effort she devotes to organizing, preparing, and
For Instructors accomplishing the task. Thank you Sue for, well—everything!
The Instructor’s Evolve Resources are available free to instructors The reviewers for this edition provided excellent recommendations
with qualified adoptions of the textbook and include the following: for revision and content emphasis and we appreciate their insightful
an Instructor’s Manual with learning objectives, difficult concepts work.
 Preface xi

A special thank you to the entire Elsevier team for the production of and friends at the University of Utah College of Nursing, School of
this book. Charlene Ketchum, our Developmental Editor, was critical. Medicine, Eccles Medical Library, and College of Pharmacy for their
She worked with us day-to-day, always unflappable, reassuring, and helpfulness, suggestions, and critiques.
focused, with a great sense of humor. Thanks again Charlene. Sandra The newly drawn and revised artwork for this edition was com-
Clark, our Senior Editor, was responsible for overseeing the entire pleted by George Barile of Accurate Art Inc. Despite our simple and
project. Thank you for your continued vigilance Sandra. Executive pathetic drawings, George interpreted, redrew, and produced fabulous
Vice President Sally Schrefer has given us years of unwavering support illustrations. He worked hard on the conceptual arrangements, labels,
and vision for the future—thanks again, Sally. and colors. Thank you so much George.
Jeanne Genz, the Project Manager for this edition, sounded the A special thanks to Mandi Counters, Mary Dowell, Susan Frazier,
alarms early with her 5:30 am e-mails. Jeanne works all the time. and April Hart for their very organized and thorough approach in pre-
Bright, always courteous, Jeanne was focused, exacting, and a breath paring the instructor materials for the Evolve website. A special thanks
of fresh air. Thanks much Jeanne. The smart and colorful book design to Mandi Counters, Linda Turchin, and Sharon Souter for the excel-
was done by Paula Catalano. Paula managed to fit numerous elements lent revisions to the glossary, review questions, test bank, quick check
into a reader-friendly style we hope students find helpful and attrac- answers, and other resources on the Evolve website. Thanks to Diane
tive. Brooke Kannady, our Editorial Assistant, routed materials to Young for revising the lecture slides on the Instructor’s Evolve website.
authors, contributors, and reviewers. Thank you Brooke for a job well- Tina Brashers, Nancy Burruss, Mandi Counters, Joe Gordon, Melissa
done. Trudi Elliott from Graphic World handled the file clean-up and J. Geist, Kay Gaehle, Stephen D. Krau, Jason Mott, and Kim Webb also
scanning of artwork obtained from many resources. Thank you Trudi updated the interactive online lessons and activities for Pathophysiol-
for your attention to detail. ogy Online. And thanks as always to Clayton Parkinson for revising the
We are grateful to Ed Reschke and Dennis Kunkel, who granted study guide.
permission for the use of their remarkable and unique micrographs. Special thanks to faculty and nursing students and other health sci-
We would like to thank the following authors for permission to use ence students for your letters, e-mail messages, and phone calls. It is
some of their outstanding figures: Kevin Patton and Gary Thibodeau, because of you, the future clinicians, that we are so motivated to put
Ivan Damjanov, Alan Stevens and James Lowe, Carol Wells (wife of our best efforts into this work.
the late Stanley Erlandsen), Vinay Kumar, and Marilyn Hockenberry. Sincerely and with great affection we thank our families, especially
We thank the Department of Dermatology at the University of Utah Mae, John, Anne, Ray, Mark, Eric, Greg, Sue, Kallie, Rosie, Margot,
School of Medicine, which provided numerous photos of skin lesions. and Sarah. Always supportive, you make the work possible!
Thanks also to Arthur R. Brothman, PhD, University of Utah School
of Medicine, for the N-myc gene amplification slides used to illustrate Sue E. Huether
the discussion of neuroblastoma and John Hoffman, MD, for the PET Kathryn L. McCance
scan figure of cancer metastases. Thank you to our many colleagues
This page intentionally left blank

     
 INTRODUCTION
TO PATHOPHYSIOLOGY

The word root “patho” is derived from the Greek word pathos, which symptoms become worse or more severe. A complication is the onset
means suffering. The Greek word root “logos” means discourse or more of a disease in a person who is already coping with another existing
simply, system of formal study, and “physio” refers to functions of an disease. For example, a person who has undergone surgery to remove a
organism. Altogether, pathophysiology is the study of the underlying diseased appendix may develop the complication of a wound infection
changes in body physiology (molecular, cellular, and organ systems) or pneumonia. Sequelae are unwanted outcomes of having a disease
that result from disease or injury. Important, however, is the inextri- or are the result of trauma, such as paralysis resulting from a stroke or
cable component of suffering. severe scarring resulting from a burn.
The science of pathophysiology seeks to provide an understanding Clinical manifestations are the signs and symptoms or evidence of
of the mechanisms of disease and how and why alterations in body disease. Signs are objective alterations that can be observed or mea-
structure and function lead to the signs and symptoms of disease. sured by another person, measures of bodily functions such as pulse
Understanding pathophysiology guides health care professionals in the rate, blood pressure, body temperature, or white blood cell count.
planning, selection, and evaluation of therapies and treatments. Some signs are local such as redness or swelling, and other signs are
Knowledge of human anatomy and physiology and the interrela- systemic such as fever. Symptoms are subjective experiences reported
tionship among the various cells and organ systems of the body is an by the person with disease, such as pain, nausea, or shortness of breath,
essential foundation for the study of pathophysiology. Review of this and they vary from person to person. The prodromal period of a dis-
subject matter enhances comprehension of pathophysiologic events ease is the time during which a person experiences vague symptoms
and processes. Understanding pathophysiology also entails the utiliza- such as fatigue or loss of appetite before the onset of specific signs and
tion of principles, concepts, and basic knowledge from other fields of symptoms. The term insidious symptoms refers to vague or nonspe-
study including pathology, genetics, immunology, and epidemiology. cific feelings and an awareness that there is a change within the body.
A number of terms are used to focus the discussion of pathophysi- Some diseases have a latent period, a time during which no symptoms
ology; they may be used interchangeably at times, but that does not are readily apparent in the affected person, but the disease is never-
necessarily indicate that they have the same meaning. Those terms are theless present in the body; an example is the incubation phase of
reviewed here for the purpose of clarification. an infection or the early growth phase of a tumor. A syndrome is a
Pathology is the investigation of structural alterations in cells, group of symptoms that occur together and may be caused by several
tissues, and organs, which can help identify the cause of a particu- interrelated problems or a specific disease. Severe acute respiratory
lar disease. Pathology differs from pathogenesis, which is the pattern syndrome (SARS), for example, presents with a set of symptoms that
of tissue changes associated with the development of disease. Etiol- include headache, fever, body aches, an overall feeling of discomfort,
ogy refers to the study of the cause of disease. Diseases may be caused and sometimes dry cough and difficulty breathing. A disorder is an
by infection, heredity, gene-environment interactions, alterations in abnormality of function; this term also can refer to an illness or a par-
immunity, malignancy, malnutrition, degeneration, or trauma. Dis- ticular problem such as a bleeding disorder.
eases that have no identifiable cause are termed idiopathic. Diseases Epidemiology is the study of tracking patterns or disease occur-
that occur as a result of medical treatment are termed iatrogenic. For rence and transmission among populations and by geographic areas.
example, some antibiotics can injure the kidney and cause renal fail- Incidence of a disease is the number of new cases occurring in a spe-
ure. Diseases that are acquired as a consequence of being in a hospital cific time period. Prevalence of a disease is the number of existing
environment are called nosocomial. An infection that develops as a cases within a population during a specific time period.
result of a person’s immune system being depressed after receiving Risk factors, also known as predisposing factors, increase the
cancer treatment during a hospital stay would be defined as a noso- probability that disease will occur, but these factors are not the cause of
comial infection. disease. Risk factors include heredity, age, gender, race, environment,
Diagnosis is the naming or identification of a disease. A diagno- and lifestyle. A precipitating factor is a condition or event that does
sis is made from an evaluation of the evidence accumulated from the cause a pathologic event or disorder. For example, asthma is precipi-
presenting signs and symptoms, health and medical history, physi- tated by exposure to an allergen, or angina (pain) is precipitated by
cal examination, laboratory tests, and imaging. A prognosis is the exertion.
expected outcome of a disease. Acute disease is the sudden appearance Pathophysiology is an exciting field of study that is ever changing as
of signs and symptoms that last only a short time. Chronic disease new discoveries are made. Understanding pathophysiology empowers
develops more slowly and the signs and symptoms last for a long time, health care professionals with the knowledge of how and why disease
perhaps for a lifetime. Chronic diseases may have a pattern of remis- develops and informs their decision making to ensure optimal health
sion and exacerbation. Remissions are periods when symptoms dis- care outcomes. Embedded in the study of pathophysiology is under-
appear or diminish significantly. Exacerbations are periods when the standing that suffering is a major component.

xiii
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 CONTENTS

Introduction to Pathophysiology, xiii Chromosomes, 38

Chromosome Aberrations and Associated
Diseases, 40
PART 1: BASIC CONCEPTS OF Elements of Formal Genetics, 46
PATHOPHYSIOLOGY Phenotype and Genotype, 46
Dominance and Recessiveness, 47
Transmission of Genetic Diseases, 47
UNIT 1: THE CELL Autosomal Dominant Inheritance, 47
1.  Cellular Biology, 1 Autosomal Recessive Inheritance, 50
Kathryn L. McCance X-Linked Inheritance, 51
Prokaryotes and Eukaryotes, 1 Evaluation of Pedigrees, 53
Cellular Functions, 2 Linkage Analysis and Gene Mapping, 53
Structure and Function of Cellular Classic Pedigree Analysis, 53
­Components, 3 Complete Human Gene Map: Prospects
Nucleus, 3 and Benefits, 54
Cytoplasmic Organelles, 3 Multifactorial Inheritance, 55
Plasma Membranes, 3 3.  Altered Cellular and Tissue Biology, 59
Cellular Receptors, 7 Kathryn L. McCance and Todd Cameron Grey
Cell-to-Cell Adhesions, 8 Cellular Adaptation, 60
Extracellular Matrix, 8 Atrophy, 60
Specialized Cell Junctions, 9 Hypertrophy, 61
Cellular Communication and Signal Hyperplasia, 61
­Transduction, 9 Dysplasia: Not a True Adaptive Change, 62
Cellular Metabolism, 13 Metaplasia, 62
Role of Adenosine Triphosphate, 13 Cellular Injury, 62
Food and Production of Cellular General Mechanisms of Cell Injury, 63
Energy, 13 Hypoxic Injury, 63
Oxidative Phosphorylation, 13 Free Radicals and Reactive Oxygen Species—
Membrane Transport: Cellular Intake and Oxidative Stress, 66
Output, 14 Chemical Injury, 66
Movement of Water and Solutes, 15 Unintentional and Intentional Injuries, 73
Transport by Vesicle Formation, 18 Infectious Injury, 80
Movement of Electrical Impulses: Membrane Immunologic and Inflammatory Injury, 80
Potentials, 21 Manifestations of Cellular Injury:
Cellular Reproduction: The Cell Cycle, 22 Accumulations, 80
Phases of Mitosis and Cytokinesis, 23 Water, 80
Rates of Cellular Division, 23 Lipids and Carbohydrates, 81
Growth Factors, 23 Glycogen, 82
Tissues, 24 Proteins, 82
Tissue Formation, 24 Pigments, 82
Types of Tissues, 24 Calcium, 83
2.  Genes and Genetic Diseases, 34 Urate, 84
Lynn B. Jorde Systemic Manifestations, 84
DNA, RNA, and Proteins: Heredity at the Cellular Death, 85
Molecular Level, 35 Necrosis, 85
Definitions, 35 Apoptosis, 87
From Genes to Proteins, 37 Autophagy, 88

xv
xvi CONTENTS

AGING & Altered Cellular and Tissue Acute and Chronic Inflammation, 132
Biology, 90 Local Manifestations of Acute
Normal Life Span and Life Expectancy, 90 Inflammation, 132
Degenerative Extracellular Changes, 91 Systemic Manifestations of Acute
Cellular Aging, 92 ­Inflammation, 132
Tissue and Systemic Aging, 93 Chronic Inflammation, 133
Frailty, 93 Wound Healing, 134
Somatic Death, 93 Phase I: Inflammation, 135
4.  Fluids and Electrolytes, Acids and Bases, 98 Phase II: Proliferation and New Tissue
Sue E. Huether ­Formation, 135
Distribution of Body Fluids, 98 Phase III: Remodeling and Maturation, 136
Maturation and the Distribution of Body Dysfunctional Wound Healing, 136
Fluids, 99 PEDIATRIC CONSIDERATIONS: ­
Water Movement Between Plasma and Age-Related Factors Affecting Innate
­Interstitial Fluid, 99 ­Immunity in the Newborn Child, 138
PEDIATRIC CONSIDERATIONS: GERIATRIC CONSIDERATIONS: ­
­Distribution of Body Fluids, 99 Age-Related Factors Affecting Innate
GERIATRIC CONSIDERATIONS: ­Immunity in the Elderly, 138
Aging & Distribution of Body Fluids, 100 6.  Adaptive Immunity, 142
Water Movement Between ICF and ECF, 100 Neal S. Rote
Alterations in Water Movement, 100 Third Line of Defense: Adaptive
Edema, 100 Immunity, 142
Sodium, Chloride, and Water Balance, 102 Humoral and Cellular Immunity, 143
Sodium and Chloride Balance, 102 Active and Passive Immunity, 143
Water Balance, 103 Antigens and Immunogens, 144
Alterations in Sodium, Water, and Chloride Humoral Immune Response, 146
Balance, 103 Antibodies, 146
Isotonic Alterations, 104 Cell-Mediated Immunity, 152
Hypertonic Alterations, 105 T Lymphocytes, 152
Hypotonic Alterations, 105 Immune Response: Collaboration of B Cells
Alterations in Potassium and Other and T Cells, 152
­Electrolytes, 106 Generation of Clonal Diversity, 152
Potassium, 106 Clonal Selection, 153
Other Electrolytes—Calcium, Magnesium, T Lymphocyte Functions, 160
and Phosphate, 109 PEDIATRIC CONSIDERATIONS: ­
Acid-Base Balance, 109 Age-Related Factors Affecting
Hydrogen Ion and pH, 109 Mechanisms of Self-Defense in the ­
Buffer Systems, 110 Newborn Child, 162
Acid-Base Imbalances, 111 GERIATRIC CONSIDERATIONS: ­
Age-Related Factors Affecting
UNIT 2: MECHANISMS OF SELF-DEFENSE Mechanisms of Self-Defense in the
Elderly, 162
5. Innate Immunity: Inflammation and Wound
Healing, 118 7. Infection and Defects in Mechanisms
Neal S. Rote of Defense, 165
Human Defense Mechanisms, 118 Neal S. Rote
Innate Immunity, 119 Infection, 165
First Line of Defense: Physical and Biochemi- Microorganisms and Humans: A Dynamic
cal Barriers and Normal Flora, 119 Relationship, 166
Second Line of Defense: Inflammation, 121 Classes of Infectious Microorganisms, 167
Plasma Protein Systems and Inflammation, 122 Pathogenic Defense Mechanisms, 168
Cellular Components of Inflammation, 125 Infection and Injury, 168
 CONTENTS xvii

Clinical Manifestations of Infection, 175 Clinical Manifestations and Treatment

Countermeasures Against Pathogenic of Cancer, 243
Defenses, 175 Clinical Manifestations of Cancer, 243
Deficiencies in Immunity, 178 Treatment of Cancer, 248
Initial Clinical Presentation, 178 10.  Cancer Epidemiology, 253
Primary (Congenital) Immune Kathryn L. McCance
Deficiencies, 179 Genes, Environmental-Lifestyle Factors,
Secondary (Acquired) Immune and Risk Factors, 253
Deficiencies, 181 Epigenetics and Genetics, 257
Evaluation and Care of Those With Immune Tobacco Use, 261
Deficiency, 181 Diet, 261
Replacement Therapies for Immune Alcohol Consumption, 266
­Deficiencies, 182 Ionizing Radiation, 267
Acquired Immunodeficiency Syndrome Ultraviolet Radiation, 274
(AIDS), 183 Electromagnetic Radiation, 276
Hypersensitivity: Allergy, Autoimmunity, Sexual and Reproductive Behavior: Human
and Alloimmunity, 188 Papillomaviruses, 277
Mechanisms of Hypersensitivity, 190 Other Viruses and Microorganisms, 278
Antigenic Targets of Hypersensitivity Physical Activity, 278
­Reactions, 197 Chemicals and Occupational Hazards as
8.  Stress and Disease, 204 Carcinogens, 278
Margaret F. Clayton, Kathryn L. McCance, and Air Pollution, 278
Beth A. Forshee 11.  Cancer in Children, 288
Historical Background and General Nancy E. Kline
Concepts, 204 Incidence and Types of Childhood Cancer, 288
Stress Overview: Multiple Mediators Etiology, 289
and Systems, 207 Genetic Factors, 289
The Stress Response, 209 Environmental Factors, 291
Neuroendocrine Regulation, 209 Prognosis, 291
Role of the Immune System, 215
Stress, Personality, Coping, and Illness, 216
Coping, 217 PART 2: BODY SYSTEMS AND
GERIATRIC CONSIDERATIONS: Aging & DISEASES
the Stress-Age Syndrome, 218

UNIT 3: CELLULAR PROLIFERATION: CANCER UNIT 4: THE NEUROLOGIC SYSTEM

9. Biology, Clinical Manifestations, and Treatment 12. Structure and Function of the Neurologic
of Cancer, 222 System, 293
David M. Virshup Richard A. Sugerman and Sue E. Huether
Cancer Terminology and Characteristics, 222 Overview and Organization of the Nervous
Tumor Classification and Nomenclature, 223 System, 293
The Biology of Cancer Cells, 227 Cells of the Nervous System, 293
Cancer Cells in the Laboratory, 227 The Neuron, 294
The Genetic Basis of Cancer, 227 Neuroglia and Schwann Cells, 296
Types of Genes Misregulated in Cancer, 234 Nerve Injury and Regeneration, 297
Cancer Stem Cells, 238 The Nerve Impulse, 297
Stroma-Cancer Interactions, 239 Synapses, 297
Inflammation, Immunity, and Cancer, 240 Neurotransmitters, 298
Cancer Invasion and Metastasis, 241 The Central Nervous System, 299
Very Few Cells in a Cancer Have the Ability The Brain, 299
to Metastasize, 242 The Spinal Cord, 304
xviii CONTENTS

Motor Pathways, 307 Seizure Disorders, 354

Sensory Pathways, 307 Data Processing Deficits, 356
Protective Structures of the Central Nervous Alterations in Cerebral Hemodynamics, 361
System, 307 Increased Intracranial Pressure, 361
Blood Supply of the Central Nervous Cerebral Edema, 362
System, 310 Hydrocephalus, 363
The Peripheral Nervous System, 311 Alterations in Neuromotor Function, 364
The Autonomic Nervous System, 313 Alterations in Muscle Tone, 364
Anatomy of the Sympathetic Nervous Alterations in Movement, 365
System, 316 Paresis/Paralysis, 365
Anatomy of the Parasympathetic Nervous Hyperkinesia, 369
System, 317 Alterations in Complex Motor
Neurotransmitters and Neuroreceptors, 317 Performance, 372
Functions of the Autonomic Nervous Disorders of Posture (Stance), 372
System, 320 Disorders of Gait, 372
GERIATRIC CONSIDERATIONS: Aging & Disorders of Expression, 373
the Nervous System, 321 Extrapyramidal Motor Syndromes, 373
13. Pain, Temperature, Sleep, and Sensory 15. Disorders of the Central and Peripheral Nervous
Function, 324 Systems and Neuromuscular Junction, 377
Jan Belden, Curtis DeFriez, and Sue E. Huether Barbara J. Boss and Sue E. Huether
Pain, 324 Central Nervous System Disorders, 377
The Experience of Pain, 324 Traumatic Brain and Spinal Cord
Evolution of Pain Theories, 324 Injury, 377
Neuroanatomy of Pain, 325 Degenerative Disorders of the Spine, 387
Clinical Descriptions of Pain, 327 Cerebrovascular Disorders, 388
Temperature Regulation, 330 Headache, 392
Control of Body Temperature, 330 Infection and Inflammation of the Central
Temperature Regulation in Infants and Nervous System, 393
Elderly Persons, 330 Demyelinating Degenerative Disorders, 397
Pathogenesis of Fever, 331 Peripheral Nervous System and Neuromuscu-
Benefits of Fever, 331 lar Junction Disorders, 399
Disorders of Temperature Regulation, 331 Peripheral Nervous System Disorders, 399
Sleep, 333 Neuromuscular Junction Disorders, 399
Sleep Disorders, 334 Tumors of the Central Nervous System, 400
The Special Senses, 335 Cranial Tumors, 400
Vision, 335 Spinal Cord Tumors, 404
Hearing, 338 16. Alterations of Neurologic Function
GERIATRIC CONSIDERATIONS: Aging & in Children, 409
Changes in Hearing, 340 Vinodh Narayanan
Olfaction and Taste, 341 Normal Growth and Development of the
GERIATRIC CONSIDERATIONS: Aging & ­Nervous System, 409
Changes in Olfaction and Taste, 341 Structural Malformations, 410
Somatosensory Function, 341 Defects of Neural Tube Closure, 410
Touch, 341 Malformations of the Axial Skeleton, 413
Proprioception, 341 Encephalopathies, 415
14. Alterations in Cognitive Systems, Cerebral Static Encephalopathies, 415
­Hemodynamics, and Motor Function, 347 Inherited Metabolic Disorders of the Central
Barbara J. Boss and Sue E. Huether Nervous System, 415
Alterations in Cognitive Systems, 347 Seizure Disorders, 417
Alterations in Arousal, 347 Acute Encephalopathies, 418
Alterations in Awareness, 353 Cerebrovascular Disease in Children, 419
 CONTENTS xix

Tumors, 419 UNIT 6: THE HEMATOLOGIC SYSTEM

Brain Tumors, 419 19. Structure and Function of the Hematologic
Embryonal Tumors, 421 System, 477
Neal S. Rote and Kathryn L. McCance
Components of the Hematologic System, 477
UNIT 5: THE ENDOCRINE SYSTEM
Composition of Blood, 477
17.  Mechanisms of Hormonal Regulation, 426 Lymphoid Organs, 482
Valentina L. Brashers and Sue E. Huether The Mononuclear Phagocyte System, 483
Mechanisms of Hormonal Regulation, 426 Development of Blood Cells, 483
Regulation of Hormone Release, 426 Hematopoiesis, 483
Hormone Transport, 427 Development of Erythrocytes, 485
Mechanisms of Hormone Action, 428 Development of Leukocytes, 489
Structure and Function of the Endocrine Development of Platelets, 489
Glands, 431 Mechanisms of Hemostasis, 489
Hypothalamic-Pituitary System, 431 Function of Platelets and Blood Vessels, 490
Pineal Gland, 435 Function of Clotting Factors, 491
Thyroid and Parathyroid Glands, 435 Retraction and Lysis of Blood Clots, 493
Endocrine Pancreas, 437 PEDIATRICS & Hematologic Value
Adrenal Glands, 439 Changes, 496
Neuroendocrine Response to Stressors, 443 AGING & Hematologic Value Changes, 496
GERIATRIC CONSIDERATIONS: Aging & 20.  Alterations of Hematologic Function, 500
Its Effects on Specific Endocrine Anna Schwartz, Neal S. Rote, and
Glands, 444 Kathryn L. McCance
18.  Alterations of Hormonal Regulation, 447 Alterations of Erythrocyte Function, 500
Robert E. Jones, Valentina L. Brashers, and Classification of Anemias, 500
Sue E. Huether Macrocytic-Normochromic Anemias, 502
Mechanisms of Hormonal Alterations, 447 Microcytic-Hypochromic Anemias, 504
Alterations of the Hypothalamic-Pituitary Normocytic-Normochromic Anemias, 505
System, 448 Myeloproliferative Red Cell Disorders, 506
Diseases of the Posterior Pituitary, 448 Polycythemia Vera, 506
Diseases of the Anterior Pituitary, 450 Iron Overload, 508
Alterations of Thyroid Function, 453 Alterations of Leukocyte Function, 508
Hyperthyroidism, 453 Quantitative Alterations of Leukocytes, 508
Hypothyroidism, 456 Qualitative Alterations of Leukocytes, 512
Thyroid Carcinoma, 457 Alterations of Lymphoid Function, 515
Alterations of Parathyroid Function, 457 Lymphadenopathy, 515
Hyperparathyroidism, 457 Malignant Lymphomas, 516
Hypoparathyroidism, 458 Alterations of Splenic Function, 521
Dysfunction of the Endocrine Pancreas: Alterations of Platelets and Coagulation, 523
­Diabetes Mellitus, 458 Disorders of Platelet Function, 523
Types of Diabetes Mellitus, 459 Alterations of Platelet Function, 526
Acute Complications of Diabetes Disorders of Coagulation, 526
Mellitus, 465 21. Alterations of Hematologic Function
Chronic Complications of Diabetes in Children, 535
Mellitus, 465 Nancy E. Kline
Alterations of Adrenal Function, 469 Disorders of Erythrocytes, 535
Disorders of the Adrenal Cortex, 469 Acquired Disorders, 536
Disorders of the Adrenal Medulla, 472 Inherited Disorders, 539
Disorders of Coagulation and Platelets, 544
Inherited Hemorrhagic Disease, 544
Antibody-Mediated Hemorrhagic Disease, 545
xx CONTENTS

Neoplastic Disorders, 546 Shock, 627

Leukemia and Lymphoma, 546 Impairment of Cellular Metabolism, 627
Clinical Manifestations of Shock, 629
UNIT 7: THE CARDIOVASCULAR AND Treatment for Shock, 629
LYMPHATIC SYSTEMS Types of Shock, 629
Multiple Organ Dysfunction Syndrome, 634
22. Structure and Function of the Cardiovascular
24. Alterations of Cardiovascular Function in
and Lymphatic Systems, 551
­Children, 643
Valentina L. Brashers and Kathryn L. McCance
Nancy L. McDaniel and Valentina L. Brashers
The Circulatory System, 551
Congenital Heart Disease, 643
The Heart, 551
Obstructive Defects, 644
Structures That Direct Circulation Through
Defects With Increased Pulmonary Blood
the Heart, 552
Flow, 647
Structures That Support Cardiac
Defects With Decreased Pulmonary Blood
­Metabolism: The Coronary Vessels, 556
Flow, 649
Structures That Control Heart Action, 557
Mixing Defects, 651
Factors Affecting Cardiac Output, 563
Congestive Heart Failure, 653
The Systemic Circulation, 567
Acquired Cardiovascular Disorders, 654
Structure of Blood Vessels, 567
Kawasaki Disease, 654
Factors Affecting Blood Flow, 570
Systemic Hypertension, 655
Regulation of Blood Pressure, 573
Regulation of the Coronary Circulation, 578
The Lymphatic System, 579 UNIT 8: THE PULMONARY SYSTEM
23.  Alterations of Cardiovascular Function, 585 25. Structure and Function of the Pulmonary
Valentina L. Brashers System, 659
Diseases of the Veins, 585 Valentina L. Brashers
Varicose Veins and Chronic Venous Structures of the Pulmonary System, 659
­Insufficiency, 585 Conducting Airways, 659
Thrombus Formation in Veins, 586 Gas-Exchange Airways, 663
Superior Vena Cava Syndrome, 586 Pulmonary and Bronchial Circulation, 663
Diseases of the Arteries, 587 Chest Wall and Pleura, 663
Hypertension, 587 Function of the Pulmonary System, 663
Orthostatic (Postural) Hypotension, 591 Ventilation, 664
Aneurysm, 591 Neurochemical Control of Ventilation, 665
Thrombus Formation, 592 Mechanics of Breathing, 667
Embolism, 593 Gas Transport, 669
Peripheral Vascular Disease, 593 Control of the Pulmonary Circulation, 675
Atherosclerosis, 594 GERIATRIC CONSIDERATIONS: Aging & the
Peripheral Artery Disease, 597 Pulmonary System, 675
Coronary Artery Disease, Myocardial 26.  Alterations of Pulmonary Function, 678
­Ischemia, and Acute Coronary Valentina L. Brashers
Syndromes, 597 Clinical Manifestations of Pulmonary
Disorders of the Heart Wall, 609 ­Alterations, 678
Disorders of the Pericardium, 609 Signs and Symptoms of Pulmonary
Disorders of the Myocardium: The Disease, 678
­Cardiomyopathies, 611 Conditions Caused by Pulmonary Disease
Disorders of the Endocardium, 612 or Injury, 680
Cardiac Complications in Acquired Disorders of the Chest Wall and Pleura, 682
­Immunodeficiency Syndrome (AIDS), 619 Chest Wall Restriction, 682
Manifestations of Heart Disease, 619 Pleural Abnormalities, 682
Dysrhythmias, 619 Pulmonary Disorders, 684
Heart Failure, 622 Restrictive Lung Diseases, 684
 CONTENTS xxi

Obstructive Lung Diseases, 689 Urinary Tract Infection, 747

Respiratory Tract Infections, 694 Causes of Urinary Tract Infection, 747
Pulmonary Vascular Disease, 698 Types of Urinary Tract Infection, 747
Malignancies of the Respiratory Tract, 700 Glomerular Disorders, 750
27. Alterations of Pulmonary Function in Glomerulonephritis, 750
Children, 707 Nephrotic and Nephritic Syndromes, 753
Kristi K. Gott and Valentina L. Brashers Acute Kidney Injury, 754
Disorders of the Upper Airways, 707 Classification of Kidney Dysfunction, 754
Infections of the Upper Airways, 707 Chronic Kidney Disease, 756
Aspiration of Foreign Bodies, 709 30. Alterations of Renal and Urinary Tract Function
Obstructive Sleep Apnea, 710 in Children, 764
Disorders of the Lower Airways, 710 Patricia Ring and Sue E. Huether
Respiratory Distress Syndrome of the Structural Abnormalities, 764
­Newborn, 710 Hypospadias, 765
Bronchopulmonary Dysplasia, 712 Epispadias and Exstrophy of the Bladder, 765
Respiratory Tract Infections, 713 Bladder Outlet Obstruction, 766
Aspiration Pneumonitis, 716 Ureteropelvic Junction Obstruction, 766
Bronchiolitis Obliterans, 716 Hypoplastic/Dysplastic Kidneys, 766
Asthma, 716 Polycystic Kidney Disease, 766
Acute Respiratory Distress Syndrome, 718 Renal Agenesis, 766
Cystic Fibrosis, 718 Glomerular Disorders, 766
Sudden Infant Death Syndrome, 720 Glomerulonephritis, 766
Immunoglobulin A Nephropathy, 767
UNIT 9: THE RENAL AND UROLOGIC SYSTEMS Nephrotic Syndrome, 767
Hemolytic Uremic Syndrome, 767
28. Structure and Function of the Renal and Urologic
Other Renal Disorders, 768
Systems, 724
Bladder Disorders, 768
Sue E. Huether
Urinary Tract Infections, 768
Structures of the Renal System, 724
Vesicoureteral Reflux, 768
Structures of the Kidney, 724
Nephroblastoma, 769
Urinary Structures, 729
Urinary Incontinence, 770
Renal Blood Flow, 729
Types of Incontinence, 770
Autoregulation of Intrarenal Blood Flow, 729
Neural Regulation of Renal Blood Flow, 730
Hormonal Regulation of Renal Blood UNIT 10: THE REPRODUCTIVE SYSTEMS
Flow, 730 31. Structure and Function of the Reproductive
Kidney Function, 731 ­Systems, 774
Nephron Function, 731 Angela Deneris and Sue E. Huether
Hormones and Nephron Function, 735 Development of the Reproductive Systems, 774
Renal Hormones, 735 Sexual Differentiation in Utero, 774
Test of Renal Function, 736 Puberty and Reproductive Maturation, 776
The Concept of Clearance, 736 The Female Reproductive System, 777
PEDIATRIC CONSIDERATIONS: External Genitalia, 778
Pediatrics & Renal Function, 738 Internal Genitalia, 779
GERIATRIC CONSIDERATIONS: Aging & Female Sex Hormones, 783
Renal Function, 738 Menstrual Cycle, 784
29. Alterations of Renal and Urinary Tract Function, 741 Structure and Function of the Breast, 787
Sue E. Huether Female Breast, 788
Urinary Tract Obstruction, 741 Male Breast, 789
Upper Urinary Tract Obstruction, 741 The Male Reproductive System, 789
Lower Urinary Tract Obstruction, 743 External Genitalia, 790
Tumors, 746 Internal Genitalia, 791
xxii CONTENTS

Spermatogenesis, 792 Gallbladder, 887

Male Sex and Reproductive Hormones, 792 Exocrine Pancreas, 888
AGING & Reproductive Function, 794 GERIATRIC CONSIDERATIONS: Aging &
Aging and the Female Reproductive the Gastrointestinal System, 890
System, 794 34.  Alterations of Digestive Function, 894
Aging and the Male Reproductive Sharon Dudley-Brown and Sue E. Huether
System, 795 Disorders of the Gastrointestinal Tract, 894
32. Alterations of the Reproductive Systems, Including Clinical Manifestations of Gastrointestinal
Sexually Transmitted Infections, 799 Dysfunction, 894
Gwen Latendresse and Kathryn L. McCance Disorders of Motility, 898
Alterations of Sexual Maturation, 799 Gastritis, 903
Delayed or Absent Puberty, 799 Peptic Ulcer Disease, 903
Precocious Puberty, 800 Malabsorption Syndromes, 907
Disorders of the Female Reproductive Inflammatory Bowel Disease, 908
System, 801 Diverticular Disease of the Colon, 910
Hormonal and Menstrual Alterations, 801 Appendicitis, 910
Infection and Inflammation, 805 Irritable Bowel Syndrome, 911
Pelvic Organ Prolapse, 808 Vascular Insufficiency, 911
Benign Growths and Proliferative Disorders of Nutrition, 912
­Conditions, 810 Disorders of the Accessory Organs of
Cancer, 813 ­Digestion, 915
Sexual Dysfunction, 818 Common Complications of Liver Disorders, 915
Impaired Fertility, 819 Disorders of the Liver, 919
Disorders of the Male Reproductive System, 819 Disorders of the Gallbladder, 923
Disorders of the Urethra, 819 Disorders of the Pancreas, 924
Disorders of the Penis, 819 Cancer of the Digestive System, 925
Disorders of the Scrotum, Testis, and Cancer of the Gastrointestinal Tract, 925
­Epididymis, 822 Cancer of the Accessory Organs of Digestion,
Disorders of the Prostate Gland, 826 929
Sexual Dysfunction, 837 35. Alterations of Digestive Function in Children, 938
Disorders of the Breast, 838 Sue E. Huether
Disorders of the Female Breast, 838 Disorders of the Gastrointestinal Tract, 938
Disorders of the Male Breast, 856 Congenital Impairment of Motility, 938
Sexually Transmitted Infections, 856 Acquired Impairment of Motility, 943
Bacterial Sources, 860 Impairment of Digestion, Absorption,
Viral Sources, 861 and Nutrition, 944
Parasite Sources, 861 Diarrhea, 948
Disorders of the Liver, 948
UNIT 11: THE DIGESTIVE SYSTEM Disorders of Biliary Metabolism and
­Transport, 948
33. Structure and Function of the Digestive
Inflammatory Disorders, 949
System, 871
Portal Hypertension, 949
Sue E. Huether
Metabolic Disorders, 951
The Gastrointestinal Tract, 871
Mouth and Esophagus, 873
Stomach, 874 UNIT 12: THE MUSCULOSKELETAL
Small Intestine, 877 AND INTEGUMENTARY SYSTEMS
Large Intestine, 881 36. Structure and Function of the Musculoskeletal
Intestinal Bacteria, 882 System, 954
Splanchnic Blood Flow, 883 Christy L. Crowther-Radulewicz and
Accessory Organs of Digestion, 883 Kathryn L. McCance
Liver, 883 Structure and Function of Bones, 954
 CONTENTS xxiii

Elements of Bone Tissue, 954 Osteochondroses, 1027

Types of Bone Tissue, 959 Legg-Calvé-Perthes Disease, 1027
Characteristics of Bone, 960 Osgood-Schlatter Disease, 1029
Maintenance of Bone Integrity, 962 Scoliosis, 1029
Structure and Function of Joints, 962 Muscular Dystrophy, 1030
Fibrous Joints, 964 Duchenne Muscular Dystrophy, 1030
Cartilaginous Joints, 964 Becker Muscular Dystrophy, 1031
Synovial Joints, 965 Facioscapulohumeral Muscular ­
Structure and Function of Skeletal Muscles, 965 Dystrophy, 1032
Whole Muscle, 965 Myotonic Muscular Dystrophy, 1032
Components of Muscle Function, 970 Musculoskeletal Tumors, 1033
Tendons and Ligaments, 974 Benign Bone Tumors, 1033
AGING & the Musculoskeletal System, 974 Malignant Bone Tumors, 1033
Aging of Bones, 974 Nonaccidental Trauma, 1035
Aging of Joints, 974 Fractures in Nonaccidental Trauma, 1035
Aging of Muscles, 974 39. Structure, Function, and Disorders of the
37. Alterations of Musculoskeletal Function, 978 ­Integument, 1038
Christy L. Crowther-Radulewicz and Noreen Heer Nicole and Sue E. Huether
Kathryn L. McCance Structure and Function of the Skin, 1038
Musculoskeletal Injuries, 978 Layers of the Skin, 1038
Skeletal Trauma, 978 Clinical Manifestations of Skin Dysfunction,
Support Structures, 982 1040
Disorders of Bones, 987 GERIATRIC CONSIDERATIONS: Aging &
Metabolic Bone Diseases, 987 Changes in Skin Integrity, 1040
Infectious Bone Disease: Osteomyelitis, 995 Disorders of the Skin, 1048
Disorders of Joints, 996 Inflammatory Disorders, 1048
Osteoarthritis, 996 Papulosquamous Disorders, 1049
Classic Inflammatory Joint Disease, 999 Vesiculobullous Disorders, 1051
Disorders of Skeletal Muscle, 1007 Infections, 1053
Secondary Muscular Dysfunction, 1007 Vascular Disorders, 1055
Fibromyalgia, 1008 Insect Bites, 1057
Muscle Membrane Abnormalities, 1010 Benign Tumors, 1057
Metabolic Muscle Diseases, 1010 Cancer, 1058
Inflammatory Muscle Diseases: Burns, 1060
Myositis, 1011 Frostbite, 1064
Toxic Myopathies, 1012 Disorders of the Hair, 1065
Musculoskeletal Tumors, 1013 Alopecia, 1065
Bone Tumors, 1013 Hirsutism, 1065
Muscle Tumors, 1017 Disorders of the Nail, 1065
38. Alterations of Musculoskeletal Function in Paronychia, 1065
­Children, 1022 Onychomycosis, 1065
Kristen Lee Carroll, Lynne M. Kerr, and 40.  Alterations of the Integument in Children, 1070
Kathryn L. McCance Noreen Heer Nicole and Sue Huether
Congenital Defects, 1022 Acne Vulgaris, 1070
Clubfoot, 1022 Dermatitis, 1071
Developmental Dysplasia of the Hip, 1023 Atopic Dermatitis, 1071
Osteogenesis Imperfecta, 1025 Diaper Dermatitis, 1072
Bone Infection, 1026 Infections of the Skin, 1072
Osteomyelitis, 1026 Bacterial Infections, 1072
Septic Arthritis, 1027 Fungal Infections, 1073
Juvenile Idiopathic Arthritis, 1027 Viral Infections, 1074
xxiv CONTENTS

Insect Bites and Parasites, 1077 Other Skin Disorders, 1080

Scabies, 1077 Miliaria, 1080
Pediculosis (Lice Infestation), 1077 Erythema Toxicum Neonatorum, 1080
Fleas, 1078
Ticks, 1078
Bedbugs, 1078 Appendix, 1083
Hemangiomas and Vascular Malformations,
1079 Glossary, 1085
Hemangiomas, 1079
Vascular Malformations, 1079 Index, 1100
 CHAPTER

1
Cellular Biology
Kathryn L. McCance

http://evolve.elsevier.com/Huether/ • Key Terms Exercises

• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Prokaryotes and Eukaryotes, 1 Membrane Transport: Cellular Intake and Output, 14
Cellular Functions, 2 Movement of Water and Solutes, 15
Structure and Function of Cellular ­Components, 3 Transport by Vesicle Formation, 18
Nucleus, 3 Movement of Electrical Impulses: Membrane Potentials, 21
Cytoplasmic Organelles, 3 Cellular Reproduction: The Cell Cycle, 22
Plasma Membranes, 3 Phases of Mitosis and Cytokinesis, 23
Cellular Receptors, 7 Rates of Cellular Division, 23
Cell-to-Cell Adhesions, 8 Growth Factors, 23
Extracellular Matrix, 8 Tissues, 24
Specialized Cell Junctions, 9 Tissue Formation, 24
Cellular Communication and Signal Transduction, 9 Types of Tissues, 24
Cellular Metabolism, 13
Role of Adenosine Triphosphate, 13
Food and Production of Cellular Energy, 13
Oxidative Phosphorylation, 13

All body functions depend on the integrity of cells. Therefore an

understanding of cellular biology is increasingly necessary to com-
PROKARYOTES AND EUKARYOTES
prehend disease processes. An overwhelming amount of information Living cells generally are divided into eukaryotes and prokaryotes. The
reveals how cells behave as a multicellular “social” organism. At the cells of higher animals and plants are eukaryotes, as are the single-
heart of it all is cellular communication (cellular “crosstalk”)—how celled organisms, fungi, protozoa, and most algae. Prokaryotes include
messages originate and are transmitted, received, interpreted, and used cyanobacteria (blue-green algae), bacteria, and rickettsiae. Prokaryotes
by the cell. Streamlined conversation between, among, and within cells traditionally were studied as core subjects of molecular biology. Today,
maintains cellular function. Cells must demonstrate a “chemical fond- emphasis is on the eukaryotic cell; much of its structure and function
ness” for other cells to maintain the integrity of the entire organism. have no counterpart in bacterial cells.
When they no longer tolerate this fondness, the conversation breaks Eukaryotes (eu = good; karyon = nucleus) are larger and have
down, and cells either adapt (sometimes altering function) or become more extensive intracellular anatomy and organization than prokary-
vulnerable to isolation, injury, or disease. otes. Eukaryotic cells have a characteristic set of membrane-bound

1
2 CHAPTER 1  Cellular Biology

intracellular compartments, called organelles, that includes a well-

CELLULAR FUNCTIONS
defined nucleus. The prokaryotes contain no organelles, and their
nuclear material is not encased by a nuclear membrane. Prokaryotic Cells become specialized through the process of differentiation, or
cells are characterized by lack of a distinct nucleus. maturation, so that some cells eventually perform one kind of function
Besides having structural differences, prokaryotic and eukaryotic and other cells perform other functions. Cells with a highly developed
cells differ in chemical composition and biochemical activity. The function, such as movement, often lack some other property, such as
nuclei of prokaryotic cells carry genetic information in a single cir- hormone production, which is more highly developed in other cells.
cular chromosome, and they lack a class of proteins called histones, The eight chief cellular functions are as follows:
which in eukaryotic cells bind with deoxyribonucleic acid (DNA) and 1. Movement. Muscle cells can generate forces that produce motion.
are involved in the supercoiling of DNA. Eukaryotic cells have several Muscles that are attached to bones produce limb movements,
or many chromosomes. Protein production, or synthesis, in the two whereas those muscles that enclose hollow tubes or cavities move
classes of cells also differs because of major structural differences in or empty contents when they contract (e.g., the colon).
ribonucleic acid (RNA)-protein complexes. Other distinctions include 2. Conductivity. Conduction as a response to a stimulus is manifested
differences in mechanisms of transport across the outer cellular mem- by a wave of excitation, an electrical potential that passes along the
brane and in enzyme content. surface of the cell to reach its other parts. Conductivity is the chief
function of nerve cells.

Nuclear Smooth
Nucleolus membrane endoplasmic
Centrioles reticulum Rough
Nucleus
Plasma endoplasmic
membrane reticulum
Microfilaments

Peroxisome

Cilia Lysosome

Cytoplasm Mitochondrion
Vault

Cell junction Cell junction

(desmosome) (gap junction)

Free ribosome Golgi

apparatus

Ribosome

Microtubule
Vesicle
Microvilli
A

FIGURE 1-1  Typical Components of a Eukaryotic Cell and Structure of the Cyto-
plasm. A, Components of a eukaryotic cell. B, The drawing is approximately to scale
and emphasizes the crowding in the cytoplasm. Only the macromolecules are shown:
RNAs are shown in blue, ribosomes in green, and proteins in pink. Enzymes and other
macromolecules diffuse relatively slowly in the cytoplasm, in part because they inter-
act with many other macromolecules; small molecules, by contrast, diffuse nearly as
rapidly as they do in water. (B adapted from Alberts B et al: Molecular biology of the
cell, ed 5, New York, 2008, Garland.)

100 nm
B
 CHAPTER 1  Cellular Biology 3

3. Metabolic absorption. All cells can take in and use nutrients and suspended in the cytoplasm are enclosed in biologic membranes, so
other substances from their surroundings. they can simultaneously carry out functions requiring different bio-
4. Secretion. Certain cells, such as mucous gland cells, can synthesize chemical environments. Many of these functions are directed by coded
new substances from substances they absorb and then secrete the messages carried from the nucleus by RNA. They include synthesis of
new substances to serve as needed elsewhere. proteins and hormones and their transport out of the cell, isolation
5. Excretion. All cells can rid themselves of waste products resulting and elimination of waste products from the cell, metabolic processes,
from the metabolic breakdown of nutrients. Membrane-bound breakdown and disposal of cellular debris and foreign proteins (anti-
sacs (lysosomes) within cells contain enzymes that break down, or gens), and maintenance of cellular structure and motility. The cytosol
digest, large molecules, turning them into waste products that are is a storage unit for fat, carbohydrates, and secretory vesicles. Table 1-1
released from the cell. lists the principal cytoplasmic organelles.
6. Respiration. Cells absorb oxygen, which is used to transform nutri-
ents into energy in the form of adenosine triphosphate (ATP).
Cellular respiration, or oxidation, occurs in organelles called 4 QUICK CHECK 1-1
mitochondria. 1. W hy is the process of differentiation essential to specialization? Give an
7. Reproduction. Tissue growth occurs as cells enlarge and reproduce example.
themselves. Even without growth, tissue maintenance requires that 2. Describe at least two cellular functions.
new cells be produced to replace cells that are lost normally through
cellular death. Not all cells are capable of continuous division (see
Chapter 3). Plasma Membranes
8. Communication. Communication is vital for cells to survive as a Whether they surround the cell or enclose an intracellular organ-
society of cells. Appropriate communication allows the mainte- elle, membranes are exceedingly important to normal physiologic
nance of a dynamic steady state. function because they control the composition of the space, or com-
partment, they enclose. Membranes can include or exclude various
STRUCTURE AND FUNCTION OF CELLULAR molecules, and by controlling the movement of substances from one
compartment to another, membranes exert a powerful influence on
­COMPONENTS
metabolic pathways. The plasma membrane also has an important
Figure 1-1, A, shows a “typical” eukaryotic cell. It consists of three role in cell-to-cell recognition. Other functions of the plasma mem-
components: an outer membrane called the plasma membrane, or brane include cellular mobility and the maintenance of cellular shape
plasmalemma; a fluid “filling” called cytoplasm (Figure 1-1, B); and (Table 1-2).
the “organs” of the cell—the membrane-bound intracellular organ-
elles, among them the nucleus. Membrane Composition
The outer surface of the plasma membrane is not smooth, but dimpled
Nucleus with cavelike indentations known as caveolae (“tiny caves”). Caveolae
The nucleus, which is surrounded by the cytoplasm and generally is serve as a storage site for many receptors and provide a route for trans-
located in the center of the cell, is the largest membrane-bound organ- port into the cell (see p. 21).
elle. Two membranes compose the nuclear envelope (Figure 1-2, A). The major chemical components of all membranes are lipids and
The outer membrane is continuous with membranes of the endoplas- proteins, but the percentage of each varies among different mem-
mic reticulum. The nucleus contains the nucleolus (a small dense branes. Intracellular membranes have a higher percentage of proteins
structure composed largely of ribonucleic acid), most of the cellular than plasma membranes have, presumably because most enzymatic
DNA, and the DNA-binding proteins (i.e., the histones) that regulate activity occurs within organelles. Carbohydrates are associated mainly
its activity. The DNA “chain” in eukaryotic cells is so long that it is with plasma membranes, where they combine chemically with lipids,
easily broken. Therefore the histones that bind to DNA cause DNA forming glycolipids, and with proteins, forming glycoproteins.
to fold into chromosomes (Figure 1-2, C), which decreases the risk of Lipids. The basic component of the plasma membrane is a bilayer
breakage and is essential for cell division in eukaryotes. of lipid molecules—phospholipids, glycolipids, and cholesterol. Lipids
The primary functions of the nucleus are cell division and control are responsible for the structural integrity of the membrane. Each lipid
of genetic information. Other functions include the replication and molecule is said to be polar, or amphipathic, which means that one
repair of DNA and the transcription of the information stored in DNA. part is hydrophobic (uncharged, or “water hating”) and another part
Genetic information is transcribed into RNA, which can be processed is hydrophilic (charged, or “water loving”) (Figure 1-3).
into messenger, transport, and ribosomal RNAs and introduced into The membrane spontaneously organizes itself into two lay-
the cytoplasm, where it directs cellular activities. Most of the process- ers because of these two incompatible solubilities. The hydropho-
ing of RNA occurs in the nucleolus. (The role of DNA and RNA in bic region (hydrophobic tail) of each lipid molecule is protected
protein synthesis is discussed in Chapter 2.) from water, whereas the hydrophilic region (hydrophilic head) is
immersed in it. The bilayer serves as a barrier to the diffusion of water
Cytoplasmic Organelles and hydrophilic substances, while allowing lipid-soluble molecules,
Cytoplasm is an aqueous solution (cytosol) that fills the cytoplas- such as oxygen (O2) and carbon dioxide (CO2), to diffuse through it
mic matrix—the space between the nuclear envelope and the plasma readily.
membrane. The cytosol represents about half the volume of a eukary- Proteins. A protein is made from a chain of amino acids, known as
otic cell. It contains thousands of enzymes involved in intermediate polypeptides. There are 20 types of amino acids in proteins and each
metabolism and is crowded with ribosomes making proteins (see type of protein has a unique sequence of amino acids. Thus they are
Figure 1-1, B). Newly synthesized proteins remain in the cytosol very versatile! Proteins can be classified as integral or peripheral mem-
if they lack a signal for transport to a cell organelle.1 The organelles brane proteins. Integral membrane proteins are embedded in the
4 CHAPTER 1  Cellular Biology

Nucleoplasm
Nuclear pores
Nucleolus

PORE

Chromosome
B

Supercoil within
chromosome
Nuclear envelope

A
Chromatin

Human
Coiling
chromosomes within
FIGURE 1-2  The Nucleus. The nucleus is composed of a double mem-
brane, called a nuclear envelope, that encloses the fluid-filled interior,
supercoil
called nucleoplasm. The chromosomes are suspended in the nucleoplasm
(illustrated here much larger than actual size to show the tightly packed
DNA strands). Swelling at one or more points of the chromosome, shown
in A, occurs at a nucleolus where genes are being copied into RNA. The Chromatin fiber
nuclear envelope is studded with pores. B, The pores are visible as dim-
ples in this freeze-etch of a nuclear envelope. C, Histone-folding DNA in
chromosomes. (B from Raven PH, Johnson GB: Biology, St Louis, 1992, DNA
Mosby.) Nucleosome
Histone

DNA double helix (duplex)

C Histone DNA

TABLE 1-1 PRINCIPAL CYTOPLASMIC ORGANELLES

ORGANELLE CHARACTERISTICS AND DESCRIPTION
Ribosomes RNA-protein complexes (nucleoproteins) synthesized in nucleolus and secreted into cytoplasm. Provide sites for cellular protein synthesis.
Endoplasmic Network of tubular channels (cisternae) that extend throughout outer nuclear membrane. Specializes in synthesis and transport of protein and
reticulum lipid components of most organelles.
Golgi complex Network of smooth membranes and vesicles located near nucleus. Responsible for processing and packaging proteins onto secretory vesicles
that break away from the complex and migrate to various intracellular and extracellular destinations, including plasma membrane. Best-
known vesicles are those that have coats largely made of the protein clathrin. Proteins in the complex bind to the cytoskeleton, generating
tension that helps organelle function and keep its stretched shape intact.
Lysosomes Saclike structures that originate from Golgi complex and contain enzymes for digesting most cellular substances to their basic form, such as
amino acids, fatty acids, and sugars. Cellular injury leads to release of lysosomal enzymes that cause cellular self-destruction.
Peroxisomes Similar to lysosomes but contain several oxidative enzymes (e.g., catalase, urate oxidase) that produce hydrogen peroxide; reactions detoxify
various wastes.
Mitochondria Contain metabolic machinery needed for cellular energy metabolism. Enzymes of respiratory chain (electron-transport chain), found in inner
membrane of mitochondria, generate most of cell’s ATP (oxidative phosphorylation). Have a role in osmotic regulation, pH control, calcium
homeostasis, and cell signaling.
Cytoskeleton “Bone and muscle” of cell. Composed of a network of protein filaments, including microtubules and actin filaments (microfilaments); forms cell
extensions (microvilli, cilia, flagella).
Caveolae Tiny indentations (caves) that can capture extracellular material and shuttle it inside the cell or across the cell.
Vaults Cytoplasmic ribonucleoproteins shaped like octagonal barrels. Believed to act as “trucks,” shuttling molecules from nucleus to elsewhere in cell.
 CHAPTER 1  Cellular Biology 5

TABLE 1-2 PLASMA MEMBRANE FUNCTIONS

CELLULAR
MECHANISM MEMBRANE FUNCTIONS
Structure Usually thicker than membranes of intracellular organelles
Containment of cellular organelles
Maintenance of relationship with cytoskeleton, endoplasmic reticulum, and other organelles
Maintenance of fluid and electrolyte balance
Outer surfaces of plasma membranes in many cells are not smooth but are dimpled with cavelike indentations called caveolae; they are
also studded with cilia or even smaller cylindrical projections called microvilli; both are capable of movement
Protection Barrier to toxic molecules and macromolecules (proteins, nucleic acids, polysaccharides)
Barrier to foreign organisms and cells
Activation of cell Hormones (regulation of cellular activity)
Mitogens (cellular division; see Chapter 2)
Antigens (antibody synthesis; see Chapter 5)
Growth factors (proliferation and differentiation; see Chapter 9)
Storage Storage site for many receptors
Transport
Diffusion and exchange diffusion
Endocytosis (pinocytosis, phagocytosis)
Exocytosis (secretion)
Active transport
Cell-to-cell interaction Communication and attachment at junctional complexes
Symbiotic nutritive relationships
Release of enzymes and antibodies to extracellular environment
Relationships with extracellular matrix

Modified from King DW, Fenoglio CM, Lefkowitch JH: General pathology: principles and dynamics, Philadelphia, 1983, Lea & Febiger.

Polar
Phosphate
(hydrophilic or
functional
water soluble)
group
head region

Hydrophilic Water
heads
Glycerol  Nonpolar
fatty acid (hydrophobic; Hydrophobic
chains not water but tails
fat soluble)
tail region Hydrophilic
heads
Interior of
A B cell
FIGURE 1-3  Structure of a Phospholipid Molecule. A, Each phospholipid molecule consists of a
phosphate functional group and two fatty acid chains attached to a glycerol molecule. B, The fatty acid
chains and glycerol form nonpolar, hydrophobic “tails,” and the phosphate functional group forms the
polar, hydrophilic “head” of the phospholipid molecule. When placed in water, the hydrophobic tails
of the molecule face inward, away from the water, and the hydrophilic head faces outward, toward
the water. (From Raven PH, Johnson GB: Understanding biology, ed 3, Dubuque, Iowa, 1995, Brown.)

lipid bilayer and linked to either phosphatidylinositol, a minor phos- structure is determined by the lipid bilayer, membrane functions are
pholipid, or a fatty acid chain. The integral proteins can be removed determined largely by proteins. Proteins act as (1) recognition and
from the membrane only by detergents that solubilize (dissolve) the binding units (receptors) for substances moving into and out of the
lipid. Peripheral membrane proteins are not embedded in the bilayer cell; (2) pores or transport channels for various electrically charged
but reside at one surface or the other, bound to an integral protein. particles, called ions or electrolytes, and specific carriers for amino acids
Proteins exist in densely folded molecular configurations rather and monosaccharides; (3) specific enzymes that drive active pumps
than straight chains, so most hydrophilic units are at the surface of the to promote concentration of certain ions, particularly potassium
molecule and most hydrophobic units are inside. Although membrane (K+), within the cell while keeping concentrations of other ions, for
6 CHAPTER 1  Cellular Biology

example, sodium (Na+), below concentrations found in the extracellu-

lar environment; (4) cell surface markers, such as glycoproteins (pro-
teins attached to carbohydrates), that identify a cell to its neighbor;
(5) cell adhesion molecules (CAMs), or proteins that allow cells to
hook together and form attachments of the cytoskeleton for maintain-
ing cellular shape; and (6) catalysts of chemical reactions, for example,
conversion of lactose to glucose (Figure 1-4).
The interaction of plasma membrane proteins with lipids is com-
plex. The role of proteins in the onset and progression of disease is
Transport channel Enzyme Cell surface receptor
important because of their enzymatic, transport, and recognition-
receptor functions in cellular physiology.
Carbohydrates. The carbohydrates (oligosaccharides) contained
within the plasma membrane are generally bound to membrane pro-
teins (glycoproteins) and lipids (glycolipids). Intercellular recognition
is an important function of membrane oligosaccharides.

Fluid Mosaic Model

In the 1960s G.L. Nicholson and S.J. Singer proposed the popular fluid
mosaic model for biologic membranes (Figure 1-5). The model, which
Cell surface markers Cell adhesion Attachment of cytoskeleton
is continually being modified, presents integral proteins as pieces of a
FIGURE 1-4  Functions of Plasma Membrane Proteins. The mosaic that float singly or as aggregates in the fluid lipid bilayer. The
plasma membrane proteins illustrated here show a variety of func- protein molecules (1) transport other molecules into and out of the
tions performed by the different types of plasma membranes. (From
cell; (2) facilitate (catalyze) membrane reactions; (3) receive messages,
Raven PH, Johnson GB: Understanding biology, ed 3, Dubuque,
Iowa, 1995, Brown.)
thus acting as receptors for extracellular and intracellular signals; and
(4) create structural linkages between the external and internal cellular
environments. The fluid mosaic model accounts for the flexibility of
cellular membranes as well as their self-sealing properties and imper-
meability to many substances.

Carbohydrate chains

External Glycolipid
membrane surface
Polar region
of phospholipid

Phospholipid
bilayer

Internal Cholesterol Protein Nonpolar region

membrane surface of phospholipid
Glycoprotein
Membrane
channel protein

FIGURE 1-5  Fluid Mosaic Model. Schematic, three-dimensional view of the fluid mosaic model of
membrane structure. The lipid bilayer provides the basic structure and serves as a relatively imperme-
able barrier to most water-soluble molecules.
 CHAPTER 1  Cellular Biology 7

New revisions of the model now state that most membrane pro- The number of receptors present may vary at different times, and the
teins do not have unrestricted lateral movement. Thus some proteins cell can modulate the effects of injurious agents by altering recep-
may randomly diffuse, others are confined, and still others are teth- tor number and pattern.1 This aspect of the fluid mosaic model has
ered to the cytoskeleton. The degree of a membrane’s fluidity depends drastically modified previously held concepts concerning the onset
on temperature. At lower temperatures the lipids are in a gel crystal- of disease.
line state, and at higher temperatures they become highly fluid. These The concentration of cholesterol in the plasma membrane affects
properties are critical for cellular growth, division, and receptor func- membrane fluidity. Increased concentration means less fluidity on the
tion. Because some proteins are free to move within the plasma mem- membrane’s hydrophilic outer surface and more fluidity at its hydro-
branes (like floating icebergs), certain foreign proteins (antigens) may phobic core. Cholesterol content changes are factors in some diseases.
become buried in the bilayer, emerging at the surface only after injury In cirrhosis of the liver, for example, the cholesterol content of the red
and then attracting antibodies (proteins produced by the immune sys- blood cell’s plasma membrane increases, causing a decrease in mem-
tem), which attack host cells. Antigens and antibodies, which are inte- brane fluidity that seriously affects the cell’s ability to transport oxygen.
gral to the immune response, are discussed in Chapter 6. The burial
and reemergence of antigens may be one cause of autoimmune disease, Cellular Receptors
described in Chapter 7. Cellular receptors are protein molecules on the plasma membrane,
Cells, however, can immobilize specific membrane proteins in a in the cytoplasm, or in the nucleus that can recognize and bind with
region of the membrane. Confinement may be needed for certain specific smaller molecules called ligands (Figure 1-6). Hormones, for
functions to occur. The fluid mosaic model describes the membrane example, are ligands. Recognition and binding depend on the chemi-
as existing in a state of change and modulation, which allows the cal configuration of the receptor and its smaller ligand, which must
cell to protect itself actively against injurious agents. Hormones, fit together somewhat like pieces of a jigsaw puzzle (see Chapter 17).
bacteria, viruses, drugs, antibodies, chemicals that transmit nerve New data illustrate that activation of a receptor also may depend on
impulses (neurotransmitters), and other substances attach to the differences in movement and binding of the extracellular face of the
plasma membrane by means of receptor molecules on its outer layer. receptor.1

Ligand binds 1 Ligand binds 3 Ligand binds

to receptor to receptor to receptor
2

FIGURE 1-6  Cellular Receptors. (A) 1, Plasma

membrane receptor for a ligand (here, a hormone
Ion channel molecule) on the surface of an integral protein. A
opens Intracellular Ion channel neurotransmitter can exert its effect on a postsyn-
message opens
A aptic cell by means of two fundamentally differ-
ent types of receptor proteins: 2, channel-linked
Inhibitors of
receptors, and 3, non–channel-linked receptors.
ligand binding
IGF-1 (Ligand) Channel-linked receptors are also known as
ligand-gated channels. (B) Example of ligand-
IGF-1R Receptor for IGF-1 receptor interaction. Insulin-like growth factor
1 (IGF-1) is a ligand and binds to the insulin-like
growth factor 1 receptor (IGF-1R). With binding
at the cell membrane the intracellular signaling
pathway is activated, causing translation of new
proteins to act as intracellular communicators.
This pathway is important for cancer growth.
Inhibitors of cell Researchers are developing pharmacologic strat-
signaling pathway egies to reduce signaling at and downstream of
the insulin-like growth factor 1 receptor (IGF-1R),
hoping this will lead to compounds useful in can-
P
Inhibitors
cer treatment.

P
Rapamycin

Translation
Cell signaling pathway
B
8 CHAPTER 1  Cellular Biology

Plasma membrane receptors protrude from or are exposed at Receptors for infectious microorganisms, or antigen receptors,
the external surface of the membrane and are important for cellular bind bacteria, viruses, and parasites. Antigen receptors on white blood
uptake of ligands (see Figure 1-6). The ligands that bind with mem- cells (lymphocytes, monocytes, macrophages, granulocytes) recognize
brane receptors include hormones, neurotransmitters, antigens, and bind with antigenic microorganisms and activate the immune and
complement components, lipoproteins, infectious agents, drugs, and inflammatory responses (see Chapter 5).
metabolites. Many new discoveries concerning the specific interactions
of cellular receptors with their respective ligands have provided a basis
for understanding disease.
CELL-TO-CELL ADHESIONS
Although the chemical nature of ligands and their receptors dif- Cells are small and squishy, not like bricks. They are enclosed only by
fers, receptors are classified based on their location and function. Cel- a flimsy membrane, yet the cell depends on the integrity of this mem-
lular type determines overall cellular function, but plasma membrane brane for its survival. How can cells be formed together strongly, with
receptors determine which ligands a cell will bind with and how the cell their membranes intact, to form a muscle that can lift this textbook?
will respond to the binding. Specific processes also control intracellular Plasma membranes not only serve as the outer boundaries of all cells
mechanisms. but also allow groups of cells to be held together robustly, in cell-to-
Receptors for different drugs are found on the plasma membrane, in cell adhesions, to form tissues and organs. Once arranged, cells are
the cytoplasm, and in the nucleus. Membrane receptors have been found held together by three different means: (1) cell adhesion molecules in
for certain anesthetics, opiates, endorphins, enkephalins, antibiotics, the cell’s plasma membrane (see p. 9), (2) the extracellular matrix, and
cancer chemotherapeutic agents, digitalis, and other drugs. Membrane (3) specialized cell junctions.
receptors for endorphins, which are opiate-like peptides isolated from
the pituitary gland, are found in large quantities in pain pathways of Extracellular Matrix
the nervous system (see Chapters 12 and 13). With binding, the endor- Cells can be united by attachment to one another or through the extra-
phins (or drugs such as morphine) change the cell’s permeability to ions, cellular matrix (also including the basement membrane), which the
increase the concentration of molecules that regulate intracellular protein cells secrete around themselves. The extracellular matrix is an intricate
synthesis, and initiate molecular events that modulate pain perception. meshwork of fibrous proteins embedded in a watery, gel-like substance

Type IV collagen
Epithelium
Basement membrane

Integrins • Type IV collagen

• Laminin
• Proteoglycan
Basement membrane

Integrins Laminin

Endothelial Capillary Proteoglycans

cells

Interstitial matrix

Fibroblasts • Fibrillar collagens

• Elastin
• Proteoglycan and
Integrins hyaluronan

Cross-linked
collagen triple helices Adhesive
glycoproteins

FIGURE 1-7  Extracellular Matrix. Tissues are not just cells but also extracellular space. The extracel-
lular space is an intricate network of macromolecules called the extracellular matrix (ECM). The mac-
romolecules that constitute the ECM are secreted locally (by mostly fibroblasts) and assembled into a
meshwork in close association with the surface of the cell that produced them. Two main classes of
macromolecules include proteoglycans, which are bound to polysaccharide chains called glycosami-
noglycans, and fibrous proteins (e.g., collagen, elastin, fibronectin, and laminin), which have structural
and adhesive properties. Together the proteoglycan molecules form a gel-like ground substance in
which the fibrous proteins are embedded. The gel permits rapid diffusion of nutrients, metabolites, and
hormones between the blood and the tissue cells. Matrix proteins modulate cell-matrix interactions
including normal tissue remodeling (which can become abnormal, for example, with chronic inflamma-
tion). Disruptions of this balance result in serious diseases such as arthritis, tumor growth, and others.
(Modified from Kumar V, Abbas A, Fausto N: Robbins and Cotran pathologic basis of disease, ed 7,
Philadelphia, 2005, Saunders.)
 CHAPTER 1  Cellular Biology 9

composed of complex carbohydrates (Figure 1-7). The matrix is like produce the matrix are scattered within it like raisins in a pudding
glue; however, it provides a pathway for diffusion of nutrients, wastes, (see Figure 1-8).
and other water-soluble substances between the blood and tissue cells. The matrix is not just a passive scaffolding for cellular attachment;
Interwoven within the matrix are three groups of macromolecules: (1) it also helps regulate the function of the cells with which it interacts.
fibrous structural proteins, including collagen and elastin; (2) adhesive The matrix helps regulate such important functions as cell growth and
glycoproteins, such as fibronectin; and (3) proteoglycans and hyal- differentiation.
uronic acid.
1. Collagen forms cablelike fibers or sheets that provide tensile Specialized Cell Junctions
strength or resistance to longitudinal stress. Collagen breakdown, Cells in direct physical contact with neighboring cells are often inter-
such as occurs in osteoarthritis, destroys the fibrils that give carti- connected at specialized plasma membrane regions called cell junc-
lage its tensile strength. tions. Cell junctions have two main functions: (1) to hold cells together
2. Elastin is a rubber-like protein fiber most abundant in tissues that and (2) to permit small molecules to pass from cell to cell, allowing
must be capable of stretching and recoiling, such as found in the coordination of the activities of cells that form tissues.
lungs. The three main types of cell junctions are (1) desmosomes (also
3. Fibronectin, a large glycoprotein, promotes cell adhesion and cell known as macula adherens), (2) tight junctions (also known as zonula
anchorage. Reduced amounts have been found in certain types of occludens), and (3) gap junctions, or adhering junctions (Figure 1-9).
cancerous cells; this allows cancer cells to travel, or metastasize, Together they form the junctional complex. Desmosomes unite cells
to other parts of the body. All of these macromolecules occur in either by forming continuous bands or belts of epithelial sheets or by
intercellular junctions and cell surfaces and may assemble into two developing button-like points of contact. Desmosomes also act as a
different components: interstitial matrix and basement membrane system of braces to maintain structural stability. Tight junctions are
(BM) (see Figure 1-7). barriers to diffusion, prevent the movement of substances through
The extracellular matrix is secreted by fibroblasts (“fiber form- transport proteins in the plasma membrane, and prevent the leakage
ers”) (Figure 1-8), local cells that are present in the matrix. The matrix of small molecules between the plasma membranes of adjacent cells.
and the cells within it are known collectively as connective tissue, Gap junctions are clusters of communicating tunnels or connexons
because they interconnect cells to form tissues and organs. Human that allow small ions and molecules to pass directly from the inside of
connective tissues are enormously varied. They can be hard and dense, one cell to the inside of another. Connexons are joining proteins that
like bone; flexible, like tendons or the dermis of the skin; resilient and extend outward from each of the adjacent plasma membranes. Cells
shock absorbing, like cartilage; or soft and transparent, similar to the connected by gap junctions are considered ionically (electrically)
jellylike substance that fills the eye. In all these examples, the major- and metabolically coupled. Gap junctions coordinate the activities
ity of the tissue is composed of extracellular matrix, and the cells that of adjacent cells; for example, they are important for synchronizing
contractions of heart muscle cells through ionic coupling and for per-
mitting action potentials to spread rapidly from cell to cell in neural
tissues. The reason that gap junctions occur in tissues that are not
electrically active is unknown. Although most gap junctions are asso-
ciated with junctional complexes, they sometimes exist as indepen-
dent structures.
The junctional complex is a highly permeable part of the plasma
membrane. Its permeability is controlled by a process called gating,
which depends on concentrations of calcium ions in the cytoplasm.
Increased cytoplasmic calcium causes decreased permeability at the
junctional complex. Gating enables uninjured cells to protect them-
selves from injured neighbors. Calcium is released from injured
cells.

CELLULAR COMMUNICATION AND SIGNAL

TRANSDUCTION
F Cells need to communicate with each other to maintain a stable inter-
nal environment, or homeostasis; to regulate their growth and divi-
sion; to oversee their development and organization into tissues; and
to coordinate their functions. Cells communicate by using hundreds
of kinds of signal molecules, for example, insulin (see Figure 1-6,
B). Cells communicate in three main ways: (1) they display plasma
membrane–bound signaling molecules (receptors) that affect the
cell itself and other cells in direct physical contact (Figure 1-10, A);
0.1 m (2) they use receptor proteins inside the target cell and the signal
FIGURE 1-8  Fibroblasts in Connective Tissue. This micrograph molecule has to enter the cell to bind to them (Figure 1-10, B); and
shows tissue from the cornea of a rat. The extracellular matrix sur- (3) they form protein channels (gap junctions) that directly coordinate
rounds the fibroblasts (F). (From Nishida T et al: The extracellular the activities of adjacent cells (Figure 1-10, C). Alterations in cellular
matrix of animal connective tissues, Invest Ophthalmol Vis Sci communication affect disease onset and progression. In fact, if a cell
29:1887–1880, 1998.) cannot perform gap junctional intercellular communication, normal
10 CHAPTER 1  Cellular Biology

Epithelial cells

Belt
desmosome

Spot
desmosomes

A Hemidesmosomes

Junctional complex

Tight junction
(zonula occludens)

Belt desmosome
(zonula adherens)

Filamentous
material in Spot desmosome
intercellular (macula adherens)
space
Intercellular filaments
Intercellular channel
Gap
junction Intercellular units
forming channels for
B extracellular transport
FIGURE 1-9  Junctional Complex. A, Schematic drawing of a belt desmosome between epithelial
cells. This junction, also called the zonula adherens, encircles each of the interacting cells. The spot
desmosomes and hemidesmosomes, like the belt desmosomes, are adhering junctions. This tight
junction is an impermeable junction that holds cells together but seals them in such a way that mol-
ecules cannot leak between them. The gap junction, as a communicating junction, mediates the pas-
sage of small molecules from one interacting cell to the other. B, Electron micrograph of desmosomes.
(From Raven PH, Johnson GB: Biology, St Louis, 1992, Mosby.)

Small hydrophobic
signal molecule
Signaling cell Target cell Gap junction
Receptor Carrier Target cell
protein

Intracellular
receptor Nucleus
Signaling molecule protein

Contact signaling by plasma Remote signaling Contact signaling

membrane-bound receptors by secreted molecules via gap junctions

A B C
FIGURE 1-10  Cellular Communication. Three primary ways in which cells communicate with one
another. (B adapted from Alberts B et al: Molecular biology of the cell, ed 5, New York, 2008, Garland.)
 CHAPTER 1  Cellular Biology 11

growth control and cell differentiation is compromised, thereby favor- other sets of cells (see Chapter 17). In neurohormonal signaling
ing cancerous tumor development (see Chapter 9). (Communication hormones are released into the blood by neurosecretory neurons.
through gap junctions was discussed earlier, and contact signaling by Like endocrine cells, neurosecretory neurons release blood-borne
plasma membrane–bound molecules is discussed on this page and on chemical messengers, whereas ordinary neurons secrete short-range
p. 12.) Secreted chemical signals involve communication locally and neurotransmitters into a small discrete space (i.e., synapse). Neu-
at a distance. Primary modes of intercellular signaling are contact- rons communicate directly with the cells they innervate by releas-
dependent, paracrine, hormonal, neurohormonal, and neurotrans- ing chemicals or neurotransmitters at specialized junctions called
mitter. Autocrine stimulation occurs when the secreting cell targets chemical synapses; the neurotransmitter diffuses across the synaptic
itself (Figure 1-11). cleft and acts on the postsynaptic target cell (see Figure 1-11). Many
Contact-dependent signaling requires cells to be in close of these same signaling molecules are receptors used in hormonal,
membrane-membrane contact. In paracrine signaling cells secrete neurohormonal, and paracrine signaling. Important differences lie
local chemical mediators that are quickly taken up, destroyed, or in the speed and selectivity with which the signals are delivered to
immobilized. Paracrine signaling usually involves different cell their targets.1
types; however, cells also can produce signals to which they alone Plasma membrane receptors belong to one of three classes that are
respond, called autocrine signaling (see Figure 1-11). For example, defined by the signaling (transduction) mechanism used. Table 1-3
cancer cells use this form of signaling to stimulate their survival summarizes these classes of receptors. Cells respond to external
and proliferation. The mediators act only on nearby cells. Hor- stimuli by activating a variety of signal transduction pathways,
monal signaling involves specialized endocrine cells that secrete which are communication pathways, or signaling cascades (Figure
chemicals called hormones; hormones are released by one set of 1-12, C). Signals are passed between cells when a particular type of
cells and travel through the bloodstream to produce a response in molecule is produced by one cell—the signaling cell—and received

Contact-Dependent Paracrine Autocrine

Secreting
cell

Secreting cell
Target cells targets itself
Membrane signal
molecule

Hormonal Neurohormone secretion

Neurohormone

Blood
Blood
Target
cell
Secreting
cell (neuron)
Target cell

Neurotransmitter

Neurotransmitter
FIGURE 1-11  Primary Modes of Chemical Signaling. Five forms of signaling mediated by
secreted molecules. Hormones, paracrines, neurotransmitters, and neurohormones are all inter-
cellular messengers that accomplish communication between cells. Autocrines bind to receptors
on the same cell. Not all neurotransmitters act in the strictly synaptic mode shown; some act in
a contact-dependent mode as local chemical mediators that influence multiple target cells in the
Receptor on area.
Nerve cell
target cell
12 CHAPTER 1  Cellular Biology

TABLE 1-3 CLASSES OF PLASMA MEMBRANE RECEPTORS

TYPE OF RECEPTOR DESCRIPTION
Ion channel coupled Also called transmitter-gated ion channels; involve rapid synaptic signaling between electrically excitable cells. Channels open and
close briefly in response to neurotransmitters, changing ion permeability of plasma membrane of postsynaptic cell.
Enzyme coupled Once activated by ligands, function directly as enzymes or associate with enzymes.
G-protein coupled Indirectly activate or inactivate plasma membrane enzyme or ion channel; interaction mediated by GTP-binding regulatory protein
(G-protein). May also interact with inositol phospholipids, which are significant in cell signaling, and with molecules involved in
inositol-phospholipid transduction pathway.

Plasma
Signaling
membrane
ligand
A Extracellular signal receptor
molecule IN

Signal Relay
transduction
pathway Intracellular
signaling Amplification
proteins

Divergence
Intracellular
signal molecule Changes in
Regulation of cytoskeleton
OUT gene expression
Changes or regulation
B C in metabolic pathway
Signal
molecule
Survive Differentiate

Grow and
divide
Die

Apoptosis
D
FIGURE 1-12  Schematic of a Signal Transduction Pathway. Like a telephone receiver that converts
an electrical signal into a sound signal, a cell converts an extracellular signal, A, into an intracellular
signal, B. C, An extracellular signal molecule (ligand) bonds to a receptor protein located on the plasma
membrane, where it is transduced into an intracellular signal. This process initiates a signaling cascade
that relays the signal into the cell interior, amplifying and distributing it en route. Amplification is often
achieved by stimulating enzymes. Steps in the cascade can be modulated by other events in the cell.
D, Different cell behaviors rely on multiple extracellular signals.
 CHAPTER 1  Cellular Biology 13

by another—the target cell—by means of a receptor protein that acid cycle and ends with oxidative phosphorylation. About two thirds
recognizes and responds specifically to the signal molecule (Figure of the total oxidation of carbon compounds in most cells is accom-
1-12, A and B). In turn, the signaling molecules activate a pathway plished during this phase. The major end products are carbon dioxide
of intracellular protein kinases that results in various responses, (CO2) and two dinucleotides, reduced nicotinamide adenine dinucle-
such as grow and reproduce, die, survive, or differentiate (Figure otide (NADH) and the reduced form of flavin adenine dinucleotide
1-12, D). (FADH2), that transfer their electrons into the electron-transport chain.

Oxidative Phosphorylation
CELLULAR METABOLISM Oxidative phosphorylation occurs in the mitochondria and is the
All of the chemical tasks of maintaining essential cellular functions mechanism by which the energy produced from carbohydrates, fats,
are referred to as cellular metabolism. The energy-using process of and proteins is transferred to ATP. During the breakdown (catabo-
metabolism is called anabolism (ana = upward), and the energy- lism) of foods, many reactions involve the removal of electrons from
releasing process is known as catabolism (kata = downward). Metab- various intermediates. These reactions generally require a coenzyme
olism provides the cell with the energy it needs to produce cellular (a nonprotein carrier molecule), such as nicotinamide adenine dinu-
structures. cleotide (NAD), to transfer the electrons and thus are called transfer
Dietary proteins, fats, and starches (i.e., carbohydrates) are reactions.
hydrolyzed in the intestinal tract into amino acids, fatty acids, and Molecules of NAD and flavin adenine dinucleotide (FAD) trans-
glucose, respectively. These constituents are then absorbed, circu- fer electrons they have gained from the oxidation of substrates to
lated, and incorporated into the cell, where they may be used for molecular oxygen, O2. The electrons from reduced NAD and FAD,
various vital cellular processes, including the production of ATP. NADH and FADH2, respectively, are transferred to the electron-
The process by which ATP is produced is one example of a series of transport chain on the inner surfaces of the mitochondria with
reactions called a metabolic pathway. A metabolic pathway involves the release of hydrogen ions. Some carrier molecules are brightly
several steps whose end products are not always detectable. A key
feature of cellular metabolism is the directing of biochemical reac-
tions by protein catalysts or enzymes. Each enzyme has a high affin-
ity for a substrate, a specific substance converted to a product of the Food
PHASE 1:
reaction. Extracellular
digestion of
Role of Adenosine Triphosphate large macro- Proteins Polysaccharides Fats
molecules to
For a cell to function, it must be able to extract and use the chemical simple subunits
energy in organic molecules. When one mole of glucose metaboli- Amino acids Simple sugars Fatty acids

Glycolysis
cally breaks down in the presence of oxygen into carbon dioxide and
water, 686 kilocalories (kcal) of chemical energy are released. The
PHASE 2: ATP
chemical energy lost by one molecule is transferred to the chemical Intracellular break-
structure of another molecule by an energy-carrying or energy-trans- down of subunits to acetyl Pyruvate
ferring molecule, such as ATP. The energy stored in ATP can be used CoA accompanied by
production of limited
in various energy-requiring reactions and in the process is generally ATP and NADH
converted to adenosine diphosphate (ADP) and inorganic phos- Acetyl CoA
phate (Pi). The energy available as a result of this reaction is about
PHASE 3:
7 kcal/mol of ATP. The cell uses ATP for muscle contraction and Production of NADH Citric
active transport of molecules across cellular membranes. ATP not yielding ATP via acid
electron transport; cycle
only stores energy but also transfers it from one molecule to another.
waste products (H2O,
Energy stored by carbohydrate, lipid, and protein is catabolized and CO2, NH3, and urea)
transferred to ATP. are excreted
Reducing power
Food and Production of Cellular Energy of NADH
Catabolism of the proteins, lipids, and polysaccharides found in food
Electron transport

can be divided into the following three phases (Figure 1-13):

Phase 1: Digestion. Large molecules are broken down into smaller Oxidative
subunits: proteins into amino acids, polysaccharides into simple phosphorylation
ATP
sugars (i.e., monosaccharides), and fats into fatty acids and glyc-
erol. These processes occur outside the cell and are activated by O2
secreted enzymes.
NH3 and CO2
Phase 2: Glycolysis and oxidation. The most important part of phase urea H2O
2 is glycolysis, the splitting of glucose. Glycolysis produces two
molecules of ATP per glucose molecule through oxidation, or the
removal and transfer of a pair of electrons. The total process is Excretion
called oxidative cellular metabolism and involves nine biochemical
reactions (Figure 1-14). FIGURE 1-13  Three Phases of Catabolism, Which Lead From
Phase 3: Citric acid cycle (Krebs cycle, tricarboxylic acid cycle). Most of Food to Waste Products. These reactions produce adenosine tri-
the ATP is generated during this final phase. It begins with the citric phosphate (ATP), which is used to power other processes in the cell.
14 CHAPTER 1  Cellular Biology

colored, iron-containing proteins known as cytochromes that accept simultaneous production of ATP. With the glycolysis of one mol-
a pair of electrons. These electrons eventually combine with molecu- ecule of glucose, two ATP molecules and two molecules of pyruvate
lar oxygen. are liberated. If oxygen is present, the two molecules of pyruvate
If oxygen is not available to the electron-transport chain, ATP will move into the mitochondria, where they enter the citric acid cycle
not be formed by the mitochondria. Instead, an anaerobic (without (Figure 1-15).
oxygen) metabolic pathway synthesizes ATP. This process, called If oxygen is absent, pyruvate is converted to lactic acid, which is
substrate phosphorylation or anaerobic glycolysis, is linked to the released into the extracellular fluid. The conversion of pyruvic acid to
breakdown (glycolysis) of carbohydrate (see Figure 1-14). Because lactic acid is reversible; therefore once oxygen is restored, lactic acid is
glycolysis occurs in the cytoplasm of the cell, it provides energy for quickly converted back to either pyruvic acid or glucose. The anaero-
cells that lack mitochondria. The reactions in anaerobic glycolysis bic generation of ATP from glucose through glycolysis is not as effi-
involve the conversion of glucose to pyruvic acid (pyruvate) with the cient as the aerobic generation process. Adding an oxygen-requiring
stage to the catabolic process (phase 3; see Figure 1-13) provides cells
with a much more powerful method for extracting energy from food
molecules.
Glucose
ATP MEMBRANE TRANSPORT: CELLULAR INTAKE
1
ADP
AND OUTPUT
Glucose-6- Cells continually incorporate nutrients, fluids, and chemical messen-
phosphate
gers from the extracellular environment and expel metabolites, or the
2
products of metabolism, and end products of lysosomal digestion.
Fructose-6-
phosphate The mechanisms involved depend on the characteristics of the sub-
ATP stance to be transported. In passive transport, water and small, elec-
3
trically uncharged molecules move easily through pores in the plasma
ADP
membrane’s lipid bilayer. This process occurs naturally through any
Fructose-1,6-
diphosphate semipermeable barrier. It is driven by osmosis, hydrostatic pressure,
4 and diffusion, all of which depend on the laws of physics and do not
require life. The process does not require any energy expenditure by
the cell.
Dihydroxyacetone Dihydroxyacetone
phosphate phosphate Other molecules are too large to pass through pores or are ligands
bound to receptors on the cell’s plasma membrane. Some of these
5
Glyceraldehyde-3- Glyceraldehyde-3-
phosphate phosphate
NAD 6 NAD Pyruvate
P P
NADH NADH CO2
1,3-Diphospho- 1,3-Diphospho-
glycerate glycerate Acetaldehyde
ADP ADP
7
ATP ATP NADH NAD + NADH
3-Phospho- 3-Phospho- NAD + NADH NAD +
glycerate glycerate
8
2-Phospho- 2-Phospho-
glycerate glycerate Ethanol Acetyl CoA Lactic acid
9
HO HO

Phosphoenol- Phosphoenol-
pyruvate pyruvate
Citric
ADP ADP
10 acid
cycle
ATP ATP

Pyruvic acid Pyruvic acid

FIGURE 1-15  What Happens to Pyruvate, the Product of Gly-
FIGURE 1-14  Glycolysis. Each of the numbered reactions is cata- colysis? In the presence of oxygen, pyruvate is oxidized to acetyl
lyzed by a different enzyme. At step 4, a six-carbon carbohydrate is coenzyme A (CoA) and enters the citric acid cycle. In the absence
metabolized to two three-carbon carbohydrates, so that the number of oxygen, pyruvate instead is reduced, accepting the electrons
of molecules at every step after this is doubled. Reactions 5 and extracted during glycolysis and carried by reduced nicotinamide
6 are responsible for the net synthesis of adenosine triphosphate adenine dinucleotide (NADH). When pyruvate is reduced directly,
(ATP) and reduced nicotinamide adenine dinucleotide (NADH) mol- as it is in muscles, the product is lactic acid. When CO2 is first
ecules. (Modified from Thibodeau GA, Patton KT: Anatomy & physi- removed from pyruvate and the remainder is reduced, as it is in
ology, ed 6, St Louis, 2007, Mosby.) yeasts, the resulting product is ethanol.
 CHAPTER 1  Cellular Biology 15

molecules are moved into and out of the cell by active transport, which membrane than on the other side, the particles diffuse spontaneously
requires life, biologic activity, and the cell’s expenditure of metabolic from the area of greater concentration to the area of lesser concentra-
energy. Unlike passive transport, active transport occurs across only tion until equilibrium is reached. The higher the concentration on one
living membranes that (1) use energy generated by cellular metabo- side, the greater the diffusion rate.
lism and (2) have receptors that can recognize and bind with the sub- The diffusion rate is influenced by differences of electrical poten-
stance to be transported. Large molecules (macromolecules), along tial across the membrane (see p. XX). Because the pores in the lipid
with fluids, are transported by endocytosis (taking in) and exocytosis bilayer are often lined with Ca++, other cations (e.g., Na+ and K+)
(expelling). Water and electrically charged molecules are transported diffuse slowly because they are repelled by positive charges in the
by protein channels embedded in the plasma membrane. Ligands enter pores.
the cell by means of receptor-mediated endocytosis. The rate of diffusion of a substance depends also on its size (dif-
fusion coefficient) and its lipid solubility (Figure 1-16). Usually, the
Movement of Water and Solutes smaller the molecule and the more soluble it is in oil, the more hydro-
Cellular membranes are semipermeable and generally allow passage phobic or nonpolar it is and the more rapidly it will diffuse across the
of water and small particles of dissolved substances called solutes, bilayer. Oxygen, carbon dioxide, and steroid hormones are all nonpo-
depending on their size, solubility, electrical properties, and concen- lar molecules. Water-soluble substances, such as glucose and inorganic
tration on either side of the membrane (also see Chapter 4). Small, ions, diffuse very slowly, whereas uncharged lipophilic (“lipid-loving”)
lipid-soluble particles, such as oxygen, carbon dioxide, and urea, read- molecules, such as fatty acids and steroids, diffuse rapidly. Ions and
ily pass through the lipid bilayers of the plasma membrane. Larger, other polar molecules generally diffuse across cellular membranes
water-soluble particles may pass through pores in the membranes. more slowly than lipid-soluble substances.
Although large protein molecules, such as albumin and globulin, pass Water readily diffuses through biologic membranes because water
through membranes by endocytosis, they exert an osmotic effect on molecules are small and uncharged. The dipolar structure of water
the movement of water (see p. 16). allows it to cross rapidly the regions of the bilayer containing the lipid
Body fluids are composed of electrolytes, which are electrically head groups. The lipid head groups constitute the two outer regions of
charged and dissociate into constituent ions when placed in solu- the lipid bilayer.
tion, and nonelectrolytes, such as glucose, urea, and creatinine, Filtration: hydrostatic pressure. Filtration is the movement of
which do not dissociate. Electrolytes account for approximately 95% water and solutes through a membrane because of a greater pushing
of the solute molecules in body water. Electrolytes exhibit polarity pressure (force) on one side of the membrane than on the other side.
by orienting themselves toward the positive or negative pole. Ions Hydrostatic pressure is the mechanical force of water pushing against
with a positive charge are known as cations and migrate toward the
negative pole, or cathode, if an electrical current is passed through
the electrolyte solution. Anions carry a negative charge and migrate
toward the positive pole, or anode, in the presence of electrical cur-
rent. Anions and cations are located in both the intracellular fluid High-solute Low-solute
(ICF) and the extracellular fluid (ECF) compartments, although their concentration Lipid bilayer concentration
concentration depends on their location. (Fluid and electrolyte bal-
Extracellular fluid Intracellular
ance between body compartments is discussed in Chapter 4.) For
fluid
example, sodium (Na+) is the predominant extracellular cation, and Hydrophobic O2
potassium (K+) is the principal intracellular cation. The difference in CO2
molecules N2
ICF and ECF concentrations of these ions is important to the trans-
mission of electrical impulses across the plasma membranes of nerve Small, H2O
uncharged Urea
and muscle cells. Glycerol
Electrolytes are measured in milliequivalents per liter (mEq/L) or molecules
milligrams per deciliter (mg/dl). The term milliequivalent indicates the
chemical-combining activity of an ion, which depends on the electrical Large, Glucose
uncharged Sucrose
charge, or valence, of its ions. In abbreviations, valence is indicated by
molecules
the number of plus or minus signs. One milliequivalent of any cation
can combine chemically with 1 mEq of any anion: one monovalent
anion will combine with one monovalent cation. Divalent ions com- H+ Na+
HCO3– K+
bine more strongly than monovalent ions. To maintain electrochemi- Ions
cal balance, one divalent ion will combine with two monovalent ions Ca++ Cl–
(e.g., Ca++ + 2Cl− = CaCl2). Mg++

Passive Transport: Diffusion, Filtration, and Osmosis

Diffusion. Diffusion is the movement of a solute molecule from FIGURE 1-16  Passive Diffusion of Solute Molecules Across the
an area of greater solute concentration to an area of lesser solute con- Plasma Membrane. Oxygen, nitrogen, water, urea, glycerol, and
carbon dioxide can diffuse readily down the concentration gradi-
centration. This difference in concentration is known as a concentra-
ent. Macromolecules are too large to diffuse through pores in the
tion gradient. Although particles in a solution move randomly in any plasma membrane. Ions may be repelled if the pores contain sub-
direction, if the concentration of particles in one part of the solution stances with identical charges. If the pores are lined with cations,
is greater than that in another part, the particles distribute themselves for example, other cations will have difficulty diffusing because the
evenly throughout the solution. According to the same principle, if positive charges will repel one another. Diffusion can still occur, but
the concentration of particles is greater on one side of a permeable it occurs more slowly.
16 CHAPTER 1  Cellular Biology

cellular membranes (Figure 1-17, A). In the vascular system, hydro- number of milliosmoles per liter of solution, or the concentration of
static pressure is the blood pressure generated in vessels when the heart molecules per volume of solution.
contracts. Blood reaching the capillary bed has a hydrostatic pressure In solutions that contain only dissociable substances, such as
of 25 to 30 mm Hg, which is sufficient force to push water across the sodium and chloride, the difference between the two measurements
thin capillary membranes into the interstitial space. Hydrostatic pres- is negligible. When considering all the different solutes in plasma (e.g.,
sure is partially balanced by osmotic pressure, whereby water moving proteins, glucose, lipids), however, the difference between osmolality
out of the capillaries is partially balanced by osmotic forces that tend and osmolarity becomes more significant. Less of plasma’s weight is
to pull water into the capillaries. Water that is not osmotically attracted water, and the overall concentration of particles is therefore greater.
back into the capillaries moves into the lymph system (see the discus- The osmolality will be greater than the osmolarity because of the
sion of Starling forces in Chapter 4). smaller proportion of water. Osmolality is thus preferred in human
Osmosis. Osmosis is the movement of water “down” a concen- clinical assessment.
tration gradient—that is, across a semipermeable membrane from a The normal osmolality of body fluids is 280 to 294 mOsm/kg.
region of higher water concentration to one of lower concentration. The osmolalities of intracellular and extracellular fluids tend to
For osmosis to occur, (1) the membrane must be more permeable to equalize, providing a measure of body fluid concentration and thus
water than to solutes and (2) the concentration of solutes on one side the body’s hydration status. Hydration is affected also by hydro-
of the membrane must be greater than that on the other side so that static pressure, because the movement of water by osmosis can be
water moves more easily. Osmosis is directly related to both hydro- opposed by an equal amount of hydrostatic pressure. The amount
static pressure and solute concentration but not to particle size or of hydrostatic pressure required to oppose the osmotic movement
weight. For example, particles of the plasma protein albumin are small of water is called the osmotic pressure of the solution. Factors that
but are more concentrated in body fluids than the larger and heavier determine osmotic pressure are the type and thickness of the plasma
particles of globulin. Therefore albumin exerts a greater osmotic force membrane, the size of the molecules, the concentration of molecules
than does globulin. or the concentration gradient, and the solubility of molecules within
Osmolality controls the distribution and movement of water the membrane.
between body compartments. The terms osmolality and osmolarity Effective osmolality is sustained osmotic activity and depends on
often are used interchangeably in reference to osmotic activity, but the concentration of solutes remaining on one side of a permeable
they define different measurements. Osmolality measures the num- membrane. If the solutes penetrate the membrane and equilibrate with
ber of milliosmoles per kilogram (mOsm/kg) of water, or the con- the solution on the other side of the membrane, the osmotic effect will
centration of molecules per weight of water. Osmolarity measures the be diminished or lost.
Plasma proteins influence osmolality because they have a nega-
tive charge (see Figure 1-17, B). The principle involved is known as
Gibbs-Donnan equilibrium; it occurs when the fluid in one compart-
ment contains small, diffusible ions, such as Na+ and chloride (Cl−),
Weight
of water together with large, nondiffusible, charged particles, such as plasma
proteins. Because the body tends to maintain an electrical equilib-
1 Hydrostaticpressure rium, the nondiffusible protein molecules cause asymmetry in the dis-
tribution of small ions. Anions such as Cl− are thus driven out of the
cell or plasma, and cations such as Na+ are attracted to the cell. The
protein-containing compartment maintains a state of electroneutral-
ity, but the osmolality is higher. The overall osmotic effect of colloids,
such as plasma proteins, is called the oncotic pressure, or colloid
osmotic pressure.

A Normal cell volume

intracellular fluid: 300 mOsm
2 Oncotic pressure nonpenetrating solutes

Solute

H2O
H2O
B
3 Membrane characteristics
FIGURE 1-17  Hydrostatic Pressure and Oncotic Pressure in
Plasma. 1, Hydrostatic pressure in plasma. 2, Oncotic pressure
exerted by proteins in the plasma usually tends to pull water 285 mOsm 200 mOsm 400 mOsm
into the circulatory system. 3, Individuals with low protein levels istotonic hypotonic hypertonic
(e.g., starvation) are unable to maintain a normal oncotic pressure; FIGURE 1-18  Tonicity. Tonicity is important, especially for red
therefore water is not reabsorbed into the circulation and, instead, blood cell function. (Adapted from Sherwood L: Human physiology,
causes body edema. ed 7, 2008, Brooks Cole.)
 CHAPTER 1  Cellular Biology 17

Tonicity describes the effective osmolality of a solution. (The Solute High concentration
terms osmolality and tonicity may be used interchangeably.) Solutions molecule
have relative degrees of tonicity. An isotonic solution (or isosmotic Transmembrane
“ping” “pong”
solution) has the same osmolality or concentration of particles (285 transport
mOsm) as the ICF or ECF. A hypotonic solution has a lower con- protein
centration and is thus more dilute than body fluids (Figure 1-18).
A hypertonic solution has a concentration of more than 285 to 294
mOsm/kg. The concept of tonicity is important when correcting water
and solute imbalances by administering different types of replacement
solutions (see Figure 1-18) (see Chapter 4).

4 QUICK CHECK 1-2

Low concentration
1. W hat does glycolysis produce?
2. Describe the difference between diffusion and osmosis.
FIGURE 1-19  Conformational Change Model of Mediated
3. Why do water and small, electrically charged molecules move easily Transport (Facilitated Diffusion). The transporter protein has two
through pores in the plasma membrane? states: “ping” and “pong.” In the ping state, sites for molecules of
a specific solute are exposed on the outside of the bilayer. In the
pong state, the sites are exposed to the inner side of the bilayer.
Mediated and Active Transport
Mediated transport. Mediated transport (passive and active)
Extracellular fluid
involves integral or transmembrane proteins with receptors that
are highly specific for the substance being transported. Inorganic
anions and cations (e.g., Na+, K+, Ca++, Cl−, HCO3− ) and charged and
uncharged organic compounds require specific transport systems to
facilitate movement (thus the term facilitated diffusion) through differ-
ent cellular membranes. Mediated transport is much faster than simple
diffusion.
A transport protein (carrier protein) is a transmembrane or inte-
gral protein that binds with and transfers a specific solute molecule
across the lipid bilayer. Each transport protein, or transporter, has
receptors for a specific solute. When the transporter is saturated—that
is, when all receptor sites are occupied by solute molecules—the rate
of transport is maximal. Solute binding can be blocked by competitive Aqueous
inhibitors that compete for the same receptor site and may or may not pore
be transported by the transport protein. Noncompetitive inhibitors Intracellular fluid
bind elsewhere but can alter the structure of the transporter.
The polypeptide chain of the transport protein crosses the lipid FIGURE 1-20  Channel Mode of Mediated Transport (Facilitated
bilayer multiple times. This chain forms a continuous pathway, Diffusion). A channel protein forms a water-filled pore across the
enabling solutes to pass across the membrane without directly contact- bilayer through which specific ions can diffuse.
ing the hydrophobic interior of the lipid bilayer (Figure 1-19).1
Another mechanism of mediated transport is the channel protein.
The protein transporter creates a water-filled pore or channel across Solute molecules
the bilayer through which specific ions can diffuse. These channels Protein
are sometimes called ion channels or K+ leak channels (Figure 1-20). transporter
The channel is controlled by a gate mechanism that determines which
r­eceptor-bound solutes can move into it. Binding stimulates confor-
mational changes in the protein transporter that move the solute
through the channel short distances until it reaches the other side of
the ­membrane. Ion channels are responsible for the electrical excitabil-
ity of nerve and muscle cells and play a critical role in the membrane
potential.
Mediated transport systems can move solute molecules singly or
two at a time. Two molecules can be moved simultaneously in one
direction (a process called symport, for example, sodium-glucose
Uniport Symport Antiport
in the digestive tract) or in opposite directions (called antiport, for
example, the sodium-potassium pump in all cells), or a single molecule
can be moved in one direction (called uniport, for example, glucose) FIGURE 1-21  Mediated Transport. Illustration shows simultane-
(Figure 1-21). ous movement of a single solute molecule in one direction (uniport),
In passive mediated transport, or facilitated diffusion, the pro- of two different solute molecules in one direction (symport), and of
tein transporter moves solute molecules through cellular membranes two different solute molecules in opposite directions (antiport).
18 CHAPTER 1  Cellular Biology

Sodium-potassium K+ K+ BOX 1-1 NEW UNDERSTANDINGS

ATPase
ABOUT ATP
Best known about ATP is its role as a universal “fuel” inside living cells. This
fuel or energy drives biologic reactions necessary for cells to function. Least
known is that ATP has an essential role outside cells—it is a messenger. Much
work has now identified ATP as a critical signaling molecule that enables cells
ATP and tissues throughout the body to communicate with one another.
Na + Na+ Na+ More than a decade of research has defined the dual role of ATP. ATP is so
abundant that its signaling properties affect a broad range of physiologic func-
tioning, providing diverse opportunities to improve human health. For example,
Na+ Na + ATP acts as a neurotransmitter involved in brain function, sensory perception,
muscle contraction, and other organs’ functions. When ATP is released by non-
Na+ neuronal cells it can initiate bone building and cell proliferation.
ATP activates receptors called P2 receptors (thus called purinergic transmis-
sion), which have been further classified as P2X and P2Y. Disrupted or dam-
aged cells release or spill ATP into the extracellular space and prompt ATP
signaling in protective and healing responses, for example, increasing clotting
to stop bleeding. Because of new insights into the signaling role of ATP, sev-
eral pharmaceutical companies are studying P2X receptors as drug targets.

From Burnstock G: Physiology and pathophysiology in purinergic  

Na +
neurotransmission, Physiol Rev 87(2):659–797, 2007.

pores or protein channels and maintaining the ionic concentration

K+
gradients needed for cellular excitation and membrane conductiv-
ATP ity (see p. 21). The maintenance of intracellular K+ concentrations
is required also for enzyme activity, including enzymes involved in
FIGURE 1-22  Active Transport and the Sodium-Potassium protein synthesis.
Pump. Three Na+ ions bind to sodium-binding sites on the carri-
er’s inner face. At the same time, an energy-containing adenosine Active Transport of Na+ and K+
triphosphate (ATP) molecule produced by the cell’s mitochondria
binds to the carrier. The ATP dissociates, transferring its stored The active transport system for Na+ and K+ is found in virtually all
energy to the carrier. The carrier then changes shape, releases the mammalian cells. The Na+, K+ antiport system (i.e., Na+ moving out
three Na+ ions to the outside of the cell, and attracts two potassium of the cell and K+ moving into the cell) uses the direct energy of ATP
(K+) ions to its potassium-binding sites. The carrier then returns to to transport these cations. The transporter protein is ATPase, which
its original shape, releasing the two K+ ions and the remnant of the requires Na+, K+, and magnesium (Mg++) ions. The concentration
ATP molecule to the inside of the cell. The carrier is now ready for of ATPase in plasma membranes is directly related to Na+, K+ trans-
another pumping cycle. (From Thibodeau GA, Patton KT: Anatomy port activity. Approximately 60% to 70% of the ATP synthesized by
& physiology, ed 6, St Louis, 2007, Mosby.) cells, especially muscle and nerve cells, is used to maintain the Na+, K+
transport system. Excitable tissues have a high concentration of Na+,
K+ ATPase, as do other tissues that transport significant amounts of
without expending metabolic energy. The direction of movement is the Na+. For every ATP molecule hydrolyzed, three molecules of Na+ are
same as in simple diffusion—down the concentration gradient. A well- transported out of the cell, whereas only two molecules of K+ move
known passive transport system is that used for glucose in erythro- into the cell. The process leads to an electrical potential and is called
cytes (red blood cells). Glucose is transported by a uniport mechanism electrogenic, with the inside of the cell more negative than the outside.
and demonstrates saturation kinetics—that is, the transport system is Although the exact mechanism for this transport is uncertain, it is pos-
saturated when all the glucose-specific receptors on the membrane are sible that ATPase induces the transporter protein to undergo several
occupied and operating at their maximal capacity. conformational changes, causing Na+ and K+ to move short distances
In active mediated transport, or active transport, the protein (see Figure 1-22). The conformational change lowers the affinity for
transporter moves molecules against, or up, the concentration gra- Na+ and K+ to the ATPase transporter, resulting in the release of the
dient. Unlike passive mediated transport, active mediated transport cations after transport.
requires the expenditure of energy. Many, but not all, active mediated Table 1-4 summarizes the major mechanisms of transport through
transport systems, or pumps, have ATP as their primary energy source. pores and protein transporters in the plasma membranes. Many dis-
Some use the electrochemical gradient of Na+ across the membrane ease states are caused or manifested by loss of these membrane trans-
(Figure 1-22). Energy in the form of ATP, however, is required for acti- port systems.
vation of the Na+ gradient (Box 1-1).
A “carrier” mechanism in the plasma membrane mediates the Transport by Vesicle Formation
transport of ions and nutrients. The best-known pump is the Na+, Endocytosis and Exocytosis
K+–dependent adenosinetriphosphatase (ATPase) pump. It con- The active transport mechanisms by which the cells move large pro-
tinuously regulates the cell’s volume by controlling leaks through teins, polynucleotides, or polysaccharides (macromolecules) across
 CHAPTER 1  Cellular Biology 19

TABLE 1-4 MAJOR TRANSPORT SYSTEMS IN MAMMALIAN CELLS

SUBSTANCE TRANSPORTED MECHANISM OF TRANSPORT* TISSUES

Carbohydrates
Glucose Passive: protein channel Most tissues
Fructose Active: symport with Na+ Small intestines and renal tubular cells
Passive Intestines and liver

Amino Acids
Amino acid specific transporters Coupled channels Intestines, kidney, and liver
All amino acids except proline Active: symport with Na+ Liver
Specific amino acids Active: group translocation Small intestine
Passive

Other Organic Molecules

Cholic acid, deoxycholic acid, and taurocholic acid Active: symport with Na+ Intestines
Organic anions (e.g., malate, α-ketoglutarate, Antiport with counter–organic anion Mitochondria of liver cells
glutamate)
ATP-ADP Antiport transport of nucleotides; can be active Mitochondria of liver cells

Inorganic Ions
Na+ Passive Distal renal tubular cells
Na+/H+ Active antiport, proton pump Proximal renal tubular cells and small intestines
Na+/K+ Active: ATP driven, protein channel Plasma membrane of most cells
Ca++ Active: ATP driven, antiport with Na+ All cells, antiporter in red cells
H+/K+ Active Parietal cells of gastric cells secreting H+
Cl−/ HCO3− (perhaps other anions) Mediated: antiport (anion transporter–band 3 protein) Erythrocytes and many other cells
Water Osmosis passive All tissues

Data from Alberts B et al: Molecular biology of the cell, ed 4, New York, 2001, Garland; Devlin TM, editor: Textbook of biochemistry: with clinical
correlations, ed 3, New York, 1992, Wiley; Raven PH, Johnson GB: Understanding biology, ed 3, Dubuque, IA, 1995, Brown.
*note: The known transport systems are listed here; others have been proposed. Most transport systems have been studied in only a few tissues,
and their sites of activity may be more limited than indicated.
ADP, Adenosine diphosphate; ATP, adenosine triphosphate.

Particle
Endocytosis

Membrane-
bound
vesicle

Fusion of
vesicle with
lysosome

Lysosome

Digestive
Membrane- vacuole
bound
vesicle
Release
of contents B
Exocytosis
A of vesicle
FIGURE 1-23  Endocytosis and Exocytosis. A, Endocytosis and fusion with lysosome and exocytosis.
B, Electron micrograph of exocytosis. (B from Raven PH, Johnson GB: Biology, ed 5, New York, 1999,
McGraw-Hill.)
20 CHAPTER 1  Cellular Biology

the plasma membrane are very different from those that medi-
BOX 1-2 THE NEW ENDOCYTIC MATRIX
ate small solute and ion transport. Transport of macromolecules
An explosion of new data is disclosing a much more involved role for endocy- involves the sequential formation and fusion of membrane-bound
tosis than just a simple way to internalize nutrients and membrane-associated vesicles.
molecules. These new data show that endocytosis not only is a master orga- In endocytosis, a section of the plasma membrane enfolds sub-
nizer of signaling pathways but also has a major role in managing signals in stances from outside the cell, invaginates (folds inward), and separates
time and space. Endocytosis appears to control signaling; therefore it deter- from the plasma membrane, forming a vesicle that moves into the
mines the net output of biochemical pathways. This occurs because endocyto- cell (Figure 1-23, A). Two types of endocytosis are designated based
sis modulates the presence of receptors and their ligands as well as effectors on the size of the vesicle formed. Pinocytosis (cell drinking) involves
at the plasma membrane or at intermediate stations of the endocytic route. the ingestion of fluids and solute molecules through formation of
The overall processes and anatomy of these new functions are sometimes small vesicles, and phagocytosis (cell eating) involves the ingestion
called the “endocytic matrix.” All of these functions ultimately have a large of large particles, such as bacteria, through formation of large vesicles
impact on almost every cellular process, including the nucleus. (vacuoles).
Because most cells continually ingest fluid and solutes by pinocy-
tosis, the terms pinocytosis and endocytosis often are used interchange-
ably. In pinocytosis, the vesicle containing fluids, solutes, or both fuses
with a lysosome, and lysosomal enzymes digest the vesicle’s contents
for use by the cell. In phagocytosis, the large molecular substances
are engulfed by the plasma membrane and enter the cell so that they
can be isolated and destroyed by lysosomal enzymes (see Chapter 5).
Substances that are not degraded by lysosomes are isolated in residual
bodies and released by exocytosis. Both pinocytosis and phagocytosis
require metabolic energy and often involve binding of the substance
with plasma membrane receptors before membrane invagination and
From Scita G, DiFiore PP: The endocytic matrix, Nature 463(28): fusion with lysosomes in the cell. New data are revealing that endo-
464–473, 2010. cytosis has an even larger and more important role than previously
known (Box 1-2).
In eukaryotic cells, secretion of macromolecules almost always
occurs by exocytosis (see Figure 1-23). Exocytosis has two main func-
tions: (1) replacement of portions of the plasma membrane that have
been removed by endocytosis and (2) release of molecules synthesized
by the cells into the extracellular matrix.

Coated pit (1)

Invagination (2)
Ligands
Clathrin Plasma membrane
bristle coat

Lysosomes Coated vesicle (3)

Recycling of Nucleus
receptors (7) Fusion with
lysosome (4)

Digestion of
ligands (5)
Receptor inside
vesicle transported
for recycling
Use of digested
B
A ligands by cell (6)
FIGURE 1-24  Ligand Internalization by Means of Receptor-Mediated Endocytosis. A, The ligand
attaches to its surface receptor (through the bristle coat or clathrin coat) and, through receptor-medi-
ated endocytosis, enters the cell. The ingested material fuses with a lysosome and is processed by
hydrolytic lysosomal enzymes. Processed molecules can then be transferred to other cellular compo-
nents. B, Electron micrograph of a coated pit showing different sizes of filaments of the cytoskeleton
(×82,000). (B from Erlandsen SL, Magney JE: Color atlas of histology, St Louis, 1992, Mosby.)
 CHAPTER 1  Cellular Biology 21

Receptor-Mediated Endocytosis using dynamin, a clathrin-coated protein, and deliver their contents to
Ligand binding to some plasma membrane receptors leads to cluster- either an endosome or the plasma membrane on the opposite side of
ing, aggregation, and immobilization of the receptors in specialized a polarized cell.1
areas of the membrane called coated pits (Figure 1-24). The pits, which Caveolae are not only uptake vehicles but also important sites for
are coated with bristlelike structures (clathrin), deepen and enfold signal transduction, a tedious process in which extracellular chemical
(invaginate), internalizing ligand-receptor complexes and forming a messages or signals are communicated to the cell’s interior for execu-
coated vesicle. The clathrin coat or bristles may be responsible for tion (see p. 12). For example, strong evidence now exists that plasma
trapping membrane receptors in coated pits. This internalization pro- membrane estrogen receptors localize in caveolae, and crosstalk with
cess, called receptor-mediated endocytosis (ligand internalization), estradiol facilitates several intracellular biologic actions.1
is rapid and enables the cell to ingest large amounts of specific ligands
without ingesting large volumes of extracellular fluid. The cellular Movement of Electrical Impulses: Membrane Potentials
uptake of cholesterol, for example, depends on receptor-mediated All body cells are electrically polarized, with the inside of the cell more
endocytosis. negatively charged than the outside. The difference in electrical charge,
or voltage, is known as the resting membrane potential and is about
Caveolae −70 to −85 millivolts. The difference in voltage across the plasma mem-
The outer surface of the plasma membrane is dimpled with tiny flask- brane results from the differences in ionic composition of ICF and
shaped pits (cavelike) called caveolae. Caveolae are thought to form ECF. Sodium ions are more concentrated in the ECF, and potassium
from membrane microdomains or lipid rafts. Caveolae are cholesterol- ions are in greater concentration in the ICF. The concentration differ-
rich domains where protein caveolae are involved in several processes, ence is maintained by the active transport of Na+ and K+ (the sodium-
including clathrin-independent endocytosis, the regulation and trans- potassium pump), which transports sodium outward and potassium
port of cellular cholesterol, and cell communication.1 Many proteins, inward (Figure 1-25). Because the resting plasma membrane is more
including a variety of receptors, cluster in these tiny chambers. Caveo- permeable to K+ than to Na+, K+ diffuses easily from the ICF to the ECF.
lae possibly invaginate and gather cargo proteins from the lipid-rich Because both sodium and potassium are cations, the net result is an excess
caveolar membrane.1 This invagination is in contrast to receptor- of anions inside the cell, resulting in the resting membrane potential.
mediated endocytosis, which also transports molecules into the cell but Nerve and muscle cells are excitable and can change their resting
with the formation of a vesicle. Caveolae pinch off from the membrane membrane potential in response to electrochemical stimuli. Changes

+ + + + + + + + + + + +
Na Na Na Na Na Na Na Na Na Na Na Na

+ + + + + +
K K K K K K
+ + + + + +
K K K K K K

+ + + + + + + + + + + +
Na Na Na Na Na Na Na Na Na Na Na Na

K+ Na+ Resting
Diffusion
Na+ Na+
Na+
K+ Na
+
Na
+
Na
+
Na
+
Na
+
Na
+

+ + + + + + + + + + + +
Na+ 3 Na+ Na+ Na K Na K Na K Na K Na K Na K
+
K K
+
Na
+
K
+
Na
+
K
+
Na
+
K
+
Na
+
K
+
Na
+
K
+
Na
+

+ Sodium- Na+
K + + + + + +
Na+
Na Na Na Na Na Na
potassium
K+ pump Na+ Depolarization

K+ 2 K+ K+
Na+
+ + + + + + + + + + + +
+
K Na K Na K Na K Na K Na K Na K

+ + + + + +
K+ Diffusion K+
Na Na Na Na Na Na
+ + + + + +
Na Na Na Na Na Na
Na+ Na+
+ + + + + + + + + + + +
K Na K Na K Na K Na K Na K Na
Inside Outside Repolarization
A B
FIGURE 1-25  Sodium-Potassium Pump and Propagation of an Action Potential. A, Concentration
difference of sodium (Na+) and potassium (K+) intracellularly and extracellularly. The direction of active
transport by the sodium-potassium pump is also shown. B, The top diagram represents the polarized
state of a neuronal membrane when at rest. The lower diagrams represent changes in sodium and
potassium membrane permeabilities with depolarization and repolarization. (From Thibodeau GA, Pat-
ton KT: Anatomy & physiology, ed 6, St Louis, 2007, Mosby.)
22 CHAPTER 1  Cellular Biology

in resting membrane potential convey messages from cell to cell. When permeability to potassium increases, a stronger-than-normal stimu-
a nerve or muscle cell receives a stimulus that exceeds the membrane lus can evoke an action potential; this time is known as the relative
threshold value, a rapid change occurs in the resting membrane poten- refractory period.
tial, known as the action potential. The action potential carries sig- When the membrane potential is more negative than normal, the
nals along the nerve or muscle cell and conveys information from one cell is in a hyperpolarized (less excitable) state. A stronger-than-
cell to another. (Nerve impulses are described in Chapter 12.) When normal stimulus is then required to reach the threshold potential
a resting cell is stimulated through voltage-regulated channels, the cell and generate an action potential. When the membrane potential is
membranes become more permeable to sodium, so a net movement more positive than normal, the cell is in a hypopolarized (more
of sodium into the cell occurs and the membrane potential decreases, excitable than normal) state and a weaker-than-normal stimulus
or moves forward, from a negative value (in millivolts) to zero. This is required to reach the threshold potential. Changes in the intra-
decrease is known as depolarization. The depolarized cell is more pos- cellular and extracellular concentrations of ions or a change in
itively charged, and its polarity is neutralized. membrane permeability can cause these alterations in membrane
To generate an action potential and the resulting depolarization, excitability.
the threshold potential must be reached. Generally this occurs when
the cell has depolarized by 15 to 20 millivolts. When the threshold is
reached, the cell will continue to depolarize with no further stimula-
tion. The sodium gates open, and sodium rushes into the cell, caus-
4 QUICK CHECK 1-3
1. Identify examples of molecules transported in one direction (symport) and
ing the membrane potential to drop to zero and then become positive opposite directions (antiport).
(depolarization). The rapid reversal in polarity results in the action 2. If oxygen is no longer available to make ATP, what happens to the trans-
potential. port of Na+?
During repolarization, the negative polarity of the resting mem- 3. Why are caveolae important to the cell?
brane potential is reestablished. As the voltage-gated sodium channels
begin to close, voltage-gated potassium channels open. Membrane
permeability to sodium decreases and potassium permeability
increases, so potassium ions leave the cell. The sodium gates close,
CELLULAR REPRODUCTION: THE CELL CYCLE
and with the loss of potassium the membrane potential becomes more Human cells are subject to wear and tear, and most do not last for
negative. The Na+, K+ pump then returns the membrane to the resting the lifetime of the individual. In most tissues, new cells are created as
potential by pumping potassium back into the cell and sodium out of fast as old cells die. Cellular reproduction is therefore necessary for the
the cell. maintenance of life. Reproduction of gametes (sperm and egg cells)
During most of the action potential, the plasma membrane can- occurs through a process called meiosis, described in Chapter 2. The
not respond to an additional stimulus. This time is known as the reproduction, or division, of other body cells (somatic cells) involves
absolute refractory period and is related to changes in permeabil- two sequential phases: mitosis, or nuclear division, and cytokinesis, or
ity to sodium. During the latter phase of the action potential, when cytoplasmic division. Before a cell can divide, however, it must double

Cyclin A

CDK2

Cyclin E
Cyclin A
VIS
ION S
DI OSIS G2
M IT CDK2 CDK1
G2/M
checkpoint
Gap 1
Gap 2

Cyclin B
SIS
ITO

CDK1
M

G1 M
S yn
thesis
Cyclin D Cyclin D
INTERPHASE

CDK6 CDK4
G0
A B
FIGURE 1-26  Interphase and the Phases of Mitosis. A, The G1/S checkpoint is to “check” for cell
size, nutrients, growth factors, and DNA damage. See text for resting phases. The G2/M checkpoint
checks for cell size and DNA replication. B, The orderly progression through the phases of the cell cycle
is regulated by cyclins (so-called because levels rise and fall) and cyclin-dependent protein kinases
(CDKs) and their inhibitors. When cyclins are complexed with CDKs, cell cycle events are triggered.
 CHAPTER 1  Cellular Biology 23

its mass and duplicate all its contents. Separation for division occurs the end of anaphase, there are 46 chromosomes lying at each side of the
during the growth phase, called interphase. The alternation between cell. Barring mitotic errors, each of the 2 groups of 46 chromosomes
mitosis and interphase in all tissues with cellular turnover is known as is identical to the original 46 chromosomes present at the start of the
the cell cycle. cell cycle.
The four designated phases of the cell cycle (Figure 1-26) are During telophase, the final stage, a new nuclear membrane is
(1) the S phase (S = synthesis), in which DNA is synthesized in the formed around each group of 46 chromosomes, the spindle fibers dis-
cell nucleus; (2) the G2 phase (G = gap), in which RNA and protein appear, and the chromosomes begin to uncoil. Cytokinesis causes the
synthesis occurs, namely, the period between the completion of DNA cytoplasm to divide into almost equal parts during this phase. At the
synthesis and the next phase (M); (3) the M phase (M = mitosis), end of telophase, two identical diploid cells, called daughter cells, have
which includes both nuclear and cytoplasmic division; and (4) the G1 been formed from the original cell.
phase, which is the period between the M phase and the start of DNA
synthesis. Rates of Cellular Division
Although the complete cell cycle lasts 12 to 24 hours, about 1 hour
Phases of Mitosis and Cytokinesis is required for the four stages of mitosis and cytokinesis. All types of
Interphase (the G1, S, and G2 phases) is the longest phase of the cell cells undergo mitosis during formation of the embryo, but many adult
cycle. During interphase, the chromatin consists of very long, slender cells, such as nerve cells, lens cells of the eye, and muscle cells, lose
rods jumbled together in the nucleus. Late in interphase, strands of their ability to replicate and divide. The cells of other tissues, particu-
chromatin (the substance that gives the nucleus its granular appear- larly epithelial cells (e.g., cells of the intestine, lung, or skin), divide
ance) begin to coil, causing shortening and thickening. continuously and rapidly, completing the entire cell cycle in less than
The M phase of the cell cycle, mitosis and cytokinesis, begins with 10 hours.
prophase, the first appearance of chromosomes. As the phase pro- The difference between cells that divide slowly and cells that divide
ceeds, each chromosome is seen as two identical halves called chro- rapidly is the length of time spent in the G1 phase of the cell cycle.
matids, which lie together and are attached by a spindle site called Once the S phase begins, however, progression through mitosis takes a
a centromere. (The two chromatids of each chromosome, which are relatively constant amount of time.
genetically identical, are sometimes called sister chromatids.) The The mechanisms that control cell division depend on genes and
nuclear membrane, which surrounds the nucleus, disappears. Spindle protein growth factors. Protein growth factors govern the prolifera-
fibers are microtubules formed in the cytoplasm. They radiate from tion of different cell types. Individual cells are members of a complex
two centrioles located at opposite poles of the cell and pull the chro- cellular society in which survival of the entire organism is key—not
mosomes to opposite sides of the cell, beginning metaphase. Next, survival or proliferation of just the individual cells. When a need arises
the centromeres become aligned in the middle of the spindle, which for new cells, as in repair of injured cells, previously nondividing cells
is called the equatorial plate (or metaphase plate) of the cell. In this must be triggered rapidly to reenter the cell cycle. With continual wear
stage, chromosomes are easiest to observe microscopically because and tear, the cell birth rate and the cell death rate must be kept in
they are highly condensed and arranged in a relatively organized balance.
fashion.
Anaphase begins when the centromeres split and the sister chro- Growth Factors
matids are pulled apart. The spindle fibers shorten, causing the sister Growth factors, also called cytokines, are peptides (protein fractions)
chromatids to be pulled, centromere first, toward opposite sides of the that transmit signals within and between cells. They have a major role
cell. When the sister chromatids are separated, each is considered to be in the regulation of tissue growth and development (Table 1-5). Hav-
a chromosome. Thus the cell has 92 chromosomes during this stage. By ing nutrients is not enough for a cell to proliferate; it must also receive

TABLE 1-5 EXAMPLES OF GROWTH FACTORS AND THEIR ACTIONS

GROWTH FACTOR PHYSIOLOGIC ACTIONS

Platelet-derived growth factor (PDGF) Stimulates proliferation of connective tissue cells and neuroglial cells
Epidermal growth factor (EGF) Stimulates proliferation of epidermal cells and other cell types
Insulin-like growth factor 1 (IGF-1) Collaborates with PDGF and EGF; stimulates proliferation of fat cells and connective tissue cells
Vascular endothelial growth factor (VEGF) Mediates functions of endothelial cells; proliferation, migration, invasion, survival,
and permeability
Insulin-like growth factor 2 (IGF-2) Collaborates with PDGF and EGF; stimulates or inhibits response of most cells to other growth
factors; regulates differentiation of some cell types (e.g., cartilage)
Transforming growth factor β (TGBβ; multiple subtypes) Stimulates or inhibits response of most cells to other growth factors; regulates differentiation of
some cell types (e.g., cartilage)
Fibroblast growth factor (FGF; multiple subtypes) Stimulates proliferation of fibroblasts, endothelial cells, myoblasts, and other multiple subtypes
Interleukin-2 (IL-2) Stimulates proliferation of T lymphocytes
Nerve growth factor (NGF) Promotes axon growth and survival of sympathetic and some sensory and central nervous system
(CNS) neurons
Hematopoietic cell growth factors (IL-3, GM-CSF, G-CSF, eryth- Promote proliferation of blood cells
ropoietin)

G-CSF, Granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor.

24 CHAPTER 1  Cellular Biology

stimulatory chemical signals (growth factors) from other cells, usu- Tissue Formation
ally its neighbors or the surrounding supporting tissue called stroma. The process by which differentiated cells create tissues and organs is
These signals act to overcome intracellular braking mechanisms that called pattern formation.5 To form tissues, cells must exhibit intercel-
tend to restrain cell growth and block progress through the cell cycle lular recognition and communication, adhesion, and memory. Spe-
(see Figure 1-27). cialized cells sense their environment through signals, such as growth
An example of a brake that regulates cell proliferation is the factors, from other cells. This type of communication ensures that new
retinoblastoma (Rb) protein, first identified through studies of cells are produced only when and where they are required. Different
a rare childhood eye tumor called retinoblastoma, in which the cell types have different adhesion molecules in their plasma mem-
Rb protein is missing or defective (see p. 423). The Rb protein branes, sticking selectively to other cells of the same type. They can
is abundant in the nucleus of all vertebrate cells. It binds to gene also adhere to extracellular matrix components. Because cells are tiny
regulatory proteins, preventing them from stimulating the tran- and squishy and enclosed by a flimsy membrane, it is remarkable that
scription of genes required for cell proliferation (see Figure 1-27). they form a strong human being. Strength can occur because of the
Extracellular signals, such as growth factors, activate intracellular extracellular matrix and the strength of the cytoskeleton with cell-cell
signaling pathways that inactivate the Rb protein, leading to cell adhesions to neighboring cells. Cells have memory because of special-
proliferation. ized patterns of gene expression evoked by signals that acted during
Different types of cells require different growth factors; for exam- embryonic development. Memory allows cells to autonomously pre-
ple, platelet-derived growth factor (PDGF) stimulates the production serve their distinctive character and pass it on to their progeny.1
of connective tissue cells. Table 1-5 summarizes the most significant
growth factors. Evidence shows that some growth factors also regu- Types of Tissues
late other cell processes, such as cellular differentiation. In addition to The four basic types of tissues are nerve, epithelial, connective, and
growth factors that stimulate cellular processes, there are factors that muscle. The structure and function of these four types underlie the
inhibit these processes; these factors are not well understood. Cells structure and function of each organ system. Neural tissue is com-
that are starved of growth factors come to a halt after mitosis and enter posed of highly specialized cells called neurons, which receive and
the arrested (resting) (G0) state of the cell cycle (see p. 22 for cell transmit electrical impulses rapidly across junctions called synapses
cycle).1 (see Figure 11-1). Different types of neurons have special characteris-
tics that depend on their distribution and function within the nervous
system. Epithelial, connective, and muscle tissues are summarized in
TISSUES Boxes 1-3, 1-4, and 1-5, respectively.
Cells of one or more types are organized into tissues, and different
types of tissues compose organs. Finally, organs are integrated to per-
form complex functions as tracts or systems.
All cells are in contact with a network of extracellular macromol-
4 QUICK CHECK 1-4
1.  hy is cell cycle communication so important?
W
ecules known as the extracellular matrix (see p. 8). This matrix not 2. Discuss the five types of intracellular communication.
only holds cells and tissues together but also provides an organized 3. Why is cell-to-cell adhesion so important?
latticework within which cells can migrate and interact with one 4. Why is the extracellular matrix important for tissue cells?
another.

Growth factor
Inactive growth Activated growth
factor receptor factor receptor

Intracellular
Inactivated Active signaling
gene pathway
Rb protein
regulatory Inactivated
protein Nucleus Rb protein

Phosphorylation
of Rb

DNA Target gene Activated gene

regulating protein Transcription

A B Translation

Cell proliferation
FIGURE 1-27  How Growth Factors Stimulate Cell Proliferation. A, Resting cell. With the absence of
growth factors, the retinoblastoma (Rb) protein is not phosphorylated; thus it holds the gene regulatory
proteins in an inactive state. The gene regulatory proteins are required to stimulate the transcription of
genes needed for cell proliferation. B, Proliferating cell. Growth factors bind to the cell surface recep-
tors and activate intracellular signaling pathways, leading to activation of intracellular proteins. These
intracellular proteins phosphorylate and thereby inactivate the Rb protein. The gene regulatory proteins
are now free to activate the transcription of genes, leading to cell proliferation.
 CHAPTER 1  Cellular Biology 25

BOX 1-3 CHARACTERISTICS OF EPITHELIAL TISSUES

SIMPLE SQUAMOUS EPITHELIUM
Structure
Single layer of cells
Location Function
Lining of blood vessels Diffusion and filtration
Lining of pulmonary alveoli (air sacs) Separation of blood from
fluids in tissues
Separation of air from fluids
in tissues

Bowman’s capsule (kidney) Filtration of substances from Simple Squamous Epithelial Cell. Photomicrograph of simple
blood, forming urine squamous epithelial cell in parietal wall of Bowman’s capsule in kidney. (From
Erlandsen SL, Magney JE: Color atlas of histology, St Louis, 1992, Mosby.)

STRATIFIED SQUAMOUS EPITHELIUM Cornified layer

Structure
Two or more layers, depending on location, with
cells closest to basement membrane tending to
be cuboidal
Location Function
Epidermis of skin Protection and secretion
Linings of mouth, pharynx, esophagus, anus

Basement membrane Basal cells Dermis

Cornified Stratified Squamous Epithelium. Diagram of stratified

squamous epithelium of skin. (Copyright Ed Reschke. Used with permission.)
TRANSITIONAL EPITHELIUM Stratified transitional
Structure Binucleate cell epithelial cells
Vary in shape from cuboidal to squamous
depending on whether basal cells of bladder are
columnar or are composed of many layers; when
bladder is full and stretched, the cells flatten
and stretch like squamous cells
Location Function
Linings of urinary bladder and other hollow Stretching that permits expan-
structures sion of hollow organs

Basement membrane Connective tissue

Stratified Squamous Transitional Epithelium. Photomicrograph

of stratified squamous transitional epithelium of urinary bladder. (Copyright Ed
Reschke. Used with permission.)

Continued
26 CHAPTER 1  Cellular Biology

BOX 1-3 CHARACTERISTICS OF EPITHELIAL TISSUES­—cont’d

SIMPLE CUBOIDAL EPITHELIUM
Structure
Simple cuboidal cells; rarely stratified (layered)
Location Function
Glands (e.g., thyroid, sweat, salivary) Secretion
Parts of kidney tubule and outer covering
of ovary

Simple Cuboidal Epithelium. Photomicrograph of simple cuboidal

epithelium of pancreatic duct. (From Erlandsen SL, Magney JE: Color atlas
of histology, St Louis, 1992, Mosby.)
SIMPLE COLUMNAR EPITHELIUM
Structure Goblet cells
Large amounts of cytoplasm and cellular organ-
elles
Location Function
Lining of digestive tract Secretion and absorption from
stomach to anus
Ducts of many glands
CILIATED SIMPLE COLUMNAR EPI-
THELIUM
Structure
Same as simple columnar epithelium but ciliated
Location Function
Linings of bronchi of lungs, nasal cavity, Secretion, absorption, and
and oviducts propulsion of fluids and
particles

Columnar epithelial cell

Simple Columnar Epithelium. Photomicrograph of simple columnar

epithelium. (Copyright Ed Reschke. Used with permission.)
STRATIFIED COLUMNAR EPITHELIUM Columnar Basement
Goblet cell
Structure Cilia cell membrane
Small and rounded basement membrane (columnar
cells do not touch basement membrane)
Location Function
Linings of epiglottis, part of pharynx, anus, and Protection
male urethra
PSEUDOSTRATIFIED CILIATED COLUMNAR EPITHELIUM
Structure
All cells in contact with basement membrane
Nuclei found at different levels within cell, giving
stratified appearance
Free surface often ciliated
Location Function
Linings of large ducts of some glands (parotid, Transport of substances
salivary), male urethra, respiratory passages,
and eustachian tubes of ears Mucous glands
Pseudostratified Ciliated Columnar Epithelium. Photomicro-
graph of pseudostratified ciliated columnar epithelium of trachea. (Copyright
Robert L. Calentine. Used with permission.)
 CHAPTER 1  Cellular Biology 27

BOX 1-4 CONNECTIVE TISSUES

LOOSE OR AREOLAR TISSUE Bundle of collagenous fibers
Structure
Unorganized; spaces between fibers
Most fibers collagenous, some elastic and reticular
Includes many types of cells (fibroblasts and macrophages most common) and large
amount of intercellular fluid
Location and Function
Attaches skin to underlying tissue; holds organs in place by filling spaces between
them; supports blood vessels
Intercellular fluid transports nutrients and waste products
Fluid accumulation causes swelling (edema)

Elastic fibers
Loose Areolar Connective Tissue. (Copyright Ed Reschke. Used with
permission.)
DENSE IRREGULAR TISSUE Fibroblast Collagenous fibers
Structure
Dense, compact, and areolar tissue, with fewer cells and greater number
of closely woven collagenous fibers than in loose tissue
Location and Function
Dermis layer of skin; acts as protective barrier

Dense, Irregular Connective Tissue. (Copyright Ed Reschke. Used

with permission.)
DENSE, REGULAR (WHITE FIBROUS) TISSUE
Structure
Collagenous fibers and some elastic fibers, tightly packed into parallel bundles,
with only fibroblast cells
Location and Function
Forms strong tendons of muscle, ligaments of joints, some fibrous membranes,
and fascia that surrounds organs and muscles

Fibroblast Collagenous fibers

Dense, Regular (White Fibrous) Connective Tissue. (Copyright

Phototake. Used with permission.)

Continued
28 CHAPTER 1  Cellular Biology

BOX 1-4 CONNECTIVE TISSUES—cont’d

ELASTIC TISSUE
Structure
Elastic fibers, some collagenous fibers, fibroblasts
Location and Function
Lends strength and elasticity to walls of arteries, trachea, vocal cords, and other
structures

Elastic Connective Tissue. (From Erlandsen SL, Magney JE: Color atlas
of histology, St Louis, 1992, Mosby.)
ADIPOSE TISSUE
Structure
Fat cells dispersed in loose tissues; each cell containing a large droplet of fat
­flattens nucleus and forces cytoplasm into a ring around cell’s periphery
Location and Function
Stores fat, which provides padding and protection
Storage area for fat Plasma membrane

B Nucleus of adipose cell

A
Adipose Tissue. A, Fat storage areas—distribution of fat in male and female bodies. B, Photomicrograph of adipose tissue. (A from Thibodeau GA, Patton
KT: Anatomy & physiology, ed 6, St Louis, 2007, Mosby; B Copyright Ed Reschke. Used with permission.)
 CHAPTER 1  Cellular Biology 29

BOX 1-4 CONNECTIVE TISSUES—cont’d

CARTILAGE (HYALINE, ELASTIC, FIBROUS) Chondrocyte
Structure Lacuna (within lacuna)
Collagenous fibers embedded in a firm matrix (chondrin); no blood supply
Location and Function
Gives form, support, and flexibility to joints, trachea, nose, ear, vertebral disks,
embryonic skeleton, and many internal structures
Perichondrium layer

B
Elastic fibers

A Matrix Chondrocyte in lacuna

Cartilage. A, Hyaline cartilage. B, Elastic cartilage. C, Fibrous cartilage.

(A and C copyright Robert L. Calentine; B copyright Ed Reshke. Used with
­permission.)

C Matrix Collagenous fibers Cartilage cell in lacuna

BONE
Structure
Rigid connective tissue consisting of cells, fibers, ground substances, and minerals
Location and Function
Lends skeleton rigidity and strength
Osteon (haversian system)
SPECIAL CONNECTIVE TISSUES
Plasma
Structure
Fluid
Location and Function
Serves as matrix for blood cells

Macrophages in Tissue, Reticuloendothelial, or Macrophage

System
Structure
Scattered macrophages (phagocytes) called Kupffer’s cells (in liver), alveolar
­macrophages (in lungs), microglia (in central nervous system)
Location and Function
Facilitate inflammatory response and carry out phagocytosis in loose connective,
lymphatic, digestive, medullary (bone marrow), splenic, adrenal, and pituitary
tissues
Bone. (Copyright Phototake. Used with permission.)
30 CHAPTER 1  Cellular Biology

BOX 1-5 MUSCLE TISSUES

SKELETAL (STRIATED) MUSCLE Cross striations of muscle cell
Structure Characteristics of Cells
Long, cylindrical cells that extend throughout
length of muscles
Striated myofibrils (proteins)
Many nuclei on periphery
Location Function
Attached to bones directly or by tendons Voluntary movement of skeleton;
maintenance of posture

Nuclei of muscle cell Muscle fiber

Skeletal (Striated) Muscle. (From Thibodeau GA, Patton KT:

Anatomy & physiology, ed 6, St Louis, 2007, Mosby.)
Nucleus
CARDIAC MUSCLE
Structure Characteristics of Cells
Branching networks throughout muscle tissue
Striated myofibrils
Location Function
Cells attached end-to-end at intercalated disks; Involuntary pumping action of
tissue forms walls of heart (myocardium) heart

Intercalated disks

Cardiac Muscle. (Copyright Ed Reschke. Used with permission.)

Smooth muscle cells
SMOOTH (VISCERAL) MUSCLE
Structure Characteristics of Cells
Long spindles that taper to a point
Absence of striated myofibrils
Location Function
Walls of hollow internal structures, such as Voluntary and involuntary contrac-
digestive tract and blood vessels (viscera) tions that move substances
through hollow structures

Smooth (Visceral) Muscle. (Copyright Phototake. Used with

­permission.)
 CHAPTER 1  Cellular Biology 31

DID YOU UNDERSTAND?

Cellular Functions 19. The ligand-receptor complex initiates a series of protein interactions, caus-
1. Cells become specialized through the process of differentiation or maturation. ing adenylate cyclase to catalyze the transformation of cellular ATP to mes-
2. The eight specialized cellular functions are movement, conductivity, senger molecules that stimulate specific responses within the cell.
metabolic absorption, secretion, excretion, respiration, reproduction, and
communication. Cell-to-Cell Adhesions
1. Cell-to-cell adhesions are formed on plasma membranes, thereby allowing
Structure and Function of Cellular Components the formation of tissues and organs. Cells are held together by three differ-
1. The eukaryotic cell consists of three general components: the plasma mem- ent means: (1) the extracellular membrane, (2) cell adhesion molecules in the
brane, the cytoplasm, and the intracellular organelles. cell’s plasma membrane, and (3) specialized cell junctions.
2. The nucleus is the largest membrane-bound organelle and is found usually 2. The extracellular matrix includes three groups of macromolecules: (1) fibrous
in the cell’s center. The chief functions of the nucleus are cell division and structural proteins (collagen and elastin), (2) adhesive glycoproteins, and
control of genetic information. (3) proteoglycans and hyaluronic acid. The matrix helps regulate cell growth,
3. Cytoplasm, or the cytoplasmic matrix, is an aqueous solution (cytosol) that movement, and differentiation.
fills the space between the nucleus and the plasma membrane. 3. The three major types of cell junctions are desmosomes, tight junctions, and
4. The organelles are suspended in the cytoplasm and are enclosed in biologic gap junctions.
membranes.
5. The endoplasmic reticulum is a network of tubular channels (cisternae) that Cellular Communication and Signal Transduction
extend throughout the outer nuclear membrane. It specializes in the synthe- 1. Cells communicate in three main ways: (1) they form protein channels (gap
sis and transport of protein and lipid components of most of the organelles. junctions); (2) they display receptors that affect intracellular processes or
6. The Golgi complex is a network of smooth membranes and vesicles located other cells in direct physical contact; and (3) they use receptor proteins inside
near the nucleus. The Golgi complex is responsible for processing and pack- the target cell.
aging proteins into secretory vesicles that break away from the Golgi com- 2. Primary modes of intercellular signaling include contact-dependent, para-
plex and migrate to a variety of intracellular and extracellular destinations, crine, hormonal, neurohormonal, and neurotransmitter.
including the plasma membrane. 3. Signal transduction involves signals or instructions from extracellular chemi-
7. Lysosomes are saclike structures that originate from the Golgi complex and cal messengers that are conveyed to the cell’s interior for execution.
contain digestive enzymes. These enzymes are responsible for digesting
most cellular substances to their basic form, such as amino acids, fatty Cellular Metabolism
acids, and sugars. 1. The chemical tasks of maintaining essential cellular functions are referred
8. Cellular injury leads to a release of the lysosomal enzymes, causing cellular to as cellular metabolism. Anabolism is the energy-using process of metabo-
self-digestion. lism, whereas catabolism is the energy-releasing process.
9. Peroxisomes are similar to lysosomes but contain several enzymes that 2. Adenosine triphosphate (ATP) functions as an energy-transferring molecule.
either produce or use hydrogen peroxide. Energy is stored by molecules of carbohydrate, lipid, and protein, which,
10. Mitochondria contain the metabolic machinery necessary for cellular energy when catabolized, transfer energy to ATP.
metabolism. The enzymes of the respiratory chain (electron-­transport 3. Oxidative phosphorylation occurs in the mitochondria and is the mechanism
chain), found in the inner membrane of the mitochondria, generate most of by which the energy produced from carbohydrates, fats, and proteins is
the cell’s ATP. transferred to ATP.
11. The cytoskeleton is the “bone and muscle” of the cell. The internal skeleton
Membrane Transport: Cellular Intake and Output
is composed of a network of protein filaments, including microtubules and
1. Water and small, electrically uncharged molecules move through pores in
actin filaments (microfilaments).
the plasma membrane’s lipid bilayer in the process called passive transport.
12. The plasma membrane encloses the cell and, by controlling the movement
2. Passive transport does not require the expenditure of energy; rather, it is
of substances across it, exerts a powerful influence on metabolic pathways.
driven by the physical effects of osmosis, hydrostatic pressure, and diffusion.
13. Protein receptors (recognition units) on the plasma membrane enable the
3. Larger molecules and molecular complexes (e.g., ligand-receptor complexes)
cell to interact with other cells and with extracellular substances.
are moved into the cell by active transport, which requires the cell to expend
14. The plasma membrane is a bilayer of lipids (phospholipids, glycolipids) and
energy (by means of ATP).
cholesterol, which gives the membrane its structural integrity.
4. The largest molecules (macromolecules) and fluids are transported by the
15. Membrane functions are determined largely by proteins. These functions
processes of endocytosis (ingestion) and exocytosis (expulsion).
include recognition by protein receptors and transport of substances into
5. Two types of solutes exist in body fluids: electrolytes and nonelectrolytes.
and out of the cell.
Electrolytes are electrically charged and dissociate into constituent ions
16. The fluid mosaic model accounts for the fluidity of the lipid bilayer and
when placed in solution. Nonelectrolytes do not dissociate when placed in
the flexibility, self-sealing properties, and selective impermeability of the
solution.
plasma membrane. The model has been updated.
6. Diffusion is the passive movement of a solute from an area of higher solute
17. Cellular receptors are protein molecules on the plasma membrane, in the
concentration to an area of lower solute concentration.
cytoplasm, or in the nucleus that are capable of recognizing and binding
7. Filtration is the measurement of water and solutes through a membrane
smaller molecules, called ligands.
because of a greater pushing pressure.
18. The dynamic nature of the fluid plasma membrane enables it to vary the
8. Hydrostatic pressure is the mechanical force of water pushing against cel-
number of receptors on its surface. Altering receptor number and pattern is
lular membranes.
related to disease states.
32 CHAPTER 1  Cellular Biology

DID YOU UNDERSTAND?—cont’d

9. Osmosis is the movement of water across a semipermeable membrane Cellular Reproduction: The Cell Cycle
from a region of lower solute concentration to a region of higher solute 1. Cellular reproduction in body tissues involves mitosis (nuclear division) and
concentration. cytokinesis (cytoplasmic division).
10. The amount of hydrostatic pressure required to oppose the osmotic move- 2. Only mature cells are capable of division. Maturation occurs during a stage
ment of water is called the osmotic pressure of the solution. of cellular life called interphase (growth phase).
11. The overall osmotic effect of colloids, such as plasma proteins, is called the 3. The cell cycle is the reproductive process that begins after interphase in
oncotic pressure or colloid osmotic pressure. all tissues with cellular turnover. There are four phases of the cell cycle:
12. Mediated transport can be passive or active. Mediated transport includes (1) the S phase, during which DNA synthesis takes place in the cell nucleus;
the movement of two molecules simultaneously in one direction (symport) (2) the G2 phase, the period between the completion of DNA synthesis and
or in opposite directions (antiport) or the movement of a single molecule in the next phase (M); (3) the M phase, which involves both nuclear (mitotic)
one direction (uniport). and cytoplasmic (cytokinetic) division; and (4) the G1 phase (growth phase),
13. Passive mediated transport is also called facilitated diffusion. It does not after which the cycle begins again.
require the expenditure of metabolic energy. 4. The M phase (mitosis) involves four stages: prophase, metaphase, ana-
14. Active mediated transport requires metabolic energy (ATP) to move mol- phase, and telophase.
ecules against the concentration gradient. 5. The mechanisms that control cell division depend on “social control genes”
15. Active transport occurs also by endocytosis, or vesicle formation, in which and protein growth factors.
the substance to be transported is engulfed by a segment of the plasma
membrane, forming a vesicle that moves into the cell. Tissues
16. Pinocytosis is a type of endocytosis in which fluids and solute molecules 1. Cells of one or more types are organized into tissues, and different types
are ingested through formation of small vesicles. of tissues compose organs. Organs are organized to function as tracts or
17. Phagocytosis is a type of endocytosis in which large particles, such as bac- systems.
teria, are ingested through formation of large vesicles, called vacuoles. 2. Three key factors that maintain the cellular organization of tissues are (a)
18. In receptor-mediated endocytosis, the plasma membrane receptors are recognition and cell communication, (b) selective cell-to-cell adhesion, and
clustered, along with bristlelike structures, in specialized areas called (c) memory.
coated pits. 3. Tissue cells are linked at cell junctions, which are specialized regions on
19. Endocytosis occurs when coated pits invaginate, internalizing ligand-recep- their plasma membranes called desmosomes, tight junctions, and gap junc-
tor complexes in coated vesicles. tions. Cell junctions attach adjacent cells and allow small molecules to pass
20. Inside the cell, lysosomal enzymes process and digest material ingested by between them.
endocytosis. 4. The four basic types of tissues are epithelial, muscle, nerve, and connective
21. Caveolae are cavelike pits, and are involved in transport and cell tissues.
communication. 5. Neural tissue is composed of highly specialized cells called neurons that
22. All body cells are electrically polarized, with the inside of the cell more receive and transmit electrical impulses rapidly across junctions called
negatively charged than the outside. The difference in voltage across the synapses.
plasma membrane is the resting membrane potential. 6. Epithelial tissue covers most internal and external surfaces of the body. The
23. When an excitable (nerve or muscle) cell receives an electrochemical stim- functions of epithelial tissue include protection, absorption, secretion, and
ulus, cations enter the cell, causing a rapid change in the resting membrane excretion.
potential known as the action potential. The action potential “moves” along 7. Connective tissue binds various tissues and organs together, supporting
the cell’s plasma membrane and is transmitted to an adjacent cell. This is them in their locations and serving as storage sites for excess nutrients.
how electrochemical signals convey information from cell to cell. 8. Muscle tissue is composed of long, thin, highly contractile cells or fibers
called myocytes. Muscle tissue that is attached to bones enables voluntary
movement. Muscle tissue in internal organs enables involuntary movement,
such as the heartbeat.
 CHAPTER 1  Cellular Biology 33

 KEY TERMS
•  bsolute refractory period  22
A •  lectrolyte  15
E •  smosis  16
O
• Action potential  22 • Electron-transport chain  13 • Osmotic pressure  16
• Active mediated transport  18 • Endocytosis  20 • Oxidation  13
• Active transport  15 • Equatorial plate (metaphase plate)  23 • Oxidative phosphorylation  13
• Amphipathic  3 • Eukaryote  1 • Paracrine signaling  11
• Anabolism  13 • Exocytosis  20 • Passive mediated transport (facilitated
• Anaphase  23 • Extracellular matrix  8 diffusion)  17
• Anion  15 • Fibroblast  9 • Passive transport  14
• Antiport  17 • Fibronectin  9 • Pattern formation  24
• Arrested (resting) (G0) state  24 • Filtration  15 • Peripheral membrane protein  5
• Autocrine signaling  11 • Fluid mosaic model  6 • Phagocytosis  20
• Basement membrane  8 • G1 phase  23 • Pinocytosis  20
• Catabolism  13 • G2 phase  23 • Plasma membrane (plasmalemma)  3
• Cation  15 • Gap junction  9 • Plasma membrane receptor  8
• Caveolae  3 • Gating  9 • Platelet-derived growth factor (PDGF)  24
• Caveolin • Glycolysis  13 • Polarity  15
• Cell adhesion molecule (CAM)  6 • Glycoprotein  6 • Polypeptide  3
• Cell cycle  23 • Growth factor (cytokine)  23 • Prokaryote  2
• Cell junction  9 • Homeostasis  9 • Prophase  23
• Cell-to-cell adhesion  8 • Hormonal signaling  11 • Protein  3
• Cellular metabolism  13 • Hydrostatic pressure  15 • Receptor protein  13
• Cellular receptor  7 • Hyperpolarized state  22 • Receptor-mediated endocytosis (ligand
• Centromere  23 • Hypertonic solution  17 internalization)  21
• Chemical synapse  11 • Hypopolarized state  22 • Relative refractory period  22
• Chromatid  23 • Hypotonic solution  17 • Repolarization  22
• Chromatin  23 • Integral membrane protein  3 • Resting membrane potential  21
• Citric acid cycle (Krebs cycle, tricarboxylic • Interphase  23 • Retinoblastoma (Rb) protein  24
acid cycle)  13 • Ion  15 • S phase  23
• Clathrin  21 • Isotonic solution  17 • Signal transduction pathway  11
• Coated pit  21 • Junctional complex  9 • Signaling cell  11
• Collagen  9 • Ligand  7 • Solute  15
• Competitive inhibitor  17 • M phase  23 • Spindle fiber  23
• Concentration gradient  15 • Macromolecule  9 • Stroma  24
• Connective tissue  9 • Mediated transport  17 • Substrate  13
• Connexon  9 • Metabolic pathway  13 • Substrate phosphorylation (anaerobic
• Cytokinesis  22 • Metaphase  23 glycolysis)  14
• Cytoplasm  3 • Mitosis  22 • Symport  17
• Cytoplasmic matrix  3 • Neurohormonal signaling  11 • Target cell  13
• Cytosol  3 • Neurotransmitter  11 • Telophase  23
• Daughter cell  23 • Nuclear envelope  3 • Threshold potential  22
• Depolarization  22 • Nucleolus  3 • Tight junction  9
• Desmosome  9 • Nucleus  3 • Tonicity  17
• Differentiation  2 • Oncotic pressure (colloid osmotic • Transfer reaction  13
• Diffusion  15 pressure)  16 • Transport protein (transporter)  17
• Digestion  13 • Organelle  3 • Uniport  17
• Effective osmolality  16 • Osmolality  16 • Valence  15
• Elastin  9 • Osmolarity  16

REFERENCES 3. L aPorte SL, et al: Molecular and structural basis of cytokine receptor
pleiotrophy in the interleukin-4/13 system, Cell 132:259–272, 2008.
1. A lberts B, et al: Molecular biology of the cell, ed 5, New York, 2008, 4. Kiss AL, et al: Oestrogen-mediated tyrosine phosphorylation of caveolin-1
Garland. and its effect on the oestrogen receptor localization: an in vivo study,
2. Catt KJ, et al: Hormonal regulation of peptide receptors and target cell Mol Cell Endocrinol 245(1-2):128–137, 2005.
responses, Nature 280(5718):109–116, 1979. 5. Jorde LB, et al: Medical genetics, ed 4, St Louis, 2010, Mosby.
CHAPTER

2
Genes and Genetic Diseases
Lynn B. Jorde

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
DNA, RNA, and Proteins: Heredity at the Molecular Level, 35 X-Linked Inheritance, 51
Definitions, 35 Evaluation of Pedigrees, 53
From Genes to Proteins, 37 Linkage Analysis and Gene Mapping, 53
Chromosomes, 38 Classic Pedigree Analysis, 53
Chromosome Aberrations and Associated Diseases, 40 Complete Human Gene Map: Prospects and Benefits, 54
Elements of Formal Genetics, 46 Multifactorial Inheritance, 55
Phenotype and Genotype, 46
Dominance and Recessiveness, 47
Transmission of Genetic Diseases, 47
Autosomal Dominant Inheritance, 47
Autosomal Recessive Inheritance, 50

Genetics occupies a central position in the entire study of biology. An the blueprints of proteins in the body, genes ultimately influence all
understanding of genetics is essential to study human, animal, plant, aspects of body structure and function. Estimates suggest that there are
or microbial life. Genetics is the study of biologic inheritance. In the approximately 20,000 to 25,000 genes. An error in one of these genes
nineteenth century, microscopic studies of cells led scientists to sus- often leads to a recognizable genetic disease.
pect that the nucleus of the cell contained the important mechanisms To date, more than 20,000 genetic traits and diseases have been
of inheritance. Scientists found that chromatin, the substance that identified and cataloged. As infectious diseases continue to be more
gives the nucleus a granular appearance, is observable in nondividing effectively controlled, the proportion of beds in pediatric hospitals
cells. Just before the cell divides, the chromatin condenses to form dis- occupied by children with genetic diseases has risen. In addition, many
crete, dark-staining organelles, which are called chromosomes. (Cell common diseases that primarily affect adults, such as hypertension,
division is discussed in Chapter 1.) With the rediscovery of Mendel’s coronary heart disease, diabetes, and cancer, are now known to have
important breeding experiments at the turn of the twentieth century, important genetic components.
it soon became apparent that the chromosomes contained genes, the Great progress is being made in the diagnosis of genetic diseases and
basic units of inheritance (Figure 2-1). in the understanding of genetic mechanisms underlying them. With
The primary constituent of chromatin is deoxyribonucleic acid the huge strides being made in molecular genetics, “gene therapy”—
(DNA). Genes are composed of sequences of DNA. By serving as the utilization of normal genes to correct genetic disease—has begun.

34
 CHAPTER 2  Genes and Genetic Diseases 35

Gene

Gene

Gene

Organism A human body Each cell nucleus One specific Each chromosome DNA is a
(human) is made up contains an identical chromosome is one long DNA double helix
of trillions complement of pair molecule, and genes
of cells chromosomes are functional regions
of this DNA
FIGURE 2-1  Successive Enlargements from a Human to the Genetic Material.

DNA, RNA, AND PROTEINS: HEREDITY

AT THE MOLECULAR LEVEL
Definitions
Composition and Structure of DNA Sugar Sugar
Genes are composed of DNA, which has three basic components: the Phosphate
five-carbon monosaccharide deoxyribose; a phosphate molecule; and
Cytosine Guanine
four types of nitrogenous bases. Two of the bases, cytosine and thy-
mine, are single carbon-nitrogen rings called pyrimidines. The other Adenine Thymine
two bases, adenine and guanine, are double carbon-nitrogen rings Hydrogen
bonds
called purines. The four bases are commonly represented by their first
letters: A, C, T, and G.
Watson and Crick demonstrated how these molecules are physi-
cally assembled as DNA, proposing the double-helix model, in which
DNA appears like a twisted ladder with chemical bonds as its rungs
(Figure 2-2). The two sides of the ladder consist of deoxyribose and
phosphate molecules, united by strong phosphodiester bonds. Project-
ing from each side of the ladder, at regular intervals, are the nitrog-
enous bases. The base projecting from one side is bound to the base
projecting from the other by a weak hydrogen bond. Therefore the
nitrogenous bases form the rungs of the ladder; adenine pairs with thy-
mine, and guanine pairs with cytosine. Each DNA subunit—consisting
of one deoxyribose molecule, one phosphate group, and one base—is
called a nucleotide.

DNA as the Genetic Code

DNA directs the synthesis of all the body’s proteins. Proteins are
composed of one or more polypeptides (intermediate protein com- FIGURE 2-2  Watson-Crick Model of the DNA Molecule. The DNA
pounds), which are in turn consist of sequences of amino acids. The structure illustrated here is based on that published by James Wat-
body contains 20 different types of amino acids; they are specified by son (left) and Francis Crick (photograph, right) in 1953. Note that each
the 4 nitrogenous bases. To specify (code for) 20 different amino acids side of the DNA molecule consists of alternating sugar and phosphate
with only 4 bases, different combinations of bases, occurring in groups groups. Each sugar group is bonded to the sugar group opposite it by
of 3, are used. These triplets of bases are known as codons. Each codon a pair of nitrogenous bases (adenine-thymine or cytosine-guanine).
specifies a single amino acid in a corresponding protein. Because there The sequence of these pairs constitutes a genetic code that deter-
mines the structure and function of a cell. (From Thibodeau GA, Pat-
are 64 (4 × 4 × 4) possible codons but only 20 amino acids, there are
ton KT: Anatomy & physiology, ed 6, St Louis, 2007, Mosby.)
many cases in which several codons correspond to the same amino
acid.
The genetic code is universal: all living organisms use precisely Replication of DNA
the same DNA codes to specify proteins except for mitochondria, the DNA replication consists of breaking the weak hydrogen bonds
cytoplasmic organelles in which cellular respiration takes place (see between the bases, leaving a single strand with each base unpaired.
Chapter 1)—they have their own extranuclear DNA. Several codons of The consistent pairing of adenine with thymine and of guanine with
mitochondrial DNA encode different amino acids, as compared to the cytosine, known as complementary base pairing, is the key to accu-
same nuclear DNA codons. rate replication. The unpaired base attracts a free nucleotide only if
36 CHAPTER 2  Genes and Genetic Diseases

DNA polymerase

A G
T C C Supercoiled DNA
T C G T
A C G
A
C A T
DNA
nucleotides A
C
G T C
A C G
C A New DNA
T strands forming C Cytosine
G A
C Old DNA strand A Adenine
A C T
G C G G Guanine
T C G G A
T Thymine

FIGURE 2-3  Replication of DNA. The two chains of the double helix separate, and each chain serves
as the template for a new complementary chain. (From Patton KT, Thibodeau GA: Anatomy & physiol-
ogy, ed 7, St Louis, 2010, Mosby.)

C T
C T G A A G C
A
G A A G C C
T
G T
C G A T DNA (normal) C A C
C A T A G
DNA (normal) T C A C C G T T T
C A T A G
C G T T T G T A G A
G T A G A

C U
C U G A
G A C G
C G C
C mRNA (normal) C A
mRNA (normal) C A C
A U A
A U A C U U
U U

Polypeptide Ala Ile Ser Ty r Phe

Polypeptide Ala Ile Ser Ty r Phe

Nonsense A for C
Missense A for G
mutation T G
mutation T C

C T
C T A A G C
G A A A A C G
C G A
T
C G T T C A A
T T A C DNA C A T T
DNA C A T T G
G C G G T A T T T A A
C G G T A T T
G A A

C U C U A
G A G
C A C G
mRNA C A
C A mRNA C A
A C A C
U A U U U A U U

Polypeptide Ala Ile Asn Ty r Phe Polypeptide Ala Ile Ser (stop •
codon)
A B
FIGURE 2-4  Base Pair Substitution. Missense mutations (A) produce a single amino acid change,
whereas nonsense mutations (B) produce a stop codon in the mRNA. Stop codons terminate transla-
tion of the polypeptide. (From Jorde L et al: Medical genetics, ed 4, St Louis, 2010, Mosby.)
 CHAPTER 2  Genes and Genetic Diseases 37

the nucleotide has the proper complementary base. When replication The frameshift mutation involves the insertion or deletion of one
is complete, a new double-stranded molecule identical to the original or more base pairs of the DNA molecule. As Figure 2-5 shows, these
is formed (Figure 2-3). The single strand is said to be a template, or mutations change the entire “reading frame” of the DNA sequence
molecule on which a complementary molecule is built, and is the basis because the deletion or insertion is not a multiple of three base pairs
for synthesizing the new double strand. (the number of base pairs in a codon). Frameshift mutations can thus
Several different proteins are involved in DNA replication. The greatly alter the amino acid sequence. (In-frame insertions or dele-
most important of these proteins is an enzyme known as DNA poly- tions, in which a multiple of three bases is inserted or lost, tend to have
merase. This enzyme travels along the single DNA strand, adding the less severe disease consequences than do frameshift mutations.)
correct nucleotides to the free end of the new strand and checking Agents known as mutagens increase the frequency of mutations.
to make sure that its base is actually complementary to the template Examples include radiation and chemicals such as nitrogen mustard,
base. This mechanism of DNA proofreading substantially enhances the vinyl chloride, alkylating agents, formaldehyde, and sodium nitrite.
accuracy of DNA replication. Mutations are rare events. The rate of spontaneous mutations
(those occurring in the absence of exposure to known mutagens) in
Mutation humans is about 10−4 to 10−7 per gene per generation. This rate varies
A mutation is any inherited alteration of genetic material. Mutations from one gene to another. Some DNA sequences have particularly high
may cause disease or be subtle, silent substitutions that do not change mutation rates and are known as mutational hot spots.
amino acids. One type of mutation is the base pair substitution, in
which one base pair replaces another. This replacement can result in From Genes to Proteins
a change in the amino acid sequence. However, because of the redun- DNA is formed and replicated in the cell nucleus, but protein synthe-
dancy of the genetic code, many of these mutations do not change the sis takes place in the cytoplasm. The DNA code is transported from
amino acid sequence and thus have no consequence. Such mutations nucleus to cytoplasm, and subsequent protein is formed through two
are called silent mutations. Base pair substitutions that alter amino basic processes: transcription and translation. These processes are
acids consist of two basic types: missense mutations, which produce a mediated by ribonucleic acid (RNA), which is chemically similar to
change (i.e., the “sense”) in a single amino acid; and nonsense muta- DNA except that the sugar molecule is ribose rather than deoxyribose,
tions, which produce one of the three stop codons (UAA, UAG, or and uracil rather than thymine is one of the four bases. The other bases
UGA) in the messenger RNA (mRNA) (Figure 2-4). Missense muta- of RNA, as in DNA, are adenine, cytosine, and guanine. Uracil is struc-
tions (Figure 2-4, A) produce a single amino acid change, whereas non- turally similar to thymine, so it also can pair with adenine. Whereas
sense mutations (Figure 2-4, B) produce a stop codon in the mRNA. DNA usually occurs as a double strand, RNA usually occurs as a single
Stop codons terminate translation of the polypeptide. strand.

Transcription
In transcription, RNA is synthesized from a DNA template, forming
C T messenger RNA (mRNA). RNA polymerase binds to a promoter site,
G A A G C
C G A T a sequence of DNA that specifies the beginning of a gene. RNA poly-
DNA (normal) T C A C
C A
T T T A G merase then separates a portion of the DNA, exposing unattached DNA
C G T A T A
G G bases. One DNA strand then provides the template for the sequence of
mRNA nucleotides.
C U The sequence of bases in the mRNA is thus complementary to the
G A
C G
C template strand, and except for the presence of uracil instead of thy-
mRNA (normal) C A
A U A C mine, the mRNA sequence is identical to the other DNA strand. Tran-
U U
scription continues until a termination sequence, codons that act as
signals for the termination of protein synthesis, is reached. Then the
Polypeptide Ala Ile Ser Ty r Phe RNA polymerase detaches from the DNA, and the transcribed mRNA
is freed to move out of the nucleus and into the cytoplasm (Figures 2-6
Frameshift A and C inserted
mutation T G and 2-7).

A Gene Splicing
G A C A G C T
C
T T
T C When the mRNA is first transcribed from the DNA template, it
DNA C A T A A
T G C G reflects exactly the base sequence of the DNA. In eukaryotes, many
C G G T A G A T
RNA sequences are removed by nuclear enzymes, and the remain-
ing sequences are spliced together to form the functional mRNA that
A
G
G
C migrates to the cytoplasm. The excised sequences are called introns
C A (intervening sequences), and the sequences that are left to code for
U
mRNA C C
A A C U proteins are called exons.
U A

Polypeptide Ala Ile Gln Ala Thr

Translation
FIGURE 2-5  Frameshift Mutations. Frameshift mutations result In translation, RNA directs the synthesis of a polypeptide (see Figure
from the addition or deletion of a number of bases that is not a 2-7), interacting with transfer RNA (tRNA), a cloverleaf-shaped strand
multiple of three. This mutation alters all of the codons downstream of about 80 nucleotides. The tRNA molecule has a site where an amino
from the site of insertion or deletion. (From Jorde L et al: Medical acid attaches. The three-nucleotide sequence at the opposite side of the
genetics, ed 4, St Louis, 2010, Mosby.) cloverleaf is called the anticodon. It undergoes complementary base
38 CHAPTER 2  Genes and Genetic Diseases

RNA polymerase
C Cytosine
C G A C A Adenine
A
mRNA strand A G A C G A T A G Guanine
A C
C G U Uracil
T U C U G C U A A T Thymine
T C
G T G U
C A G C
G C
RNA nucleotide C G
C G A C G T
A T
DNA A
C
double helix C G
T C T G C T A T
A

Nucleus
Gene
DNA

Exon
Intron Transcription

Cap G Poly-A tail

Pre-mRNA AAA
Editing FIGURE 2-6  General Scheme of Ribonucleic Acid (RNA) Tran-
Splicing scription. A, Transcription of messenger RNA (mRNA). A DNA mol-
AAA ecule “unzips” in the region of the gene to be transcribed. RNA
nucleotides already present in the nucleus temporarily attach them-
selves to exposed DNA bases along one strand of the unzipped
G
DNA molecule according to the principle of complementary pairing.
As the RNA nucleotides attach to the exposed DNA, they bind to
each other and form a chainlike RNA strand called a messenger
Cytoplasm RNA (mRNA) molecule. Notice that the new mRNA strand is an
mRNA Transport
G exact copy of the base sequence on the opposite side of the DNA
AAA
molecule. As in all metabolic processes, the formation of mRNA
is controlled by an enzyme—in this case, the enzyme is called
Translation
RNA polymerase. B, Editing of an mRNA transcript. (From Patton
Protein
KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010,
B Mosby.)

CHROMOSOMES
pairing with an appropriate codon in the mRNA, which specifies the
sequence of amino acids through tRNA. Human cells can be categorized into gametes (sperm and egg cells) and
The site of actual protein synthesis is in the ribosome, which somatic cells, which include all cells other than gametes. Each somatic
consists of approximately equal parts of protein and ribosomal RNA cell nucleus has 46 chromosomes in 23 pairs (Figure 2-8). These are
(rRNA). During translation, the ribosome first binds to an initiation diploid cells, and the individual’s father and mother each donate one
site on the mRNA sequence and then binds to its surface, so that chromosome per pair. New somatic cells are formed through mitosis
base pairing can occur between tRNA and mRNA. The ribosome and cytokinesis. Gametes are haploid cells: they have only 1 member
then moves along the mRNA sequence, processing each codon and of each chromosome pair, for a total of 23 chromosomes. Haploid cells
translating an amino acid by way of the interaction of mRNA and are formed from diploid cells by meiosis (Figure 2-9).
tRNA. In 22 of the 23 chromosome pairs, the 2 members of each pair are
The ribosome provides an enzyme that catalyzes the formation of virtually identical in microscopic appearance: thus they are homolo-
covalent peptide bonds between the adjacent amino acids, resulting in gous. These 22 chromosome pairs are homologous in both males and
a growing polypeptide. When the ribosome arrives at a termination females and are termed autosomes. The remaining pair of chromo-
signal on the mRNA sequence, translation and polypeptide forma- somes, the sex chromosomes, consists of two homologous X chromo-
tion cease; the mRNA, ribosome, and polypeptide separate from one somes in females and a nonhomologous pair, X and Y, in males.
another; and the polypeptide is released into the cytoplasm to perform Figure 2-10, A, illustrates a metaphase spread, which is a photo-
its required function. graph of the chromosomes as they appear in the nucleus of a somatic
 CHAPTER 2  Genes and Genetic Diseases 39

Small ribosome unit

G G A G Codon

G
A A
G A

U
G Direction of

G
U ribosome
C

U
C U advance
U U A G
G

C
A C
C C
C G C
Large ribosome unit G U G U G
G A C

C
E K S
Cytoplasm E

A
(site of P A

C
translation) Growing
T
Edited polypeptide Anticodon
mRNA transported L chain Peptide bond V (mRNA binding site)
out of nucleus forming
H
E
V Peptide L
M bonds Amino
acids
mRNA
is edited K
Amino acid
tRNA binding site
DNA Nuclear envelope

Nucleus Polyribosome
mRNA
(site of
transcription)

Nuclear pores

FIGURE 2-7  Protein Synthesis. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 7, St
Louis, 2010, Mosby.)

DNA COILED DNA

The structure of DNA The DNA in each cell
is similar to a twisted would be about 6 feet NUCLEUS
ladder, with base pairs long if stretched out. CHROMOSOMES Each nucleus of a
forming the rungs. To fit inside the cell, One chromosome of somatic cell contains CELLS
Genes are composed the DNA is tightly every pair is from 46 chromosomes A nucleus resides in
of DNA segments. coiled. each parent. arranged in 23 pairs. most human cells.

A T
T A
C G
G C

A T

FIGURE 2-8  Molecular Parts to the Whole Somatic Cell.

40 CHAPTER 2  Genes and Genetic Diseases

MITOSIS MEIOSIS
Prophase Chiasma (site of MEIOSIS I
Parent cell
(before chromosome replication) crossing over) Prophase I
Duplicated Tetrad formed
chromosome by synapsis of
(two sister Chromosome Chromosome homologous
chromatids) replication replication chromosomes
2n = 4

Metaphase Metaphase I

Tetrads align
Chromosomes align at the metaphase
at the metaphase plate plate

Anaphase Sister chromatids Homologous chro- Anaphase I

Telophase separate during mosomes separate Telophase I
anaphase during anaphase 1;
sister chromatids Haploid
remain together n=2
2n 2n Daughter cells
of mitosis I
Daughter cells
of mitosis MEIOSIS II

n n n n
Daughter cells of mitosis II
No further chromosomal replication;
sister chromatids separate during anaphase II
FIGURE 2-9  Phases of Meiosis and Comparison to Mitosis (From Jorde LB et al: Medical genetics,
ed 4, St Louis, 2010, Mosby.)

cell during metaphase. (Chromosomes are easiest to visualize during Chromosome Aberrations and Associated Diseases
this stage of mitosis.) In Figure 2-10, B, the chromosomes are arranged Chromosome abnormalities are the leading known cause of mental
according to size, with the homologous chromosomes paired (this is retardation and miscarriage. Estimates indicate that a major chromo-
now typically done by a computer). The 22 autosomes are numbered some aberration occurs in at least 1 in 12 conceptions. Most of these
according to length, with chromosome number 1 the longest and chro- fetuses do not survive to term; about 50% of all recovered first-tri-
mosome 22 the shortest. A karyotype, or karyogram, is an ordered mester spontaneous abortuses have major chromosome aberrations.1
display of chromosomes. Some natural variation in relative chromo- The number of live births affected by these abnormalities is, however,
some length can be expected from person to person, so it is not always significant; approximately 1 in 150 has a major diagnosable chromo-
possible to distinguish each chromosome by its length. Therefore some abnormality.1
the position of the centromere also is used to classify chromosomes
­(Figure 2-11). Polyploidy
The chromosomes in Figure 2-10 were stained with Giemsa stain, Cells with a multiple of the normal number of chromosomes are
resulting in distinctive chromosome bands. These form various pat- euploid cells (Greek eu = good or true). Because normal gametes
terns in the different chromosomes so that each chromosome can are haploid and most normal somatic cells are diploid, they are both
be distinguished easily. Using banding techniques, researchers can euploid forms. When a euploid cell has more than the diploid number
number chromosomes and study individual variations. Missing or of chromosomes, it is said to be a polyploid cell. Several types of body
duplicated portions of chromosomes, which often result in serious tissues, including some liver, bronchial, and epithelial tissues, are nor-
diseases, also are readily identified. More recently, techniques have mally polyploid. A zygote that has three copies of each chromosome,
been devised that permit each chromosome to be visualized with a rather than the usual two, has a form of polyploidy called triploidy.
different color. Tetraploidy, a condition in which euploid cells have 92 chromosomes,
 CHAPTER 2  Genes and Genetic Diseases 41

3
1 2 4 5
Homologous chromosomes Homologous chromosomes

6 7 8 9 10 Kinetochore

Replication
11 12 13 14 15 Cohesin
Centromere proteins
Kinetochores
Y
16 18
17
X

19 20 21 22 Sister chromatids
A 9.2 m B Sister chromatids
FIGURE 2-10  Karyotype of Chromosomes. A, Human karyotype. B, Homologous chromosomes and
sister chromatids. (From Raven PH et al: Biology, ed 8, New York, 2008, McGraw-Hill.)

Spindle fiber apparatus

derived from centriole
Centromere
Chromosome
Chromatids
Plane at which
the cell divides

Short
arm (p)

A B
Long
arm (q)
Centromere

2 5 13
FIGURE 2-11  Structure of Chromosomes. A, Human chromosomes 2, 5, and 13. Each is replicated
and consists of two chromatids. Chromosome 2 is a metacentric chromosome because the centro-
mere is close to the middle; chromosome 5 is submetacentric because the centromere is set off from
the middle; chromosome 13 is acrocentric because the centromere is at or very near the end. B, During
mitosis, the centromere divides and the chromosomes move to opposite poles of the cell. At the time
of centromere division, the chromatids are designated as chromosomes.
42 CHAPTER 2  Genes and Genetic Diseases

has been observed also. Both of these conditions are incompatible Autosomal aneuploidy. Trisomy can occur for any chromosome,
with postnatal survival. Nearly all triploid fetuses are spontaneously but the only forms seen with an appreciable frequency in live births are
aborted or stillborn. The prevalence of triploidy among live births is trisomies of the thirteenth, eighteenth, or twenty-first chromosomes.
approximately 1 in 10,000. Tetraploidy has been found primarily in Fetuses with most other chromosomal trisomies do not survive to
early abortuses, although occasionally affected infants have been born term. Trisomy 16, for example, is the most common trisomy among
alive. Like triploid infants, however, they do not survive. Triploidy and abortuses, but it is not seen in live births.3
tetraploidy are relatively common conditions, accounting for approxi- Partial trisomy, in which only an extra portion of a chromosome
mately 10% of all known miscarriages.2 is present in each cell, can occur also. The consequences of partial tri-
somies are not as severe as those of complete trisomies. Trisomies may
Aneuploidy occur in only some cells of the body. Individuals thus affected are said
A cell that does not contain a multiple of 23 chromosomes is an to be chromosomal mosaics, meaning that the body has two or more
aneuploid cell. A cell containing three copies of one chromosome is different cell lines, each of which has a different karyotype. Mosaics are
said to be trisomic (a condition termed trisomy) and is aneuploid. often formed by early mitotic nondisjunction occurring in one embryo
Monosomy, the presence of only one copy of a given chromosome in cell but not in others.
a diploid cell, is the other common form of aneuploidy. Among the The best-known example of aneuploidy in an autosome is tri-
autosomes, monosomy of any chromosome is lethal, but newborns somy of the twenty-first chromosome, which causes Down syndrome
with trisomy of some chromosomes can survive. This difference illus- (named after J. Langdon Down, who first described the disease in
trates an important principle: in general, loss of chromosome material 1866). Down syndrome is seen in approximately 1 in 800 to 1 in 1000
has more serious consequences than duplication of chromosome material. live births4; its principal features are shown and outlined in Figure 2-13
Aneuploidy of the sex chromosomes is less serious than that of and Table 2-1.
the autosomes. Very little genetic material—only about 40 genes—is The risk of having a child with Down syndrome increases greatly
located on the Y chromosome. For the X chromosome, inactivation of with maternal age. As Figure 2-14 demonstrates, women younger than
extra chromosomes (see p. 51) largely diminishes their effect. A zygote 30 years have a risk ranging from about 1 in 1000 births to 1 in 2000
bearing no X chromosome, however, will not survive. births. The risk begins to rise substantially after 35 years of age, and
Aneuploidy is usually the result of nondisjunction, an error in it reaches 3% to 5% for women older than 45 years. This dramatic
which homologous chromosomes or sister chromatids fail to separate increase in risk is caused by the age of maternal egg cells, which are held
normally during meiosis or mitosis (Figure 2-12). Nondisjunction in an arrested state of prophase I from the time they are formed in the
produces some gametes that have two copies of a given chromosome female embryo until they are shed in ovulation. Thus an egg cell formed
and others that have no copies of the chromosome. When such gam- by a 45-year-old woman is itself 45 years old. This long suspended state
etes unite with normal haploid gametes, the resulting zygote is mono- may allow defects to accumulate in the cellular proteins responsible for
somic or trisomic for that chromosome. Occasionally, a cell can be meiosis, leading to nondisjunction. The risk of Down syndrome, as well
monosomic or trisomic for more than one chromosome. as other trisomies, does not increase with paternal age.4

Parent

Meiosis I Nondisjunction

Meiosis II Nondisjunction

Gametes

Fertilization
with normal
gamete

Offspring

Trisomy Monosomy Monosomy Trisomy

FIGURE 2-12  Nondisjunction. Nondisjunction causes aneuploidy when chromosomes or sister chro-
matids fail to divide properly. (From Jorde LB et al: Medical genetics, ed 4, St Louis, 2010, Mosby.)
 CHAPTER 2  Genes and Genetic Diseases 43

Sex chromosome aneuploidy. The incidence of sex chromosome

aneuploidies is fairly high. Among live births, about 1 in 500 males and
1 in 900 females have a form of sex chromosome aneuploidy.5 Because
these conditions are generally less severe than autosomal aneuploidies,
all forms except complete absence of any X chromosome material
allow at least some individuals to survive.
One of the most common sex chromosome aneuploidies, affect-
ing about 1 in 1000 newborn females, is trisomy X. Instead of two X
chromosomes, these females have three X chromosomes in each cell.
Most of these females have no overt physical abnormalities, although
sterility, menstrual irregularity, or mental retardation is sometimes
seen. Some females have four X chromosomes, and they are more
often mentally retarded. Those with five or more X chromosomes
generally have more severe mental retardation and various physical
defects.
A condition that leads to somewhat more serious problems is the
presence of a single X chromosome and no homologous X or Y chro-
FIGURE 2-13  Child With Down Syndrome. (Courtesy Drs. A. Olney
mosome, so that the individual has a total of 45 chromosomes. The and M. MacDonald, University of Nebraska Medical Center, Omaha.)

TABLE 2-1 CHARACTERISTICS OF VARIOUS CHROMOSOME DISORDERS

DISEASE/DISORDER FEATURES
Down Syndrome
Trisomy of Chromosome 21
IQ Usually ranges from 20 to 70 (mental retardation)
Male/female findings Virtually all males are sterile; some females can reproduce
Face Distinctive: low nasal bridge, epicanthal folds, protruding tongue, low-set ears
Musculoskeletal system Poor muscle tone (hypotonia), short stature
Systemic disorders Congenital heart disease (one third to one half of cases), reduced ability to fight respiratory tract infections, increased
susceptibility to leukemia—overall reduced survival rate; by age 40 years usually develop symptoms similar to those of
Alzheimer disease
Mortality About 76% of fetuses with Down syndrome abort spontaneously or are stillborn; 20% of infants die before age 10 years;
those who live beyond 10 years have life expectancy of about 60 years
Causative factors 97% caused by nondisjunction during formation of one of parent’s gametes or during early embryonic development; 3%
result from translocations; in 95% of cases, nondisjunction occurs when mother’s egg cell is formed; remainder involve
paternal nondisjunction; 1% are mosaics—these have a large number of normal cells, and effects of trisomic cells are
attenuated and symptoms are generally less severe

Turner Syndrome
(45,X) Monosomy of X Chromosome
IQ Not considered retarded, although some impairment of spatial and mathematical reasoning ability is found
Male/female findings Found only in females
Musculoskeletal system Short stature common, characteristic webbing of neck, widely spaced nipples, reduced carrying angle at elbow
Systemic disorders Coarctation (narrowing) of aorta, edema of feet in newborns, usually sterile and have gonadal streaks rather than ovaries;
streaks are sometimes susceptible to cancer
Mortality About 15-20% of spontaneous abortions with chromosome abnormalities have this karyotype, most common single-chromo-
some aberration; highly lethal during gestation, only about 0.5% of these conceptions survive to term
Causative factors 75% inherit X chromosome from mother, thus caused by meiotic error in father; frequency low compared with other sex
chromosome aneuploidies (1:5000 newborn females); 50% have simple monosomy of X chromosome; remainder have
more complex abnormalities; combinations of 45X cells with XX or XY cells common

Klinefelter Syndrome
(47,XXY) XXY Condition
IQ Moderate degree of mental impairment may be present
Male/female findings Have a male appearance but usually sterile; 50% develop female-like breasts (gynecomastia); occurs in 1:1000 male births
Face Voice somewhat high pitched
Systemic disorders Sparse body hair, sterile, testicles small
Causative factors 50% of cases the result of nondisjunction of X chromosomes in mother, frequency rises with increasing maternal age; also
involves XXY and XXXY karyotypes with degree of physical and mental impairment increasing with each added X chromo-
some; mosaicism fairly common with most prevalent combination of XXY and XY cells
44 CHAPTER 2  Genes and Genetic Diseases

Incidence of Down syndrome

per 1000 live births

100

30
20
10

3
2
1

0.3
20 25 30 35 40 45 50
Maternal age (yr) A

FIGURE 2-14  Down Syndrome Increases With Maternal Age.

Rate is per 1000 live births related to maternal age.

1 2 3 4 5

karyotype is usually designated 45,X, and it causes a set of symptoms

X 6 7 8 9 10 11 12
known as Turner syndrome (Figure 2-15; see Table 2-1).
Individuals with at least two X chromosomes and one Y chromo-
some in each cell (47,XXY karyotype) have a disorder known as Kline-
felter syndrome (Figure 2-16; see Table 2-1). 13 14 15 16 17 18 19 20
Abnormalities of Chromosome Structure
In addition to the loss or gain of whole chromosomes, parts of chro-
mosomes can be lost or duplicated as gametes are formed, and the Y 21 22
arrangement of genes on chromosomes can be altered. Unlike aneu-
ploidy and polyploidy, these changes sometimes have no serious con-
sequences for an individual’s health. Some of them can even go entirely B
unnoticed, especially when very small pieces of chromosomes are FIGURE 2-15  Turner Syndrome. A, A sex chromosome is miss-
involved. Nevertheless, abnormalities of chromosome structure can ing, and the person’s chromosomes are 45,X. Characteristic signs
also produce serious disease in individuals or their offspring. are short stature, female genitalia, webbed neck, shieldlike chest
During meiosis and mitosis, chromosomes usually maintain their with underdeveloped breasts and widely spaced nipples, and
structural integrity, but chromosome breakage occasionally occurs. imperfectly developed ovaries. B, As this karyotype shows, Turner
Mechanisms exist to “heal” these breaks and usually repair them per- syndrome results from monosomy of sex chromosomes (genotype
fectly with no damage to the daughter cell. However, some breaks XO). (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 7,
remain or heal in a way that alters the chromosome’s structure. The St Louis, 2010, Mosby.)
risk of chromosome breakage increases when harmful agents called
clastogens, such as ionizing radiation, viral infections, or some chemi-
cals, are present.
Deletions. Broken chromosomes and lost DNA cause deletions Other symptoms include low birth weight, severe mental retardation,
(Figure 2-17). Usually, a gamete with a deletion unites with a nor- microcephaly (smaller than normal head size), and heart defects. The
mal gamete to form a zygote. The zygote thus has one chromosome disease is caused by a deletion of part of the short arm of chromo-
with the normal complement of genes and one with some missing some 5.
genes. Because many genes can be lost in a deletion, serious conse- Duplications. A deficiency of genetic material is more harmful than
quences result even though one normal chromosome is present. an excess, so duplications usually have less serious consequences than
The most often cited example of a disease caused by a chromosomal deletions. For example, a deletion of a region of chromosome 5 causes
deletion is the cri du chat syndrome. The term literally means “cry cri du chat syndrome, but a duplication of the same region causes
of the cat” and describes the characteristic cry of the affected child. mental retardation but less serious physical defects.
 CHAPTER 2  Genes and Genetic Diseases 45

Inversions. An inversion occurs when two breaks take place on a

chromosome, followed by the reinsertion of the missing fragment at its
original site but in inverted order. Therefore a chromosome symbol-
ized as ABCDEFG might become ABEDCFG after an inversion.
Unlike deletions and duplications, no loss or gain of genetic mate-
rial occurs, so inversions are “balanced” alterations of chromosome
structure, and they often have no apparent physical effect. Some genes
are influenced by neighboring genes, however, and this position effect,
a change in a gene’s expression caused by its position, sometimes
results in physical defects in these persons. Inversions can cause serious
problems in the offspring of individuals carrying the inversion because
the inversion can lead to duplications and deletions in the chromo-
somes transmitted to the offspring.
Translocations. The interchange of genetic material between non-
homologous chromosomes is called translocation. A reciprocal trans-
location occurs when breaks take place in two different chromosomes
and the material is exchanged (Figure 2-18, A). As with inversions, the
carrier of a reciprocal translocation is usually normal, but his or her
offspring can have duplications and deletions.
A second and clinically more important type of translocation is
robertsonian translocation. In this disorder, the long arms of two
nonhomologous chromosomes fuse at the centromere, forming a
single chromosome. Robertsonian translocations are confined to
chromosomes 13, 14, 15, 21, and 22 because the short arms of these
FIGURE 2-16  Klinefelter Syndrome. This young man exhibits chromosomes are very small and contain no essential genetic mate-
many characteristics of Klinefelter syndrome: small testes, some rial. The short arms are usually lost during subsequent cell divisions.
development of the breasts, sparse body hair, and long limbs. Because the carriers of robertsonian translocations lose no impor-
This syndrome results from the presence of two or more X chro- tant genetic material, they are normal, although they have only 45
mosomes with one Y chromosome (genotypes XXY or XXXY, for chromosomes in each cell. Their offspring, however, may have seri-
example). (From Patton KT, Thibodeau GA: Anatomy & physiology, ous monosomies or trisomies. For example, a common robertsonian
ed 7, St Louis, 2010, Mosby.) translocation involves the fusion of the long arms of chromosomes 21
and 14. An offspring who inherits a gamete carrying the fused chro-
mosome can receive an extra copy of the long arm of chromosome
21 and develop Down syndrome. Robertsonian translocations are
A B C D E F G H I J K L M N O P Q R
responsible for approximately 3% to 5% of Down syndrome cases.
Parents who carry a robertsonian translocation involving chromo-
Breaks occur Lost
some 21 have an increased risk for producing multiple offspring with
A B C D E F G H I J K L M P Q R
Down syndrome.
A Deletion

A B C D E F G H I J K L M N O P Q R
Normal crossing over Reciprocal Pairing of
Normal translocation meiosis I
a b c d e f g h i j k l m n o p q r

A B C D E F G H I J K L m n o p q r
and
a b c d e f g h i j k l M N O P Q R
B A B

A B C D E F G H I J K L M N O P Q R Normal Balanced Unbalanced

Unequal crossover
a b c d e f g h i j k l m n o p q r
Duplication for M
A B C D E F G H I J K L M m n o p q r
and
a b c d e f g h i j k l N O P Q R C
Deletion for M
Gametes
C
FIGURE 2-18  Normal and Abnormal Chromosome Translo-
FIGURE 2-17  Abnormalities of Chromosome Structure. cation. A, Normal chromosomes and reciprocal translocation.
A, Deletion occurs when a chromosome segment is lost. B, Normal B, Pairing at meiosis. C, Consequences of translocation in gametes;
crossing over. C, The generation of duplication and deletion through unbalanced gametes result in zygotes that are partially trisomic and
unequal crossing over. partially monosomic and consequently develop abnormally.
46 CHAPTER 2  Genes and Genetic Diseases

Fragile sites. A number of areas on chromosomes develop dis-

tinctive breaks and gaps (observable microscopically) when the cells Phenotype and Genotype
are cultured. Most of these fragile sites do not appear to be related The composition of genes at a given locus is known as the genotype. The
to disease. However, one fragile site, located on the long arm of the outward appearance of an individual, which is the result of both geno-
X chromosome, is associated with fragile X syndrome. The most type and environment, is the phenotype. For example, an infant who is
important feature of this syndrome is mental retardation. With a born with an inability to metabolize the amino acid phenylalanine has
relatively high population prevalence (affecting approximately 1 in the single-gene disorder known as phenylketonuria (PKU) and thus has
4000 males and 1 in 8000 females), fragile X syndrome is the sec- the PKU genotype. If the condition is left untreated, abnormal metabo-
ond most common genetic cause of mental retardation (after Down lites of phenylalanine will begin to accumulate in the infant’s brain and
syndrome). irreversible mental retardation will occur. Mental retardation is thus
In fragile X syndrome, females who inherit the mutation do not one aspect of the PKU phenotype. By imposing dietary restrictions to
necessarily express the disease condition but they can pass it on to exclude food that contains phenylalanine, however, retardation can be
descendants who do express it. Ordinarily, a male who inherits a dis- prevented. Foods high in phenylalanine include proteins found in milk,
ease gene on the X chromosome expresses the condition, because he dairy products, meat, fish, chicken, eggs, beans, and nuts. Although the
has only one X chromosome. An uncommon feature of this disease child still has the PKU genotype, a modification of the environment (in
is that about one third of carrier females are affected, although less this case, the child’s diet) produces an outwardly normal phenotype.
severely than males. Unaffected transmitting males have been shown
to have more than about 50 repeated DNA sequences near the begin-
Normal female
ning of the fragile X gene. These “repeats” consist of CGG sequences
duplicated many times. Affected males have 230 or more.6 Increased
Normal male
numbers of these repeated sequences in successive generations can lead
to expression of fragile X syndrome. More than a dozen other genetic Sex not specified
diseases, including Huntington disease and myotonic dystrophy, also
are caused by this mechanism.7
Single bar indicates mating

I
4 QUICK CHECK 2-1
Normal parents and normal offspring,
two girls and a boy, in birth order
1. What is the major composition of DNA? II indicated by the numbers; I and II
2. Define the terms mutation, autosomes, and sex chromosomes. indicate generations
1 2 3
3. What is the significance of mRNA?
4. What is the significance of chromosomal translocation?
Single parent as presented means
partner is normal or of no significance to
the analysis

ELEMENTS OF FORMAL GENETICS Double bar indicates a consanguineous

The mechanisms by which an individual’s set of paired chromosomes mating (mating between close relatives)
produces traits are the principles of genetic inheritance. Mendel’s work
with garden peas first defined these principles. Later geneticists have Fraternal twins (not identical)
refined Mendel’s work to explain patterns of inheritance for traits and
diseases that appear in families.
Analysis of traits that occur with defined, predictable patterns has Identical twins
helped geneticists link the pieces of the human gene map. Current
research focuses on determining the protein products of each gene and
understanding the way they contribute to disease. Eventually, diseases
and defects caused by single genes can be traced and therapies to pre- 2 and 6 Multiple individuals of each sex
vent and treat such diseases can be developed.
Traits caused by single genes are called mendelian traits (after and Darkened square or circle means
Gregor Mendel). Each gene occupies a position along a chromosome affected individual; arrow (when present)
known as a locus. The genes at a particular locus can have different indicates the affected individual is
the propositus (proband)
forms (i.e., they can be composed of different nucleotide sequences)
called alleles. A locus that has two or more alleles that each occur with
an appreciable frequency in a population is said to be polymorphic (or Carrier—not likely to manifest disease
a polymorphism).
Because humans are diploid organisms, each chromosome is rep- and Dead
resented twice, with one member of the chromosome pair contributed
by the father and one by the mother. At a given locus, an individual has Stillbirth at 29 weeks gestation
one allele whose origin is paternal and one whose origin is maternal. SB
When the two alleles are identical, the individual is homozygous at 29 wk
that locus. When the alleles are not identical, the individual is hetero- FIGURE 2-19  Symbols Commonly Used in Pedigrees. (From
zygous at that locus. Jorde LB et al: Medical genetics, ed 4, St Louis, 2010, Mosby.)
 CHAPTER 2  Genes and Genetic Diseases 47

the mid-nineteenth century by performing breeding experiments with

Dominance and Recessiveness garden peas, even though he had no knowledge of chromosomes. Early
In many loci, the effects of one allele mask those of another when the twentieth-century geneticists found that chromosomal behavior essen-
two are found together in a heterozygote. The allele whose effects are tially corresponds to Mendel’s laws, which now form the basis for the
observable is said to be dominant. The allele whose effects are hidden chromosome theory of inheritance.
is said to be recessive (from the Latin root for “hiding”). Tradition- The known single-gene diseases can be classified into four major
ally, for loci having two alleles, the dominant allele is denoted by an modes of inheritance: autosomal dominant, autosomal recessive,
uppercase letter and the recessive allele is denoted by a lowercase letter. X-linked dominant, and X-linked recessive. The first two types involve
When one allele is dominant over another, the heterozygote genotype genes known to occur on the 22 pairs of autosomes. The last two types
Aa has the same phenotype as the dominant homozygote AA. For the occur on the X chromosome; very few disease genes occur on the Y
recessive allele to be expressed, it must exist in the homozygote form, chromosome.
aa. When the heterozygote is distinguishable from both homozygotes, The pedigree chart summarizes family relationships and shows
the locus is said to exhibit codominance. which members of a family are affected by a genetic disease (Figure
A carrier is an individual who has a disease gene but is phenotypically 2-19). Generally, the pedigree begins with one individual in the family,
normal. Many genes for a recessive disease occur in heterozygotes who the proband. This individual is usually the first person in the family
carry one copy of the gene but do not express the disease. When reces- diagnosed or seen in a clinic.
sive genes are lethal in the homozygous state, they are eliminated from
the population when they occur in homozygotes. By “hiding” in carriers, Autosomal Dominant Inheritance
however, recessive genes for diseases are passed on to the next generation. Characteristics of Pedigrees
Diseases caused by autosomal dominant genes are rare, with the most
common occurring in fewer than 1 in 500 individuals. Therefore it
TRANSMISSION OF GENETIC DISEASES is uncommon for two individuals that are both affected by the same
The pattern in which a genetic disease is inherited through generations autosomal dominant disease to produce offspring together. Figure
is termed the mode of inheritance. Knowing the mode of inheritance 2-20, A, illustrates this unusual pattern. Affected offspring are usually
can reveal much about the disease gene itself, and members of families produced by the union of a normal parent with an affected hetero-
with the disease can be given reliable genetic counseling. zygous parent. The Punnett square in Figure 2-20, B, illustrates this
Gregor Mendel systematically studied modes of inheritance and mating. The affected parent can pass either a disease gene or a normal
formulated two basic laws of inheritance. His principle of segrega- gene to the next generation. On average, half the children will be het-
tion states that homologous genes separate from one another during erozygous and will express the disease, and half will be normal.
reproduction and that each reproductive cell carries only one homolo- The pedigree in Figure 2-21 shows the transmission of an autoso-
gous gene. Mendel’s second law, the principle of independent assort- mal dominant gene. Several important characteristics of this pedigree
ment, states that the hereditary transmission of one gene does not support the conclusion that the trait is caused by an autosomal domi-
affect the transmission of another. Mendel discovered these laws in nant gene:
1. The two sexes exhibit the trait in approximately equal proportions,
and males and females are equally likely to transmit the trait to their
Affected parent
offspring.
D d 2. No generations are skipped. If an individual has the trait, one parent
must also have it. If neither parent has the trait, none of the children
DD have it (with the exception of new mutations, as discussed later).
Dd
D Homozygous affected
Heterozygous affected 3. Affected heterozygous individuals transmit the trait to approxi-
(usually rare)
Affected mately half their children, and because gamete transmission is sub-
parent ject to chance fluctuations, all or none of the children of an affected
Dd dd parent may have the trait. When large numbers of matings of this
d
Heterozygous affected Homozygous normal type are studied, however, the proportion of affected children
A closely approaches one half.

Normal parent
d d

Dd Dd Aa aa
D Heterozygous affected Heterozygous affected
Affected
parent
dd dd aa aa Aa aa
d Homozygous normal Homozygous normal
B
FIGURE 2-20  Punnett Square and Autosomal Dominant Traits. aa aa aa Aa aa Aa
A, Punnett square for the mating of two individuals with an auto- FIGURE 2-21  Pedigree Illustrating the Inheritance Pattern
somal dominant gene. Here both parents are affected by the trait.  of Postaxial Polydactyly, an Autosomal Dominant Disorder.
B, Punnett square for the mating of a normal individual with a carrier Affected individuals are represented by shading. (From Jorde LB
for an autosomal dominant gene. et al: Medical genetics, ed 4, St Louis, 2010, Mosby.)
48 CHAPTER 2  Genes and Genetic Diseases

before reaching reproductive age and the occurrence of the disease-

Recurrence Risks causing allele in the population would be much lower. An individual
Parents at risk for producing children with a genetic disease nearly whose parent has the disease has a 50% chance of developing it during
always ask the question, “What is the chance that our child will have middle age. He or she is thus confronted with a torturous question:
this disease?” The probability that an individual will develop a genetic Should I have children, knowing that there is a 50:50 chance that I may
disease is termed the recurrence risk. When one parent is affected by have this disease-causing gene and will pass it to half of my children?
an autosomal dominant disease (and is a heterozygote) and the other is A DNA test can now be used to determine whether an individual has
unaffected, the recurrence risk for each child is one half. inherited the mutation that causes Huntington disease.
An important principle is that each birth is an independent event,
much like a coin toss. Thus, even though parents may have already had Penetrance and Expressivity
a child with the disease, their recurrence risk remains one half. Even The penetrance of a trait is the percentage of individuals with a spe-
if they have produced several children, all affected (or all unaffected) cific genotype who also exhibit the expected phenotype. Incomplete
by the disease, the law of independence dictates that the probability penetrance means that individuals who have the disease-causing gen-
that their next child will have the disease is still one half. Parents’ mis- otype may not exhibit the disease phenotype at all, even though the
understanding of this principle is a common problem encountered in genotype and the associated disease may be transmitted to the next
genetic counseling. generation. A pedigree illustrating the transmission of an autosomal
If a child is born with an autosomal dominant disease and there is dominant mutation with incomplete penetrance is given in Figure
no history of the disease in the family, the child is probably the product 2-22. Retinoblastoma, the most common malignant eye tumor affect-
of a new mutation. The gene transmitted by one of the parents has thus ing children, typically exhibits incomplete penetrance. About 10% of
undergone a mutation from a normal to a disease-causing allele. The the individuals who are obligate carriers of the disease-causing muta-
genes at this locus in most of the parent’s other germ cells are still nor- tion (i.e., those who have an affected parent and affected children and
mal. In this situation the recurrence risk for the parent’s subsequent therefore must themselves carry the mutation) do not have the disease.
offspring is not greater than that of the general population. The off- The penetrance of the disease-causing genotype is then said to be 90%.
spring of the affected child, however, will have a recurrence risk of one The gene responsible for retinoblastoma has been mapped to the
half. Because these diseases often reduce the potential for reproduc- long arm of chromosome 13, and its DNA sequence has been stud-
tion, many autosomal dominant diseases result from new mutations. ied extensively. This gene is known as a tumor-suppressor gene: the
Occasionally, two or more offspring have symptoms of an autoso- normal function of its protein product is to regulate the cell cycle so
mal dominant disease when there is no family history of the disease. that cells do not divide uncontrollably. When the protein is altered
Because mutation is a rare event, it is unlikely that this disease would because of a genetic mutation, its tumor-suppressing capacity is lost
be a result of multiple mutations in the same family. The mechanism and a tumor can form9 (see Chapters 9 and 16).
most likely responsible is termed germline mosaicism. During the
embryonic development of one of the parents, a mutation occurred
that affected all or part of the germline but few or none of the somatic
cells of the embryo. Thus the parent carries the mutation in his or her
germline but does not actually express the disease. As a result, the unaf-
fected parent can transmit the mutation to multiple offspring. This
phenomenon, although relatively rare, can have significant effects on
recurrence risks.8

Delayed Age of Onset

One of the best-known autosomal dominant diseases is Huntington
disease, a neurologic disorder whose main features are progressive
dementia and increasingly uncontrollable limb movements (chorea;
discussed further in Chapter 14). A key feature of this disease is its
delayed age of onset: symptoms usually are not seen until 40 years of
age or later. Thus those who develop the disease often have borne chil-
dren before they are aware that they have the disease-causing mutation.
If the disease was present at birth, nearly all affected persons would die

II

FIGURE 2-23  Neurofibromatosis. Tumors. The most common is

III sessile or pedunculated. Early tumors are soft, dome-shaped pap-
FIGURE 2-22  Pedigree for Retinoblastoma Showing Incom- ules or nodules that have a distinctive violaceous hue. Most are
plete Penetrance. Female with marked arrow in line II must be benign. (From Habif et  al: Skin disease: diagnosis and treatment,
heterozygous, but she does not express the trait. ed 2, St Louis, 2005, Mosby.)
 CHAPTER 2  Genes and Genetic Diseases 49

Expressivity is the extent of variation in phenotype associated (premature termination of translation) usually produces a more severe
with a particular genotype. If the expressivity of a disease is variable, form of this blood coagulation disorder.
penetrance may be complete but the severity of the disease can vary
greatly. A good example of variable expressivity in an autosomal domi- Epigenetics and Genomic Imprinting
nant disease is neurofibromatosis type 1, or von Recklinghausen dis- Although this chapter focuses on DNA sequence variation and its con-
ease. The gene that causes neurofibromatosis has been mapped to the sequence for disease, there is increasing evidence that the same DNA
long arm of chromosome 17, and studies of its DNA sequence indicate sequence can produce dramatically different phenotypes because of
that, like the retinoblastoma gene, it is a tumor-suppressor gene.10 The chemical modifications that alter the expression of genes (these modi-
expression of this disease varies from a few harmless café-au-lait (light fications are collectively termed epigenetic). An important example of
brown) spots on the skin to numerous neurofibromas, scoliosis, sei- such a modification is DNA methylation, the attachment of a methyl
zures, gliomas, neuromas, malignant peripheral nerve sheath tumors, group to a cytosine base that is followed by a guanine base in the DNA
hypertension, and learning disorders (Figure 2-23). sequence (Figure 2-24). These sequences, which are common near
Several factors cause variable expressivity. Genes at other loci some- many genes, are termed CpG islands. When the CpG islands located
times modify the expression of a disease-causing gene. Environmental near a gene become heavily methylated, the gene is less likely to be tran-
factors can influence expression of a disease-causing gene. Finally, dif- scribed into mRNA. In other words, the gene becomes transcriptionally
ferent mutations at a locus can cause variation in severity. For example, inactive. One study showed that identical (monozygotic) twins accu-
a mutation that alters only one amino acid of the factor VIII gene usu- mulate different methylation patterns in the DNA sequences of their
ally produces a mild form of hemophilia A, whereas a “stop” codon somatic cells as they age, causing increasing numbers of phenotypic

DNA strands Chromatin coils

Histone Chromosome

DNA Coiling
DNA  Nucleosome
Histones

Nucleosome

Methylation

Chemical modification by methylation

NH2 NH2

C C
N C N N C CH3 Methylation

C CH Enzyme C CH
O N O N

H H

FIGURE 2-24  Epigenetic Modifications. Because DNA is a long molecule, it needs packaging to fit in
the tiny nucleus. Packaging involves coiling of the DNA in a “left-handed” spiral around spools, made
of four pairs of proteins individually known as histones and collectively as the histone octamer. The
entire spool is called a nucleosome (also see Figure 1-2). Nucleosomes are organized into chromatin,
the repeating building blocks of a chromosome. Histone modifications are correlated with methylation,
are reversible, and occur at multiple sites. Methylation occurs at the 5 position of cytosine and provides
a “footprint” or signature as a unique epigenetic alteration (red). When genes are expressed, chromatin
is open or active; however, when chromatin is condensed because of methylation and histone modifi-
cation, genes are inactivated.
50 CHAPTER 2  Genes and Genetic Diseases

differences.11 Intriguingly, twins with more differences in their life- Figure 2-25 shows a pedigree for cystic fibrosis. The gene respon-
styles (e.g., smoking versus nonsmoking) accumulated larger numbers sible for cystic fibrosis encodes a chloride ion channel in some epithe-
of differences in their methylation patterns. The twins, despite having lial cells. Defective transport of chloride ions leads to a salt imbalance
identical DNA sequences, become more and more different as a result that results in secretions of abnormally thick, dehydrated mucus. Some
of epigenetic changes, which in turn affect the expression of genes. digestive organs, particularly the pancreas, become obstructed, causing
Epigenetic alteration of gene activity can have important disease malnutrition, and the lungs become clogged with mucus, making them
consequences. For example, a major cause of one form of inherited highly susceptible to bacterial infections. Death from lung disease or
colon cancer (termed hereditary nonpolyposis colorectal cancer heart failure occurs before 40 years of age in about one half of persons
[HNPCC]) is the methylation of a gene whose protein product repairs with cystic fibrosis.
damaged DNA. When this gene becomes inactive, damaged DNA The important criteria for discerning autosomal recessive inheri-
accumulates, eventually resulting in colon tumors. Epigenetic changes tance include the following:
are also discussed in Chapters 9 and 10. 1. Males and females are affected in equal proportions.
Approximately 100 human genes are thought to be methylated dif- 2. Consanguinity (marriage between related individuals) is some-
ferently, depending on which parent transmits the gene. This epigen- times present, especially for rare recessive diseases.
etic modification, characterized by methylation and other changes, is 3. The disease may be seen in siblings of affected individuals but usu-
termed genomic imprinting. For each of these genes, one of the par- ally not in their parents.
ents imprints the gene (inactivates it) when it is transmitted to the off- 4. On average, one fourth of the offspring of carrier parents will be
spring. An example is the insulin-like growth factor 2 gene (IGF2) on affected.
chromosome 11, which is transmitted by both parents, but the copy
inherited from the mother is normally methylated and inactivated Recurrence Risks
(imprinted). Thus only one copy of IGF2 is active in normal individu- In most cases of recessive disease, both of the parents of affected indi-
als. However, the maternal imprint is occasionally lost, resulting in two viduals are heterozygous carriers. On average, one fourth of their off-
active copies of IGF2. This causes excess fetal growth and a condition spring will be normal homozygotes, one half will be phenotypically
known as Beckwith-Weidemann syndrome. normal carrier heterozygotes, and one fourth will be homozygotes with
A second example of genomic imprinting is a deletion of part of the the disease (Figure 2-26). Thus the recurrence risk for the offspring of
long arm of chromosome 15 (15q11-q13), which, when inherited from carrier parents is 25%. However, in any given family, there are chance
the father, causes the offspring to manifest a disease known as Prader- fluctuations.
Willi syndrome (short stature, obesity, hypogonadism). When the same If two parents have a recessive disease, they each must be homo-
deletion is inherited from the mother, the offspring develop Angelman zygous for the disease. Therefore all their children also must be
syndrome (mental retardation, seizures, ataxic gait). The two different affected. This distinguishes recessive from dominant inheritance
phenotypes reflect the fact that different genes are normally active in because two parents both affected by a dominant gene are nearly
the maternally and paternally transmitted copies of this region of chro- always both heterozygotes and thus one fourth of their children will
mosome 15. be unaffected.
Because carrier parents usually are unaware that they both carry
Autosomal Recessive Inheritance the same recessive allele, they often produce an affected child before
Characteristics of Pedigrees becoming aware of their condition. Carrier detection tests can identify
Like autosomal dominant diseases, diseases caused by autosomal reces- heterozygotes by measuring the reduced amount of a critical enzyme.
sive genes are rare in populations, although there can be numerous This enzyme is totally lacking in a homozygous recessive individual,
carriers. The most common lethal recessive disease in white children, but a carrier, although phenotypically normal, will typically have half
cystic fibrosis, occurs in about 1 in 2500 births. Approximately 1 in 25 the normal enzyme level. Increasingly, carriers are now detected by
whites carries a copy of the gene for cystic fibrosis (see Chapter 27). direct examination of their DNA to reveal a mutation. Some recessive
Carriers are phenotypically normal. Some autosomal recessive diseases diseases for which carrier detection tests are now available are PKU,
are characterized by delayed age of onset, incomplete penetrance, and sickle cell disease, cystic fibrosis, Tay-Sachs disease, hemochromatosis,
variable expressivity. and galactosemia.

Consanguinity
Consanguinity and inbreeding are related concepts. Consanguin-
I
ity refers to the mating of two related individuals, and the offspring

II D d

DD Dd
III D Homozygous Heterozygous
normal carrier

Dd dd
IV
d Heterozygous Homozygous
FIGURE 2-25  Pedigree for Cystic Fibrosis. Cystic fibrosis is an carrier affected
autosomal recessive disorder. The double bar denotes a consan-
guineous mating. Because cystic fibrosis is relatively common in FIGURE 2-26  Punnett Square for the Mating of Heterozygous
European populations, most cases do not involve consanguinity. Carriers Typical of Most Cases of Recessive Disease.
 CHAPTER 2  Genes and Genetic Diseases 51

of such matings are said to be inbred. Consanguinity is sometimes an chromatin bodies, termed Barr bodies (after Barr and Bertram, who
important characteristic of pedigrees for recessive diseases because discovered them in the late 1940s). Normal females have one Barr body
relatives share a certain proportion of genes received from a common in each somatic cell, whereas normal males have no Barr bodies.
ancestor. The proportion of shared genes depends on the closeness of X inactivation occurs very early in embryonic development—approx-
their biologic relationship. Consanguineous matings produce a signifi- imately 7 to 14 days after fertilization. In each somatic cell, one of the two
cant increase in recessive disorders and are seen most often in pedi- X chromosomes is inactivated. In some cells, the inactivated X chromo-
grees for rare recessive disorders. some is the one contributed by the father; in other cells it is the one con-
tributed by the mother. Once the X chromosome has been inactivated in
X-Linked Inheritance a cell, all the descendants of that cell have the same chromosome inac-
Some genetic conditions are caused by mutations in genes located tivated (Figure 2-27). Thus inactivation is said to be random but fixed.
on the sex chromosomes, and this mode of inheritance is termed sex Some individuals do not have the normal number of X chromo-
linked. Only a few diseases are known to be inherited as X-linked dom- somes in their somatic cells. For example, males with Klinefelter syn-
inant or Y chromosome traits, so only the more common X-linked drome typically have two X chromosomes and one Y chromosome.
recessive diseases are discussed here. These males do have one Barr body in each cell. Females whose cell
Because females receive two X chromosomes, one from the father and nuclei have three X chromosomes have two Barr bodies in each cell,
one from the mother, they can be homozygous for a disease allele at a and females whose cell nuclei have four X chromosomes have three
given locus, homozygous for the normal allele at the locus, or heterozy- Barr bodies in each cell. Females with Turner syndrome have only one
gous. Males, having only one X chromosome, are hemizygous for genes X chromosome and no Barr bodies. Thus the number of Barr bodies is
on this chromosome. If a male inherits a recessive disease gene on the X always one less than the number of X chromosomes in the cell. All but
chromosome, he will be affected by the disease because the Y chromosome one X chromosome are always inactivated.
does not carry a normal allele to counteract the effects of the disease gene. Persons with abnormal numbers of X chromosomes, such as those
Because a single copy of an X-linked recessive gene will cause disease in a with Turner syndrome or Klinefelter syndrome, are not physically nor-
male, whereas two copies are required for disease expression in females, mal. This situation presents a puzzle because they presumably have
more males are affected by X-linked recessive diseases than are females. only one active X chromosome, the same as individuals with normal
numbers of chromosomes. This is probably because the distal tips of
X Inactivation the short and long arms of the X chromosome, as well as several other
In the late 1950s Mary Lyon proposed that one X chromosome in the regions on the chromosome arm, are not inactivated. Thus X inactiva-
somatic cells of females is permanently inactivated, a process termed tion is also known to be incomplete.
X inactivation.12,13 This proposal, the Lyon hypothesis, explains why Methylation of X chromosome DNA appears to be involved
most gene products coded by the X chromosome are present in equal in X inactivation. Inactive X chromosomes can be at least partially
amounts in males and females, even though males have only one X ­reactivated in  vitro by administering 5-azacytidine, a demethylating
chromosome and females have two X chromosomes. This phenomenon agent.
is called dosage compensation. The inactivated X chromosomes are
observable in many interphase cells as highly condensed intranuclear Sex Determination
The process of sexual differentiation, in which the embryonic gonads
become either testes or ovaries, begins during the sixth week of gesta-
m
tion. A key principle of mammalian sex determination is that one copy
Zygote p
of the Y chromosome is sufficient to initiate the process of gonadal
differentiation that produces a male fetus. The number of X chromo-
Early cell
somes does not alter this process. For example, an individual with two
m m
division p p X chromosomes and one Y chromosome in each cell is still phenotypi-
cally a male. Thus the Y chromosome contains a gene that begins the
Barr body process of male gonadal development.
X-Chromosome
m p m p
inactivation This gene, termed SRY (for “sex-determining region on the Y”),
has been located on the short arm of the Y chromosome.14 The SRY
gene lies just outside the pseudoautosomal region (Figure 2-28),
m m p p m m p p
which pairs with the distal tip of the short arm of the X chromosome
during meiosis and exchanges genetic material with it (crossover), just
as autosomes do. The DNA sequences of these regions on the X and
Y chromosomes are highly similar. The rest of the X and Y chromo-
Mosaic somatic somes, however, do not exchange material and are not similar in DNA
cells in female sequence.
Other genes that contribute to male differentiation are located on
other chromosomes. Thus SRY triggers the action of genes on other
chromosomes. This concept is supported by the fact that the SRY
FIGURE 2-27  The X Inactivation Process. The maternal (m) and
protein product is similar to other proteins known to regulate gene
paternal (p) X chromosomes are both active in the zygote and in
early embryonic cells. X inactivation then takes place, resulting in expression.
cells having either an active paternal X or an active maternal X. Occasionally, the crossover between X and Y occurs closer to the
Females are thus X chromosome mosaics, as shown in the tissue centromere than it should, placing the SRY gene on the X chromosome
sample at the bottom of the page. (From Jorde LB et al: Medical after crossover. This variation can result in offspring with an appar-
genetics, ed 4, St Louis, 2010, Mosby.) ently normal XX karyotype but a male phenotype. Such XX males are
52 CHAPTER 2  Genes and Genetic Diseases

The following are important principles of X-linked recessive

Xp Yp inheritance:
SRY
1. The trait is seen much more often in males than in females.
Pseudo- 2. Because a father can give a son only a Y chromosome, the trait is
autosomal never transmitted from father to son.
region Normal 3. The gene can be transmitted through a series of carrier females,
Xp Yp crossover causing the appearance of one or more “skipped generations.”
4. The gene is passed from an affected father to all his daughters, who,
SRY
as phenotypically normal carriers, transmit it to approximately half
their sons, who are affected.
Gametes Normal Normal A relatively common X-linked recessive disorder is Duchenne
muscular dystrophy (DMD), which affects approximately 1 in 3500
males. As its name suggests, this disorder is characterized by progres-
Xp Yp sive muscle degeneration. Affected individuals usually are unable to
Crossover walk by age 10 or 12 years. The disease affects the heart and respira-
SRY tory muscles, and death caused by respiratory or cardiac failure usu-
occurs below
SRY ally occurs before 20 years of age. Identification of the disease-causing
gene (on the short arm of the X chromosome) has greatly increased
our understanding of the disorder.15 The DMD gene is the largest gene
ever found in humans, spanning more than 2 million DNA bases. It
encodes a previously undiscovered muscle protein, termed dystro-
phin. Extensive study of dystrophin indicates that it plays an essential
XY role in maintaining the structural integrity of muscle cells: it may also
XX
help to regulate the activity of membrane proteins. When dystrophin
is absent, as in DMD, the cell cannot survive, and muscle deterioration
ensues. Most cases of DMD are caused by frameshift deletions of por-
FIGURE 2-28  Distal Short Arms of the X and Y Chromosomes
tions of the DMD gene and thus involve alterations of all the amino
Exchange Material During Meiosis in the Male. The region of the
Y chromosome in which this crossover occurs is called the pseu-
acids encoded by the DNA following the deletion.
doautosomal region. The SRY gene, which triggers the process
leading to male gonadal differentiation, is located just outside the
Recurrence Risks
pseudoautosomal region. Occasionally, the crossover occurs on the The most common mating type involving X-linked recessive genes is
centromeric side of the SRY gene, causing it to lie on an X chromo- the combination of a carrier female and a normal male (Figure 2-29,
some instead of a Y chromosome. An offspring receiving this X A). On average, the carrier mother will transmit the disease-causing
chromosome will be an XX male, and an offspring receiving the Y allele to half her sons (who are affected) and half her daughters (who
chromosome will be an XY female. are carriers).
The other common mating type is an affected father and a nor-
mal mother (Figure 2-29, B). In this situation, all the sons will be nor-
seen in about 1 in 20,000 live births and resemble males with Klinefel- mal because the father can transmit only his Y chromosome to them.
ter syndrome. Conversely, it is possible to inherit a Y chromosome that Because all the daughters must receive the father’s X chromosome,
has lost the SRY gene (the result of either a crossover error or a deletion they will all be heterozygous carriers. Because the sons must receive
of the gene). This situation produces an XY female. Such females have the Y chromosome and the daughters must receive the X chromosome
gonadal streaks rather than ovaries and have poorly developed second- with the disease gene, these are precise outcomes and not probabilities.
ary sex characteristics. None of the children will be affected.
The final mating pattern, less common than the other two, involves
an affected father and a carrier mother (see Figure 2-29, C). With this
4 QUICK CHECK 2-2 pattern, on average, half the daughters will be heterozygous carriers,
and half will be homozygous for the disease allele and thus affected.
1. Why is the influence of environment significant to phenotype?
2. Discuss the differences between a dominant and a recessive allele. Half the sons will be normal, and half will be affected. Some X-linked
3. Why are the concepts of variable expressivity, incomplete penetrance, and recessive diseases, such as DMD, are fatal or incapacitating before the
delayed age of onset so important in relation to genetic diseases? affected individual reaches reproductive age, and therefore affected
4. What is the recurrence risk for autosomal dominant inheritance and reces- fathers are rare.
sive inheritance?
Sex-Limited and Sex-Influenced Traits
A sex-limited trait can occur in only one sex, often because of ana-
tomic differences. Inherited uterine and testicular defects are two
Characteristics of Pedigrees obvious examples. A sex-influenced trait occurs much more often
X-linked pedigrees show distinctive modes of inheritance. The most in one sex than the other. For example, male-pattern baldness occurs
striking characteristic is that females seldom are affected. To express an in both males and females but is much more common in males.
X-linked recessive trait, a female must be homozygous: either both her ­Autosomal dominant breast cancer, which is now much more com-
parents are affected, or her father is affected and her mother is a carrier. monly expressed in females than males, is another example of a sex-­
Such matings are rare. influenced trait.
 CHAPTER 2  Genes and Genetic Diseases 53

Mother
XH Xh Evaluation of Pedigrees
With complications such as incomplete penetrance, variable expres-
XH XHXH XhXH sivity, delayed age of onset, and sex-influenced traits, it is not
always possible simply to look at a disease pedigree and determine
Father the mode of inheritance. A sophisticated statistical methodologic
Y XHY XhY approach has evolved to deal with such complications. Incorpo-
rated into computer programs, these statistical techniques assess the
A
probability of observing a certain pedigree if a particular mode of
inheritance (e.g., autosomal dominant with incomplete penetrance)
Mother is in effect.
XH XH
LINKAGE ANALYSIS AND GENE MAPPING
Xh XHXh XHXh
Locating genes on specific regions of chromosomes has been one of
Father the most important goals of human genetics. The location and iden-
tification of a gene can tell much about the function of the gene, the
Y XHY X HY
interaction of the gene with other genes, and the likelihood that certain
B individuals will develop a genetic disease.

Classic Pedigree Analysis

Mother
Mendel’s second law, the principle of independent assortment, states
XH Xh
that an individual’s genes will be transmitted to the next generation
independently of one another. This law is only partly true, however,
Xh XHXh XhXh because genes located close together on the same chromosome do tend
Father to be transmitted together to the offspring. Thus Mendel’s principle
of independent assortment holds true for most pairs of genes but not
Y XHY XhY
those that occupy the same region of a chromosome. Such loci demon-
C strate linkage and are said to be linked.
Normal Carrier Affected
During the first meiotic stage, the arms of homologous chromo-
some pairs intertwine and sometimes exchange portions of their DNA
FIGURE 2-29  Punnett Square and X-Linked Recessive Traits.
(Figure 2-30) in a process known as crossover. During crossover, new
A, Punnett square for the mating of a normal male (XHY) and a female
carrier of an X-linked recessive gene (XHXh). B, Punnett square for combinations of alleles can be formed. For example, two loci on a
the mating of a normal female (XHXH) with a male affected by an chromosome have alleles A and a and alleles B and b. Alleles A and B
X-linked recessive disease (XhY). C, Punnett square for the mating are located together on one member of a chromosome pair, and alleles
of a female who carries an X-linked recessive gene (XHXh) with a a and b are located on the other member. The genotype of this indi-
male who is affected with the disease caused by the gene (XhY). vidual is denoted as AB/ab.

A1 B1
A1B1
A1 B1
A1B1 FIGURE 2-30  Genetic Results of Crossing Over. A, No crossing over.
A2 B2
B, Crossing over with recombination. C, Double crossing over, resulting
A2B2
in no recombination.
A2 B2
A A2B2
A1 B1 A1 B1
A1B1
A1 B1 A2 B1
A2B1
A2 B2 A1 B2
A1B2
A2 B2 A2 B2
A2B2
B
A1 B1 A1 B1
A1B1
A1 B1 A1 B1
A1B1
A2 B2 A2 B2
A2B2
A2 B2 A2 B2
C A2B2
54 CHAPTER 2  Genes and Genetic Diseases

As Figure 2-30, A, shows, the allele pairs AB and ab would be trans- phlebotomy) can be initiated to deplete iron stores and ensure a nor-
mitted together when no crossover occurs. However, when crossover mal life span.
occurs (Figure 2-30, B), all four possible pairs of alleles can be trans-
mitted to the offspring: AB, aB, Ab, and ab. The process of forming Complete Human Gene Map: Prospects and Benefits
such new arrangements of alleles is called recombination. Crossover The major goals of the Human Genome Project were to find the loca-
does not necessarily lead to recombination, however, because double tions of all human genes (the “gene map”) and to determine the entire
crossover between two loci can result in no actual recombination of the human DNA sequence. These goals have now been accomplished and
alleles at the loci (Figure 2-30, C). the genes responsible for most mendelian conditions have been identi-
Once a close linkage has been established between a disease locus fied (Figure 2-31).1,16,17 This has greatly increased our understanding of
and a “marker” locus (a DNA sequence that varies among individu- the mechanisms that underlie many diseases, such as retinoblastoma,
als) and once the alleles of the two loci that are inherited together cystic fibrosis, neurofibromatosis, and Huntington disease. It also has
within a family have been determined, reliable predictions can be led to more accurate diagnosis of these conditions, and in some cases
made as to whether a member of a family will develop the disease. more effective treatment.
Linkage has been established between several DNA polymorphisms DNA sequencing has become much less expensive and more effi-
and each of the two major genes that can cause autosomal domi- cient in recent years. Consequently, dozens of individuals have now
nant breast cancer (about 5% of breast cancer cases are caused by been completely sequenced, leading in some cases to the identification
these autosomal dominant genes). Determining this kind of linkage of disease-causing genes (see Health Alert: Gene Therapy).18
means that it is possible for offspring of an individual with autosomal
dominant breast cancer to know whether they also carry the gene and
thus could pass it on to their own children. In most cases, specific HEALTH ALERT
disease-causing mutations can be identified, allowing direct detec- Gene Therapy
tion and diagnosis. For some genetic diseases, prophylactic treatment
More than 6000 individuals are enrolled in more than 1300 protocols. Most of
is available if the condition can be diagnosed in time. An example of
these protocols involve the genetic alteration of cells to combat various types
this is hemochromatosis, a recessive genetic disease in which excess
of cancer. Other protocols involve the treatment of inherited diseases, such as
iron is absorbed, causing degeneration of the heart, liver, brain, and
β-thalassemia, severe combined immunodeficiency, and retinitis pigmentosa.
other vital organs. Individuals at risk for developing the disease can
be determined by testing for a mutation in the hemochromatosis Data from Edelstein ML, Abedi MR, Wixon J: Gene therapy clinical tri-
gene and through clinical tests, and preventive therapy (periodic als worldwide to 2007—an update, J Gene Med 9:833–842, 2007.

Rh disease
ALD
Muscular dystrophy Gaucher disease
Hemophilia, A & B Familial colon cancer

Neurofibromatosis, type 2 Retinitis pigmentosa

Achondroplasia
Huntington disease
Amyotrophic lateral sclerosis

ADA deficiency
Familial polyposis of the colon
Spinal muscular atrophy, types 2 and 3
Familial Hemochromatosis
hypercholesterolemia XY 1 2 3
22
21 4 Spinocerebellar ataxia, type 1
Myotonic 20 5 Congenital adrenal
dystrophy 19 CHROMOSOME 6 hyperplasia
18 7 Cystic fibrosis
PAIRS
17 8
Amyloidosis 16 9
15 10
14 13 12 11
Neurofibromatosis

Breast cancer
and ovarian cancer
Malignant melanoma
Polycystic
kidney disease
Multiple endocrine
Tay-Sachs disease neoplasia, type 2
Marfan syndrome
Alzheimer disease Sickle cell disease
Retinoblastoma PKU
FIGURE 2-31  Example of Diseases: A Gene Map. ADA, Adenosine deaminase; ALD, adrenoleuko-
dystrophy; PKU, phenylketonuria.
 CHAPTER 2  Genes and Genetic Diseases 55

individual. Yet they do not follow the patterns expected of single-gene

MULTIFACTORIAL INHERITANCE
diseases. Many of these are probably polygenic or multifactorial, but
Not all traits are produced by single genes; some traits result from a certain threshold of liability must be crossed before the disease is
several genes acting together. These are called polygenic traits. When expressed. Below the threshold the individual appears normal; above
environmental factors influence the expression of the trait (as is usu- it, the individual is affected by the disease (Figure 2-33).
ally the case), the term multifactorial inheritance is used. Many mul- One of the best-known examples of such a threshold trait is pyloric
tifactorial and polygenic traits tend to follow a normal distribution in stenosis, a disorder characterized by a narrowing or obstruction of the
populations (the familiar bell-shaped curve). Figure 2-32 shows how pylorus, the area between the stomach and intestine. Chronic vom-
three loci acting together can cause grain color in wheat to vary in a iting, constipation, weight loss, and electrolyte imbalance can result
gradual way from white to red, exemplifying multifactorial inheri- from the condition, but it is easily corrected by surgery. The prevalence
tance. If both alleles at each of the three loci are white alleles, the color of pyloric stenosis is about 3 in 1000 live births in whites. This disor-
is pure white. If most alleles are white but a few are red, the color is der is much more common in males than females, affecting 1 in 200
somewhat darker; if all are red, the color is dark red. males and 1 in 1000 females. The apparent reason for this difference is
Other examples of multifactorial traits include height and IQ. that the threshold of liability is much lower in males than females, as
Although both height and IQ are determined in part by genes, they shown in Figure 2-33. Thus fewer defective alleles are required to gen-
are influenced also by environment. For example, the average height of erate the disorder in males. This situation also means that the offspring
many human populations has increased by 5 to 10 cm in the past 100 of affected females are more likely to have pyloric stenosis because
years because of improvements in nutrition and health care. Also, IQ affected females necessarily carry more disease-causing alleles than do
scores can be improved by exposing individuals (especially children) most affected males.
to enriched learning environments. Thus both genes and environment A number of other common diseases are thought to correspond to
contribute to variation in these traits. a threshold model. They include cleft lip and cleft palate, neural tube
A number of diseases do not follow the bell-shaped distribu- defects (anencephaly, spina bifida), clubfoot (talipes), and some forms
tion. Instead they appear to be either present in or absent from an of congenital heart disease.
Although recurrence risks can be given with confidence for single-
gene diseases (e.g., 50% for autosomal dominants, 25% for autosomal
AABBCC aabbcc recessives), it is considerably more difficult to do so for multifacto-
rial diseases. The number of genes contributing to the disease is not
known, the precise allelic constitution of the parents is not known, and
F1
the extent of environmental effects can vary from one population to
AaBbCc another. For most multifactorial diseases, empirical risks (i.e., those
based on direct observation) have been derived. To determine empiri-
ABC Male abc Female cal risks, a large sample of families in which one child has developed
ABc gametes abC gametes the disease is examined. The siblings of each child are then surveyed to
AbC aBc calculate the percentage who also develop the disease.
F2 aBC Abc
Abc aBC
aBc AbC Threshold
abC ABc
abc ABC
Male

Threshold
25
Class frequency

20 High
Female
15
10
5

0 1 2 3 4 5 6
+
Number of dominant alleles
FIGURE 2-32  Multifactorial Inheritance. Analysis of mode of Low Liability
inheritance for grain color in wheat. The trait is controlled by three FIGURE 2-33  Threshold of Liability for Pyloric Stenosis in
independently assorted gene loci. Males and Females.
56 CHAPTER 2  Genes and Genetic Diseases

Another difficulty is distinguishing polygenic or multifactorial

BOX 2-1 CRITERIA USED TO DEFINE
diseases from single-gene diseases that have incomplete penetrance
MULTIFACTORIAL DISEASES or variable expressivity. Large data sets and good epidemiologic data
1. The recurrence risk becomes higher if more than one family member is often are necessary to make the distinction. Box 2-1 lists criteria that
affected. For example, the recurrence risk for neural tube defects in a Brit- are commonly used to define multifactorial diseases.
ish family increases to 10% if two siblings have been born with the dis- The genetics of common disorders such as hypertension, heart
ease. By contrast, the recurrence risk for single-gene diseases remains the disease, and diabetes is complex and often confusing. Nevertheless,
same regardless of the number of siblings affected. the public health impact of these diseases, together with the evidence
2. If the expression of the disease is more severe, the recurrence risk is higher. for hereditary factors in their etiology, demands that genetic studies
This is consistent with the liability model; a more severe expression indicates be pursued. Hundreds of genes that contribute to susceptibility for
that the individual is at the extreme end of the liability distribution. Relatives these diseases have been discovered, and the next decade will undoubt-
of the affected individual are thus at a higher risk for inheriting disease genes. edly witness substantial advancements in our understanding of these
Cleft lip or cleft palate is a condition in which this has been shown to be true. disorders.
3. Relatives of probands of the less commonly affected are more likely to
develop the disease. As with pyloric stenosis, this occurs because an
affected individual of the less susceptible sex is usually at a more extreme
position on the liability distribution.
4. Generally, if the population frequency of the disease √ is f, the risk for off-
4 QUICK CHECK 2-3
1. Define linkage analysis; cite an example.
spring and siblings of probands is approximately f . This does not usually
2. Why is “threshold of liability” an important consideration in multifactorial
hold true for single-gene traits.
inheritance?
5. The recurrence risk for the disease decreases rapidly in more remotely
3. Discuss the concept of multifactorial inheritance, and include two
related relatives. Although the recurrence risk for single-gene diseases
examples.
decreases by 50% with each degree of relationship (e.g., an autosomal
dominant disease has a 50% recurrence risk for siblings, 25% for uncle-
nephew relationship, 12.5% for first cousins), the risk for multifactorial
inheritance decreases much more quickly.

DID YOU UNDERSTAND?

DNA, RNA, and Proteins: Heredity at the Molecular Level Chromosomes
1. Genes, the basic units of inheritance, are composed of deoxyribonucleic 1. Human cells consist of diploid somatic cells (body cells) and haploid gam-
acid (DNA) and are located on chromosomes. etes (sperm and egg cells).
2. DNA is composed of deoxyribose, a phosphate molecule, and four types of 2. Humans have 23 pairs of chromosomes. Twenty-two of these pairs are
nitrogenous bases. The physical structure of DNA is a double helix. autosomes. The remaining pair consists of the sex chromosomes. Females
3. The DNA bases code for amino acids, which in turn make up proteins. The have two homologous X chromosomes as their sex chromosomes; males
amino acids are specified by triplet codons of nitrogenous bases. have an X and a Y chromosome.
4. DNA replication is based on complementary base pairing, in which a single 3. A karyotype is an ordered display of chromosomes arranged according to
strand of DNA serves as the template for attracting bases that form a new length and the location of the centromere.
strand of DNA. 4. Various types of stains can be used to make chromosome bands more
5. DNA polymerase is the primary enzyme involved in replication. It adds visible.
bases to the new DNA strand and performs “proofreading” functions. 5. About 1 in 150 live births has a major diagnosable chromosome abnor-
6. A mutation is an inherited alteration of genetic material (i.e., DNA). mality. Chromosome abnormalities are the leading known cause of mental
7. Substances that cause mutations are called mutagens. retardation and miscarriage.
8. The mutation rate in humans varies from locus to locus and ranges from 6. Polyploidy is a condition in which a euploid cell has some multiple of the
10−4 to 10−7 per gene per generation. normal number of chromosomes. Humans have been observed to have
9. Transcription and translation, the two basic processes in which proteins are triploidy (three copies of each chromosome) and tetraploidy (four copies of
specified by DNA, both involve ribonucleic acid (RNA). RNA is chemically each chromosome); both conditions are lethal.
similar to DNA, but it is single stranded, has a ribose sugar molecule, and 7. Somatic cells that do not have a multiple of 23 chromosomes are aneuploid.
has uracil rather than thymine as one of its four nitrogenous bases. Aneuploidy is usually the result of nondisjunction.
10. Transcription is the process by which DNA specifies a sequence of mes- 8. Trisomy is a type of aneuploidy in which one chromosome is present in
senger RNA (mRNA). three copies in somatic cells. A partial trisomy is one in which only part of
11. Much of the RNA sequence is spliced from the mRNA before the mRNA a chromosome is present in three copies.
leaves the nucleus. The excised sequences are called introns, and those 9. Monosomy is a type of aneuploidy in which one chromosome is present in
that remain to code for proteins are called exons. only one copy in somatic cells.
12. Translation is the process by which RNA directs the synthesis of polypep- 10. In general, monosomies cause more severe physical defects than do triso-
tides. This process takes place in the ribosomes, which consist of proteins mies, illustrating the principle that the loss of chromosome material has
and ribosomal RNA (rRNA). more severe consequences than the duplication of chromosome material.
13. During translation, mRNA interacts with transfer RNA (tRNA), a molecule
that has an attachment site for a specific amino acid.
 CHAPTER 2  Genes and Genetic Diseases 57

DID YOU UNDERSTAND?—cont’d

11. Down syndrome, a trisomy of chromosome 21, is the best-known disease 16. Consanguinity is sometimes present in families with autosomal recessive
caused by a chromosome aberration. It affects 1 in 800 live births and is diseases, and it becomes more prevalent with rarer recessive diseases.
much more likely to occur in the offspring of women older than 35 years. 17. Carrier detection tests for an increasing number of autosomal recessive
12. Most aneuploidies of the sex chromosomes have less severe consequences diseases are available.
than those of the autosomes. 18. The frequency of genetic diseases approximately doubles in the offspring of
13. The most commonly observed sex chromosome aneuploidies are the 47,XXX first-cousin matings.
karyotype, 45,X karyotype (Turner syndrome), 47,XXY karyotype (Klinefelter 19. In each normal female somatic cell, one of the two X chromosomes is inac-
syndrome), and 47,XYY karyotype. tivated early in embryogenesis.
14. Abnormalities of chromosome structure include deletions, duplications, 20. X inactivation is random, fixed, and incomplete (i.e., only part of the chro-
inversions, and translocations. mosome is actually inactivated). It may involve methylation.
21. Gender is determined embryonically by the presence of the SRY gene on
Elements of Formal Genetics the Y chromosome. Embryos that have a Y chromosome (and thus the SRY
1. Mendelian traits are caused by single genes, each of which occupies a gene) become males, whereas those lacking the Y chromosome become
position, or locus, on a chromosome. females. When the Y chromosome lacks the SRY gene, an XY female can
2. Alleles are different forms of genes located at the same locus on a be produced. Similarly, an X chromosome that contains the SRY gene can
chromosome. produce an XX male.
3. At any given locus in a somatic cell, an individual has two genes, one from 22. X-linked genes are those that are located on the X chromosome. Nearly all
each parent. An individual may be homozygous or heterozygous for a locus. known X-linked diseases are caused by X-linked recessive genes.
4. An individual’s genotype is his or her genetic makeup, and the phenotype 23. Males are hemizygous for genes on the X chromosome.
reflects the interaction of genotype and environment. 24. X-linked recessive diseases are seen much more often in males than in
5. In a heterozygote, a dominant gene’s effects mask those of a recessive females because males need only one copy of the gene to express the
gene. The recessive gene is expressed only when it is present in two copies. disease.
25. Fathers cannot pass X-linked genes to their sons.
Transmission of Genetic Diseases 26. Skipped generations often are seen in X-linked recessive disease pedigrees
1. Genetic diseases caused by single genes usually follow autosomal domi- because the gene can be transmitted through carrier females.
nant, autosomal recessive, or X-linked recessive modes of inheritance. 27. Recurrence risks for X-linked recessive diseases depend on the carrier and
2. Pedigree charts are important tools in the analysis of modes of inheritance. affected status of the mother and father.
3. Recurrence risks specify the probability that future offspring will inherit 28. A sex-limited trait is one that occurs only in one sex (gender).
a genetic disease. For single-gene diseases, recurrence risks remain the 29. A sex-influenced trait is one that occurs more often in one sex than in the
same for each offspring, regardless of the number of affected or unaffected other.
offspring.
4. The recurrence risk for autosomal dominant diseases is usually 50%. Linkage Analysis and Gene Mapping
5. Germline mosaicism can alter recurrence risks for genetic diseases because 1. During meiosis I, crossover occurs and can cause recombinations of alleles
unaffected parents can produce multiple affected offspring. This situation located on the same chromosome.
occurs because the germline of one parent is affected by a mutation but the 2. The frequency of recombinations can be used to infer the map distance
parent’s somatic cells are unaffected. between loci on the same chromosome.
6. Skipped generations are not seen in classic autosomal dominant pedigrees. 3. A marker locus, when closely linked to a disease-gene locus, can be used
7. Males and females are equally likely to exhibit autosomal dominant dis- to predict whether an individual will develop a genetic disease.
eases and to pass them on to their offspring. 4. A more complete gene map will facilitate marker studies, gene cloning,
8. Many genetic diseases have a delayed age of onset. studies of gene function and interaction, and gene therapy.
9. A gene that is not always expressed phenotypically is said to have incom-
plete penetrance. Multifactorial Inheritance
10. Variable expressivity is a characteristic of many genetic diseases. 1. Traits that result from the combined effects of several loci are polygenic.
11. Genomic imprinting, which is associated with methylation, results in differ- When environmental factors also influence the trait, it is multifactorial.
ing expression of a disease gene, depending on which parent transmitted 2. Many multifactorial traits have a threshold of liability. Once the threshold
the gene. of liability has been crossed, the disease may be expressed.
12. Epigenetics involves changes, such as the methylation of DNA bases, that 3. Empirical risks, based on direct observation of large numbers of families,
do not alter the DNA sequence but can alter the expression of genes. are used to estimate recurrence risks for multifactorial diseases.
13. Most commonly, parents of children with autosomal recessive diseases are 4. Recurrence risks for multifactorial diseases become higher if more than one
both heterozygous carriers of the disease gene. family member is affected or if the expression of the disease in the proband
14. The recurrence risk for autosomal recessive diseases is 25%. is more severe.
15. Males and females are equally likely to be affected by autosomal recessive 5. Recurrence risks for multifactorial diseases decrease rapidly for more
diseases. remote relatives.
58 CHAPTER 2  Genes and Genetic Diseases

 KEY TERMS
•  denine  35
A •  ragile site  46
F •  olymorphic (polymorphism)  46
P
• Allele  46 • Frameshift mutation  37 • Polypeptide  35
• Amino acid  35 • Gamete  38 • Polyploid cell  40
• Aneuploid cell  42 • Gene  34 • Position effect  45
• Anticodon  37 • Genomic imprinting  50 • Principle of independent assortment  47
• Autosome  38 • Genotype  46 • Principle of segregation  47
• Barr body  51 • Germline mosaicism  48 • Proband  47
• Base pair substitution  37 • Guanine  35 • Promoter site  37
• Carrier  47 • Haploid cell  38 • Pseudoautosomal  51
• Carrier detection test  50 • Hemizygous  51 • Purine  35
• Chromosomal mosaic  42 • Heterozygote  47 • Pyrimidine  35
• Chromosome  34 • Heterozygous  46 • Recessive  47
• Chromosome band  40 • Homologous  38 • Reciprocal translocation  45
• Chromosome breakage  40 • Homozygote  47 • Recombination  54
• Chromosome theory of inheritance  47 • Homozygous  46 • Recurrence risk  48
• Clastogen  44 • Inbreeding  50 • Ribonucleic acid (RNA)  37
• Codominance  47 • Intron  37 • Ribosomal RNA (rRNA)  38
• Codon  35 • Inversion  45 • Ribosome  38
• Complementary base pairing  35 • Karyotype (karyogram)  40 • RNA polymerase  37
• Consanguinity  50 • Klinefelter syndrome  44 • Robertsonian translocation  45
• CpG islands  49 • Linkage  53 • Sex-influenced trait  52
• Cri du chat syndrome  44 • Locus  46 • Sex-limited trait  52
• Crossover  53 • Meiosis  38 • Sex linked (inheritance)  51
• Cytokinesis  38 • Messenger RNA (mRNA)  37 • Silent mutation  37
• Cytosine  35 • Metaphase spread  38 • Somatic cell  38
• Delayed age of onset  48 • Methylation  51 • Spontaneous mutation  37
• Deletion  44 • Missense  37 • Template  37
• Deoxyribonucleic acid (DNA)  34 • Mitosis  38 • Termination sequence  37
• Diploid cell  38 • Mode of inheritance  47 • Tetraploidy  40
• DNA methylation  49 • Multifactorial inheritance  55 • Threshold of liability  55
• DNA polymerase  37 • Mutagen  37 • Thymine  35
• Dominant  47 • Mutation  37 • Transcription  37
• Dosage compensation  51 • Mutational hot spot  37 • Transfer RNA (tRNA)  37
• Double-helix model  35 • Nondisjunction  42 • Translation  37
• Down syndrome  42 • Nonsense  37 • Translocation  45
• Duplication  44 • Nucleotide  35 • Triploidy  40
• Dystrophin  52 • Obligate carrier  48 • Trisomy  42
• Empirical risk  55 • Partial trisomy  42 • Tumor-suppressor gene  48
• Epigenetic  49 • Pedigree  47 • Turner syndrome  44
• Euploid cell  40 • Penetrance  48 • X inactivation  51
• Exon  37 • Phenotype  46
• Expressivity  49 • Polygenic trait  55

REFERENCES 10. Lee MJ, Stephenson DA: Recent developments in neurofibromatosis type
1, Curr Opin Neurol 20:135–141, 2007.
1. Jorde LB, et al: Medical genetics, ed 4, St Louis, 2010, Mosby. 11. Fraga MF, et al: Epigenetic differences arise during the lifetime of mono-
2. Hassold TJ: Chromosome abnormalities in human reproductive wastage, zygotic twins, Proc Natl Acad Sci U S A 102:10604–10609, 2005.
Trends Genet 2:105–110, 1986. 12. Lyon MF: X-chromosome inactivation, Curr Biol 9(7):R235–R237, 1999.
3. Hassold T, Hunt PA: To err (meiotically) is human: the genesis of human 13. Wutz A, Gribnau J: X inactivation Xplained, Curr Opin Genet Dev
aneuploidy, Nat Rev Genet 2(4):280–291, 2001. 17:387–393, 2007.
4. Antonarakis SE, Epstein CJ: The challenge of Down syndrome, Trends Mol 14. Fleming A, Vilain E: The endless quest for sex determination genes, Clin
Med 12:473–479, 2006. Genet 67(1):15–25, 2005.
5. Graham GE, Allanson JE, Gerritsen JA: Sex chromosome abnormalities. In 15. Emery AEH: Duchenne and other X-linked muscular dystrophies. In
Rimoin DL, editor: Emery and Rimoin’s principles and practice of medical Rimoin DL, editor: Emery and Rimoin’s principles and practice of medical
genetics, ed 5, London, 2007, Churchill Livingstone. genetics, ed 5, London, 2007, Churchill Livingstone.
6. Garber KB, Visootsak J, Warren ST: Fragile X syndrome, Eur J Hum Genet 16. Collins FS, Morgan M, Patrinos A: The Human Genome Project: lessons
16:666–672, 2008. from large-scale biology, Science 300(5617):286–290, 2003.
7. Orr HT, Zoghbi HY: Trinucleotide repeat disorders, Annu Rev Neurosci 17. McKusick VA: A 60-year tale of spots, maps, and genes, Annu Rev Genom
30:575–621, 2007. Hum Genet 7:1–27, 2006.
8. Zlotogora J: Germ line mosaicism, Hum Genet 102(4):381–386, 1998. 18. Anonymous: Human genome at ten: the sequence explosion, Nature
9. Vogelstein G, Kinzler KW, editors: The genetic basis of human cancer, ed 2, 464:670–671, 2010.
New York, 2002, McGraw-Hill.
 CHAPTER

3
Altered Cellular and Tissue Biology
Kathryn L. McCance and Todd Cameron Grey

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Cellular Adaptation, 60 Proteins, 82
Atrophy, 60 Pigments, 82
Hypertrophy, 61 Calcium, 83
Hyperplasia, 61 Urate, 84
Dysplasia: Not a True Adaptive Change, 62 Systemic Manifestations, 84
Metaplasia, 62 Cellular Death, 85
Cellular Injury, 62 Necrosis, 85
General Mechanisms of Cell Injury, 63 Apoptosis, 87
Hypoxic Injury, 63 Autophagy, 88
Free Radicals and Reactive Oxygen Species—Oxidative Stress, 66 Aging and Altered Cellular and Tissue Biology, 90
Chemical Injury, 66 Normal Life Span and Life Expectancy, 90
Unintentional and Intentional Injuries, 73 Degenerative Extracellular Changes, 91
Infectious Injury, 80 Cellular Aging, 92
Immunologic and Inflammatory Injury, 80 Tissue and Systemic Aging, 93
Manifestations of Cellular Injury: ­Accumulations, 80 Frailty, 93
Water, 80 Somatic Death, 93
Lipids and Carbohydrates, 81
Glycogen, 82

All forms of disease begin with alterations in cells. Injury to cells and high blood pressure, myocardial cells are stimulated to enlarge by the
their surrounding environment, called the extracellular matrix, leads increased work of pumping. Like most of the body’s adaptive mecha-
to tissue and organ injury. Although the normal cell is restricted by nisms, however, cellular adaptations to adverse conditions are usually
a narrow range of structure and function, it can adapt to physiologic only temporarily successful. Severe or long-term stressors overwhelm
demands or stress to maintain a steady state called homeostasis. Adap- adaptive processes, and cellular injury or death ensues. Altered cellular
tation is a reversible, structural, or functional response both to nor- and tissue biology can result from adaptation, injury, neoplasia, aging,
mal or physiologic conditions and to adverse or pathologic conditions. or death (neoplasia is discussed in Chapters 9 to 11).
For example, the uterus adapts to pregnancy—a normal physiologic Injury may be reversible (sublethal) or irreversible (lethal) and
state—by enlarging. Enlargement occurs because of an increase in is classified broadly as chemical, hypoxic (lack of sufficient oxygen),
the size and number of uterine cells. In an adverse condition such as free radical, intentional, unintentional, immunologic, infection, and

59
60 CHAPTER 3  Altered Cellular and Tissue Biology

inflammatory. Cellular injuries from various causes have different

clinical and pathophysiologic manifestations. Cellular death is con- Atrophy
firmed by structural changes seen when cells are stained and examined Atrophy is a decrease or shrinkage in cellular size. If atrophy occurs
under a microscope. in a sufficient number of an organ’s cells, the entire organ shrinks or
Cellular aging causes structural and functional changes that even- becomes atrophic. Atrophy can affect any organ, but it is most com-
tually may lead to cellular death or a decreased capacity to recover mon in skeletal muscle, the heart, secondary sex organs, and the brain.
from injury. Mechanisms explaining how and why cells age are not Atrophy can be classified as physiologic or pathologic. Physiologic
known, and distinguishing between pathologic changes and physi- atrophy occurs with early development. For example, the thymus
ologic changes that occur with aging is often difficult. Aging clearly gland undergoes physiologic atrophy during childhood. Pathologic
causes alterations in cellular structure and function, yet growing old is atrophy occurs as a result of decreases in workload, pressure, use,
both inevitable and normal. blood supply, nutrition, hormonal stimulation, and nervous stimu-
lation (Figure 3-2). Individuals immobilized in bed for a prolonged
time exhibit a type of skeletal muscle atrophy called disuse atrophy.
CELLULAR ADAPTATION Aging causes brain cells to become atrophic and endocrine-depen-
Cells adapt to their environment to escape and protect themselves dent organs, such as the gonads, to shrink as hormonal stimulation
from injury. An adapted cell is neither normal nor injured—its con- decreases. Whether atrophy is caused by normal physiologic condi-
dition lies somewhere between these two states. Cellular adaptations, tions or by pathologic conditions, atrophic cells exhibit the same basic
however, are a common and central part of many disease states. In the changes.
early stages of a successful adaptive response, cells may have enhanced The atrophic muscle cell contains less endoplasmic reticulum and
function; thus it is hard to know whether the response is pathologic or fewer mitochondria and myofilaments (part of the muscle fiber that
an extreme adaptation to an excessive functional demand. The most controls contraction) than found in the normal cell. In muscular atro-
significant adaptive changes in cells include atrophy (decrease in cell phy caused by nerve loss, oxygen consumption and amino acid uptake
size), hypertrophy (increase in cell size), hyperplasia (increase in cell are immediately reduced. The biochemical changes of atrophy are
number), and metaplasia (reversible replacement of one mature just beginning to be understood. The mechanisms probably include
cell type by another less mature cell type). Dysplasia (deranged cel- decreased protein synthesis, increased protein catabolism, or both. The
lular growth) is not considered a true cellular adaptation but rather an primary pathway of protein catabolism is the ubiquitin-proteosome
atypical hyperplasia. These changes are shown in Figure 3-1. pathway and catabolism involves proteosomes (protein degrading
complexes). Proteins degraded in this pathway are first conjugated to
ubiquitin (another small protein) and then degraded by proteosomes.
Muscles atrophy can occur because of this pathway. Deregulation of
Nucleus
this pathway often leads to abnormal cell growth and is associated with
cancer and other diseases.
Atrophy as a result of chronic malnutrition is often accompanied
by a “self-eating” process called autophagy that creates autophagic
Basement Normal vacuoles (see p. 88). These vacuoles are membrane-bound vesicles
membrane

Atrophy

Hypertrophy

Hyperplasia

A B
Metaplasia
FIGURE 3-2  Atrophy. A, Normal brain of a young adult. B, Atro-
phy of the brain in an 82-year-old male with atherosclerotic cere-
brovascular disease, resulting in reduced blood supply. Note that
loss of brain substance narrows the gyri and widens the sulci. The
meninges have been stripped from the right half of each specimen
to reveal the surface of the brain. (From Kumar V et  al: Cellular
Dysplasia responses to stress and toxic insults: adaptation, injury, and death.
FIGURE 3-1  Adaptive and Dysplastic Alterations in Simple In Kumar V et  al, editors: Robbins and Cotran pathologic basis of
Cuboidal Epithelial Cells. disease, ed 8, St Louis, 2010, Saunders.)
 CHAPTER 3  Altered Cellular and Tissue Biology 61

within the cell that contain cellular debris and hydrolytic enzymes, have caused cell death. Loss of epithelial cells and cells of the liver and
which function to break down substances to the simplest units of fat, kidney triggers deoxyribonucleic acid (DNA) synthesis and mitotic
carbohydrate, or protein. The level of hydrolytic enzymes rises rapidly division. Increased cell growth is a multistep process involving the
in atrophy. The enzymes are isolated in autophagic vacuoles to prevent production of growth factors, which stimulate the remaining cells to
uncontrolled cellular destruction. Thus the vacuoles form as needed synthesize new cell components and, ultimately, to divide. Hyperplasia
to protect uninjured organelles from the injured organelles and are and hypertrophy often occur together, and both take place if the cells
eventually engulfed and destroyed by lysosomes. Certain contents of can synthesize DNA; however, in nondividing cells (e.g., myocardial
the autophagic vacuole may resist destruction by lysosomal enzymes fibers) only hypertrophy occurs.
and persist in membrane-bound residual bodies. An example of this Two types of normal, or physiologic, hyperplasia are (1) compen-
is granules that contain lipofuscin, the yellow-brown age pigment. satory and (2) hormonal. Compensatory hyperplasia is an adaptive
Lipofuscin accumulates primarily in liver cells, myocardial cells, and mechanism that enables certain organs to regenerate. For example,
atrophic cells. removal of part of the liver leads to hyperplasia of the remaining liver
cells (hepatocytes) to compensate for the loss. Even with removal of
Hypertrophy 70% of the liver, regeneration is complete in about 2 weeks. Several
Hypertrophy is an increase in the size of cells and consequently in growth factors and cytokines (chemical messengers) are induced and
the size of the affected organ (Figure 3-3). The cells of the heart and play critical roles in liver regeneration.1
kidneys are particularly prone to enlargement. The increased cellular Some cells—such as nerve, skeletal muscle, and myocardial cells
size is associated with an increased accumulation of protein in the cel- and the lens cells of the eye—are classically known not to regenerate.
lular components (plasma membrane, endoplasmic reticulum, myo- Additional skeletal muscle cells, however, can be made by the fusion
filaments, mitochondria) and not with an increase in cellular fluid. of myoblasts.2 Much new research also is being done with the periph-
Hypertrophy can be physiologic or pathologic and is caused by specific eral nervous system (PNS). PNS nerve regeneration enables severed
hormone stimulation or by increased functional demand. The trig- limbs to be reattached and continue growing. Significant compensa-
gers for hypertrophy include two types of signals: (1) mechanical sig- tory hyperplasia occurs in epidermal and intestinal epithelia, hepa-
nals, such as stretch, and (2) trophic signals, such as growth factors, tocytes, bone marrow cells, and fibroblasts, and some hyperplasia is
hormones, and vasoactive agents. For example, in skeletal muscles, noted in bone, cartilage, and smooth muscle cells. Another example
physiologic hypertrophy occurs in response to heavy work. Muscular of compensatory hyperplasia is the callus, or thickening, of the skin as
hypertrophy tends to diminish if the excessive workload diminishes. a result of hyperplasia of epidermal cells in response to a mechanical
When a diseased kidney is removed, the remaining kidney adapts to stimulus.
the increased workload with an increase in both the size and the num- Hormonal hyperplasia occurs chiefly in estrogen-dependent
ber of cells. The major contributing factor to this renal enlargement organs, such as the uterus and breast. After ovulation, for example,
is hypertrophy. Another example of normal or physiologic hyper- estrogen stimulates the endometrium to grow and thicken in prepara-
trophy is the increased growth of the uterus and mammary glands tion for receiving the fertilized ovum. If pregnancy occurs, hormonal
in response to pregnancy. A pathologic example is pathophysiologic hyperplasia, as well as hypertrophy, enables the uterus to enlarge.
hypertrophy in the heart secondary to hypertension or diseased heart (Hormone function is described in Chapters 18 and 32.)
valves. Pathologic hyperplasia is the abnormal proliferation of normal
cells, usually in response to excessive hormonal stimulation or growth
Hyperplasia factors on target cells (Figure 3-4). The most common example is
Hyperplasia is an increase in the number of cells resulting from an pathologic hyperplasia of the endometrium (caused by an imbalance
increased rate of cellular division. Hyperplasia, as a response to injury, between estrogen and progesterone secretion, with oversecretion of
occurs when the injury has been severe and prolonged enough to estrogen) (see Chapter 32). Pathologic endometrial hyperplasia, which

A B C
FIGURE 3-3  Hypertrophy of Cardiac Muscle in Response to Valve Disease. A, Transverse slices of
a normal heart and a heart with hypertrophy of the left ventricle (L, normal thickness of left ventricular
wall; T, thickened wall from heart in which severe narrowing of aortic valve caused resistance to sys-
tolic ventricular emptying). B, Histology of cardiac muscle from the normal heart. C, Histology of cardiac
muscle from a hypertrophied heart. (From Stevens A, Lowe J: Pathology: illustrated review in color,
ed 2, Edinburgh, 2000, Mosby.)
62 CHAPTER 3  Altered Cellular and Tissue Biology

causes excessive menstrual bleeding, is under the influence of regular of either “low grade” or “high grade” instead. If the inciting stimulus
growth-inhibition controls. If these controls fail, hyperplastic endome- is removed, dysplastic changes often are reversible. (Dysplasia is dis-
trial cells can undergo malignant transformation. cussed further in Chapter 9.)

Dysplasia: Not a True Adaptive Change Metaplasia

Dysplasia refers to abnormal changes in the size, shape, and organiza- Metaplasia is the reversible replacement of one mature cell type
tion of mature cells. Dysplasia is not considered a true adaptive process by another, sometimes less differentiated, cell type. It is thought
but is related to hyperplasia and is often called atypical hyperplasia. to develop from a reprogramming of stem cells that exist on most
Dysplastic changes often are encountered in epithelial tissue of the epithelia or of undifferentiated mesenchymal (tissue from embry-
cervix and respiratory tract, where they are strongly associated with onic mesoderm) cells present in connective tissue. These precursor
common neoplastic growths and often are found adjacent to cancer- cells mature along a new pathway because of signals generated by
ous cells. Importantly, however, the term dysplasia does not indicate growth factors in the cell’s environment. The best example of meta-
cancer and may not progress to cancer. Dysplasia is often classified plasia is replacement of normal columnar ciliated epithelial cells
as mild, moderate, or severe; yet, because this classification scheme of the bronchial (airway) lining by stratified squamous epithelial
is somewhat subjective, it has prompted some to recommend the use cells (Figure 3-5). The newly formed cells do not secrete mucus or
have cilia, causing loss of a vital protective mechanism. Bronchial
metaplasia can be reversed if the inducing stimulus, usually ciga-
rette smoking, is removed. With prolonged exposure to the induc-
ing stimulus, however, dysplasia and cancerous transformation can
occur.

CELLULAR INJURY
Most diseases begin with cell injury. Cellular injury occurs if the
cell is unable to maintain homeostasis—a normal or adaptive steady
state—in the face of injurious stimuli. Injured cells may recover
(reversible injury) or die (irreversible injury). Injurious stimuli
include chemical agents, lack of sufficient oxygen (hypoxia), free
radicals, infectious agents, physical and mechanical factors, immu-
Lumen nologic reactions, genetic factors, and nutritional imbalances. Types
Enlarged
of injuries and their responses are summarized in Table 3-1 and
prostate
Figure 3-6.
FIGURE 3-4  Hyperplasia of the Prostate With Secondary The extent of cellular injury depends on the type, state (includ-
Thickening of the Obstructed Urinary Bladder. The enlarged ing level of cell differentiation and increased susceptibility to fully
prostate is seen protruding into the lumen of the bladder, which differentiated cells), and adaptive processes of the cell, as well as the
appears trabeculated. These “trabeculae” result from hypertrophy type, severity, and duration of the injurious stimulus. Two individuals
and hyperplasia of smooth muscle cells that occur in response exposed to an identical stimulus may incur varying degrees of cellular
to increased intravesical pressure caused by urinary obstruction. injury. Modifying factors, such as nutritional status, can profoundly
(From ­Damjanov I: Pathology for the health professions, ed 3,
influence the extent of injury. The precise “point of no return” that
St Louis, 2006, Saunders.)

Normal ciliated epithelium

Metaplasia Dysplasia
Chronic injury or irritation Persistent severe injury or irritation
FIGURE 3-5  Reversible Changes in Cells Lining the Bronchi.
 CHAPTER 3  Altered Cellular and Tissue Biology 63

leads to cellular death is a biochemical puzzle, and the exact mecha-

TABLE 3-1 TYPES OF PROGRESSIVE CELL
nisms responsible for the transition from reversible to irreversible cel-
INJURY AND RESPONSES lular damage are being debated.
TYPE RESPONSES
Adaptation Atrophy, hypertrophy, hyperplasia,
General Mechanisms of Cell Injury
metaplasia Common biochemical themes are important to understanding cell
Active cell injury Immediate response of “entire” cell injury and cell death regardless of the injuring agent. These include
Reversible Loss of ATP, cellular swelling, ­detachment ATP (adenosine triphosphate) depletion, mitochondrial damage, oxy-
of ribosomes, autophagy gen and oxygen-derived free radicals, membrane damage (depletion of
of lysosomes ATP), protein folding defects, DNA damage defects, and calcium level
Irreversible “Point of no return” structurally when alterations (Table 3-2). Examples of common forms of cell injury are
severe vacuolization of mitochondria (1) hypoxic injury, (2) free radicals and reactive oxygen species injury,
occurs and Ca++ moves into cell and (3) chemical injury.
Necrosis Common type of cell death with
severe cell swelling and breakdown of
Hypoxic Injury
­organelles Hypoxia, or lack of sufficient oxygen, is the single most common cause
Apoptosis, or programmed Cellular self-destruction for elimination of of cellular injury (Figure 3-7). Hypoxia can result from a reduced
cell death unwanted cell populations amount of oxygen in the air, loss of hemoglobin or decreased efficacy
Autophagy Eating of self, cytoplasmic vesicles engulf of hemoglobin, decreased production of red blood cells, diseases of
cytoplasm and organelles, recycling the respiratory and cardiovascular systems, and poisoning of the oxi-
factory dative enzymes (cytochromes) within the cells. Hypoxia can induce
Chronic cell injury Persistent stimuli response may involve
(subcellular alterations) only specific organelles or cytoskeleton
(e.g., phagocytosis of bacteria)
Accumulations or infiltrations Water, pigments, lipids, glycogen,
TABLE 3-2 COMMON THEMES IN CELL
proteins
Pathologic calcification Dystrophic and metastatic calcification
INJURY AND CELL DEATH
THEME COMMENTS
ATP, Adenosine triphosphate; Ca++, calcium.
ATP depletion Loss of mitochondrial ATP and decreased ATP
­synthesis; results include cellular swelling, de-
creased protein synthesis, decreased membrane
transport, and lipogenesis, all changes that con-
tribute to loss of integrity of plasma membrane
Reactive oxygen Lack of oxygen is key in progression of cell injury in
Stress ­species (↑ROS) ischemia (reduced blood supply); activated oxygen
Normal cell Adapted
species (ROS, O–2̇ , H2O2, OH·) cause destruction of
cell membranes and cell structure
Does not Ca++ entry Normally intracellular cytosolic calcium concen-
adapt trations are very low; ischemia and certain
chemicals cause an increase in cytosolic Ca++
Reversible Mild, temporary Cell concentrations; sustained levels of Ca++ continue
injury injury to increase with damage to plasma membrane;
Ca++ causes intracellular damage by activating a
number of enzymes
Mitochondrial Can be damaged by increases in cytosolic Ca++,
­damage ROS; two outcomes of mitochondrial damage
Irreversible are loss of membrane potential, which causes
injury
depletion of ATP and eventual death or necrosis
of cell, and activation of another type of cell death
(apoptosis) (see p. 87)
Membrane damage Early loss of selective membrane permeability found
in all forms of cell injury, lysosomal membrane
Cell death damage with release of enzymes causing cellular
digestion
FIGURE 3-6  Stages of Cellular Adaptation, Injury, and Death. Protein misfolding, Proteins may misfold, triggering unfolded protein
The normal cell responds to physiologic and pathologic stresses by DNA damage response that activates corrective responses; if
adapting (atrophy, hypertrophy, hyperplasia, metaplasia). Cell injury overwhelmed, response activates cell suicide
occurs if the adaptive responses are exceeded or compromised by program or apoptosis; DNA damage (genotoxic
injurious agents, stress, and mutations. The injury is reversible if stress) also can activate apoptosis (see p. 87)
it is mild or transient, but if the stimulus persists the cell suffers
irreversible injury and eventually death. ATP, Adenosine triphosphate; Ca++, calcium.
64 CHAPTER 3  Altered Cellular and Tissue Biology

Obstruction or cessation of blood flow

Ischemia

Severe vacuolization
Mitochondrial oxygenation
of mitochondria

ATP ATP

Na1 pump Anaerobic glycolysis

H+
Dilation
Intracellular Na+ of endoplasmic Glycogen
Altered membrane permeability
Extracellular K+ reticulum
Intracellular Ca++
Lactate
Loss of membrane potential Pro-apoptotic proteins
Detachment
H2O of ribosomes Nuclear chromatin
pH clumping
Cannot make ATP Apoptosis
Acute cellular Protein
swelling synthesis
Necrosis

Lipid
deposition
A
B

Ca++

FIGURE 3-7  Hypoxic Injury Induced by Ischemia. A, Con-

sequences of decreased oxygen delivery or ischemia with
Ca++ decreased ATP. The structural and physiologic changes
Ca++ are reversible if oxygen is delivered quickly. Significant
decreases in ATP result in cell death, mostly by necrosis. B,
Mitochondria Smooth Mitochondrial damage can result in changes in membrane
Increased cytosolic Ca++ endoplasmic permeability, loss of membrane potential, and decreased
reticulum ATP. Between the outer and inner membranes of the mito-
chondria are proteins that can activate the cell’s suicide path-
Ca++ Cellular enzyme activities ways, called apoptosis. C, Calcium ions are critical mediators
of cell injury. Calcium ions are usually maintained at low con-
centrations in the cell’s cytoplasm; thus ischemia and certain
Activate Activate Activate Activate toxins can initially cause an increase in the release of Ca++
Mitochondrial ATPase phospholipases proteases endonuclease
permeability changes from intracellular stores and later an increased movement
(influx) across the plasma membrane.
Membrane Nucleus
ATP damage damage
C

inflammation and inflamed lesions can become hypoxic (Figure 3-8).3 the blood supply is not restored, whereas the gradual onset of isch-
The cellular mechanisms involved in hypoxia and inflammation are emia usually results in myocardial adaptation. Myocardial infarction
emerging and include activation of immune responses and oxygen- and stroke, which are common causes of death in the United States,
sensing compounds called ptolyl hydroxylases (PHDs) and hypoxia generally result from atherosclerosis (a type of arteriosclerosis) and
–inducible transcription factor (HIF). Hypoxia induced signaling consequent ischemic injury. (Vascular obstruction is discussed in
involves complicated cross-talk between hypoxia and inflammation Chapter 23.)
linking hypoxia and inflammation to inflammatory bowel disease, cer- Cellular responses to hypoxic injury caused by ischemia have been
tain cancers, and infections.3 demonstrated in studies of the heart muscle. Within 1 minute after
The most common cause of hypoxia is ischemia (reduced blood blood supply to the myocardium is interrupted, the heart becomes
supply). Ischemic injury often is caused by the gradual narrowing pale and has difficulty contracting normally. Within 3 to 5 minutes,
of arteries (arteriosclerosis) and complete blockage by blood clots the ischemic portion of the myocardium ceases to contract because of a
(thrombosis). Progressive hypoxia caused by gradual arterial obstruc- rapid decrease in mitochondrial phosphorylation, causing insufficient
tion is better tolerated than the acute anoxia (total lack of oxygen) ATP production. Lack of ATP leads to increased anaerobic metabo-
caused by a sudden obstruction, as with an embolus (a blood clot or lism, which generates ATP from glycogen when there is insufficient
other plug in the circulation). An acute obstruction in a coronary oxygen. When glycogen stores are depleted, even anaerobic metabo-
artery can cause myocardial cell death (infarction) within minutes if lism ceases.
 CHAPTER 3  Altered Cellular and Tissue Biology 65

FIGURE 3-8  Hypoxia and Inflammation. Shown is a simplified drawing of clinical conditions characterized
by tissue hypoxia that causes inflammatory changes (left) and inflammatory diseases that ultimately lead
to hypoxia (right). These diseases and conditions are discussed in more detail in their respective chapters.
(Adapted from Eltzschig HK, Carmeliet P: Hypoxia and inflammation, N Engl J Med 364:656-665, 2011.)

A reduction in ATP levels causes the plasma membrane’s sodium- damage, extracellular calcium readily moves into the cell and intracel-
potassium (Na+-K+) pump and sodium-calcium exchange mecha- lular calcium stores are released. Increased intracellular calcium levels
nism to fail, which leads to an intracellular accumulation of sodium activate cell enzymes (caspases) that promote cell death by apoptosis
and calcium and diffusion of potassium out of the cell. Sodium and (see Figures 3-23 and 3-30). If ischemia persists, irreversible injury is
water then can enter the cell freely, and cellular swelling, as well as associated structurally with severe swelling of the mitochondria, severe
early dilation of the endoplasmic reticulum, results. Dilation causes the damage to plasma membranes, and swelling of lysosomes.
ribosomes to detach from the rough endoplasmic reticulum, reduc- Restoration of oxygen, however, can cause additional injury called
ing protein synthesis. With continued hypoxia, the entire cell becomes reperfusion injury (Figure 3-9). Reperfusion injury results from the
markedly swollen, with increased concentrations of sodium, water, generation of highly reactive oxygen intermediates (oxidative stress),
and chloride and decreased concentrations of potassium. These dis- including hydroxyl radical (OH−), superoxide radical (O−2̇ ), and hydro-
ruptions are reversible if oxygen is restored. If oxygen is not restored, gen peroxide (H2O2) (see p. 67). These radicals can all cause further
however, vacuolation (formation of vacuoles) occurs within the cyto- membrane damage and mitochondrial calcium overload. The white
plasm and swelling of lysosomes and marked mitochondrial swelling blood cells (neutrophils) are especially affected with reperfusion
result from damage to the outer membrane. Continued hypoxic injury injury, including neutrophil adhesion to the endothelium. Antioxidant
with accumulation of calcium subsequently activates multiple enzyme treatment not only reverses neutrophil adhesion but also can reverse
systems resulting in membrane damage, cytoskeleton disruption, DNA neutrophil-mediated heart injury. Other potential and current treat-
and chromatin degradation, ATP depletion, and eventual cell death ments may include blockage of inflammatory mediators and inhibition
(see Figures 3-7, C, and 3-20). Structurally, with plasma membrane of certain cell death pathways.
66 CHAPTER 3  Altered Cellular and Tissue Biology

unstable; the molecule becomes stabilized either by donating or by

Thrombus Swollen cell
accepting an electron from another molecule. When the attacked
Anoxia molecule loses its electron, it becomes a free radical. Therefore it is
capable of injurious chemical bond formation with proteins, lipids,
and carbohydrates—key molecules in membranes and nucleic acids.
Blood vessel Free radicals are difficult to control and initiate chain reactions. They
are highly reactive because they have low chemical specificity, mean-
O2
ing they can react with most molecules in their proximity.
Free radicals may be initiated within cells by (1) absorption of
Necrotic cell extreme energy sources (e.g., ultraviolet light, radiation); (2) activation
Reperfusion of endogenous reactions by systems involved in electron and oxygen
transport; for example, reduction of oxygen to water (redox reac-
tions); all biologic membranes contain redox systems important for
cell defense (e.g., inflammation, iron uptake, growth and proliferation,
O2—, H2O2 OH • and signal transduction) (Figure 3-10); and (3) enzymatic metabolism
O2 ’
of exogenous chemicals or drugs (e.g., CCl3·, a product of carbon tetra-
Radicals
chloride [CCl4]). Table 3-3 describes the most significant free radicals.
FIGURE 3-9  Reperfusion Injury. Without oxygen, or anoxia, the During normal metabolism, the mitochondria are the greatest
cells display hypoxic injury and become swollen. With reoxy- source and target of ROS. These ROS contribute to mitochondria dys-
genation, reperfusion injury increases because of the forma-
function and are related to many human diseases and the aging process.
tion of reactive oxygen radicals that can cause cell necrosis.
Usually ROS are reduced by intracellular antioxidant enzymes, includ-
(Redrawn from Damjanov I: Pathology for the health professions,
ed 3, St Louis, 2006, Saunders.) ing superoxide dismutase (SOD), glutathione peroxidase, and catalase,
as well as antioxidant molecules such as glutathione and vitamin E.
In pathologic conditions, however, the large numbers of ROS over-
whelm the balance by antioxidants. This inefficiency of antioxidants
HEALTH ALERT is even more serious in mitochondria because mitochondria in most
Whole Food Antioxidants cells lack catalase.4 Consequently, the excessive production of hydro-
gen peroxide and eventually hydroxyl radical (OH•) in mitochondria
Nutrient antioxidants—vitamin C, vitamin E, and β-carotene (a precursor to vitamin
will damage lipid, proteins, and mitochondrial DNA (mDNA), result-
A)—work by inactivating free radicals. Especially important is the prevention of oxi-
ing either in cell death by necrosis or in a specific type of cell suicide
dative damage to mitochondrial DNA. Vitamin C, found in citrus fruits, broccoli, and
called apoptosis.4-7 Mitochondrial oxidative stress has been implicated
potatoes, is probably the most notable of the antioxidant nutrients. A water-soluble
in heart disease, Alzheimer disease, Parkinson disease, prion diseases,
vitamin, it is the first line of defense, scavenging free radicals before they enter
and amyotrophic lateral sclerosis (ALS), as well as aging itself.8-11 Cur-
cell membranes. Vitamin C promotes wound healing, growth, and tissue repair. It
rently, investigators are trying to identify the polypeptides (i.e., pro-
also enhances the effect of vitamin E. It is known to lower the risk of cataracts and
teomes) directly involved in diseases associated with mitochondrial
heart disease. Most of the protective antioxidant effects of vitamin E, which is fat
dysfunction.
soluble and available in unprocessed oils, wheat germ, hazelnuts, almonds, egg
Free radicals cause several damaging effects by (1) lipid peroxida-
yolk, and butter, occur within the lipid-rich cell membrane. It is an anticoagulant
tion, which is the destruction of polyunsaturated lipids (the same pro-
and important in the formation of blood cells. It also helps to utilize vitamin K, and
cess by which fats become rancid), leading to membrane damage and
it reduces the risk of cataracts. β-Carotene, found in carrots, dark green and yellow-
increased permeability; (2) protein alterations, causing fragmentation
orange vegetables and fruits, leafy vegetables, sweet potatoes, tomatoes, spinach,
of polypeptide chains; (3) DNA fragmentation, causing decreased pro-
squash, and broccoli, is converted to vitamin A in the small intestine and may be
tein synthesis; and (4) mitochondrial damage, causing the liberation
associated with reduced risk of cancer, cataracts, and heart disease.
of calcium into the cytosol (see p. 83 and Fig. 3-7, C). Because of the
increased understanding of free radicals, a growing number of diseases
and disorders have been linked either directly or indirectly to these

4 QUICK CHECK 3-1

reactive species (Box 3-1).
It is fortunate that the body can sometimes eliminate free radicals.
1. When does a cell become irreversibly injured? The oxygen free radical superoxide may spontaneously decay into oxy-
2. Why are oxidative free radicals damaging to cells? gen and hydrogen peroxide. Table 3-4 summarizes other methods that
3. How do cells become markedly swollen with hypoxic injury? contribute to inactivation or termination of free radicals. The toxicity
of certain drugs and chemicals can be attributed either to conversion of
these chemicals to free radicals or to the formation of oxygen-derived
metabolites (see the following discussion).
Free Radicals and Reactive Oxygen
Species—Oxidative Stress Chemical Injury
An important mechanism of cellular injury is injury induced by Mechanisms
free radicals, especially by reactive oxygen species (ROS); this form About 4 billion pounds of toxic chemicals are released per year in the
of injury is called oxidative stress. Oxidative stress occurs when United States. Of these, approximately 72 million pounds are known
excess ROS overwhelm endogenous antioxidant systems. A free radi- carcinogens (see Chapter 10). Only a very small proportion of the
cal is an electrically uncharged atom or group of atoms that has an 100,000 chemicals in use for commercial purposes have been tested
unpaired electron. Having one unpaired electron makes the molecule for health effects. Individual sensitivities to chemicals vary because of
 CHAPTER 3  Altered Cellular and Tissue Biology 67

O2 Peroxisome

ER

Mitochondrion

H+

Radiation
Chemicals
Ubiquinone Inflammation
H+ Reperfusion injury

Mitochondria

O2 Partial
reduction
Fenton reaction
1
_ SOD Fe2+, Cu+
O2 H2O2 OH• H2O + O2
Superoxide Hydrogen peroxide Hydroxyl radical

2 Glutathione Glutathione
peroxidase reductase

_
ROS (O2 , H2O2, OH•) or ROS or Removal

1 • SOD superoxide dismutase

(mitochondria)
• Disruption of plasma membrane 2 Glutathione peroxidase converts
• Protein destruction/loss/misfolding
•OH H2O2 H2O + O2 (mitochondria)
• DNA mutation, breaks
3 Catalase converts in peroxidase
H2O2 H2O + O2

FIGURE 3-10  Generation of Reactive Oxygen Species and Antioxidant Mechanisms in Biologic
Systems. Free radicals are generated within cells in several ways, including from normal respiration;
absorption of radiant energy; activation of leukocytes during inflammation; metabolism of chemicals
or drugs; transition metals, such as iron (Fe+++) or copper (Cu+), where the metals donate or accept
electrons as in the Fenton reaction; nitric oxide (NO) generated by endothelial cells (not shown); and
reperfusion injury. Ubiquinone (coenzyme Q), a lipophilic molecule, transfers electrons in the inner
membrane of mitochondria, ultimately enabling their interaction with oxygen (O2) and hydrogen (H2) to
yield water (H2O). In so doing, the transport allows free energy change and the synthesis of 1 mole of
adenosine triphosphate (ATP). With the transport of electrons, free radicals are generated within the
mitochondria. Reactive oxygen species (O− 2̇
, H2O2, OH·) act as physiologic modulators of some mito-
chondrial functions but may also cause cell damage. O2 is converted to superoxide (O− 2̇
) by oxidative
enzymes in the mitochondria, endoplasmic reticulum (ER), plasma membrane, peroxisomes, and cyto-
sol. O2 is converted to H2O2 by superoxide dismutase (SOD) and further to OH· by the Cu/Fe Fenton
reaction. Superoxide catalyzes the reduction of Fe++ to Fe+++, thus increasing OH· formation by the
Fenton reaction. H2O2 is also derived from oxidases in peroxisomes. The three reactive oxygen species
(H2O2, OH·, and O− 2̇
) cause free radical damage to lipids (peroxidation of the membrane), proteins (ion
pump damage), and DNA (impaired protein synthesis). The major antioxidant enzymes include SOD,
catalase, and glutathione peroxidase.
68 CHAPTER 3  Altered Cellular and Tissue Biology

TABLE 3-3 BIOLOGICALLY RELEVANT FREE RADICALS

Reactive oxygen species (ROS) Generated either (1) directly during autoxidation in mitochondria or (2) enzymatically by enzymes in cytoplasm, such as
Superoxide O–2̇ xanthine oxidase or cytochrome P-450; once produced, it can be inactivated spontaneously or more rapidly by enzyme
−
O2 Oxidase O2˙ superoxide dismutase (SOD): O−2˙ + O−2˙ + – H−2˙ SOD H2O2 + O2
Hydrogen peroxide (H2O2) Generated by SOD or directly by oxidases in intracellular peroxisomes; note: SOD is considered an antioxidant because
it converts superoxide to H2O2; catalase (another antioxidant) can then decompose H2O2 to O2 + H2O.)
SOD
O−2˙ + O−2˙ + –H H2O2 + O2
Or
Oxidases present in peroxisomes
O2 peroxisome O−2˙ SOD H2O2
Hydroxyl radicals (OH¯) Generated by hydrolysis of water caused by ionizing radiation or by interaction with metals—especially iron (Fe) and
H2 O → H · + OH · copper (Cu); iron is important in toxic oxygen injury because it is required for maximal oxidative cell damage
Or
Fe + + + H2 O2 → Fe + + + OH · + OH−
Or
H2 O2 + O− 2̇
→ OH · + OH− + O2
Nitric oxide (NO) NO by itself is an important mediator that can act as a free radical; it can be converted to another radical—­
NO · + O− 2̇
→ ONOO− + H + peroxynitrite anion (ONOO−), as well as NO.2 and CO− 3̇

Data from Cotran RS, Kumar V, Collins T: Robbins pathologic basis of disease, ed 6, Philadelphia, 1999, Saunders.

BOX 3-1 DISEASES AND DISORDERS TABLE 3-4 METHODS CONTRIBUTING

LINKED TO OXYGEN-DERIVED TO INACTIVATION OR
FREE RADICALS TERMINATION OF FREE
RADICALS
Deterioration noted in aging
Atherosclerosis METHOD PROCESS
Ischemic brain injury Antioxidants Endogenous or exogenous; either blocks synthesis or
Alzheimer disease inactivates (e.g., scavenges) free radicals; includes
Neurotoxins vitamin E, vitamin C, cysteine, glutathione, albumin,
Cancer ceruloplasmin, transferrin, γ-lipoacid, others
Cardiac myopathy Enzymes Superoxide dismutase,* which converts superoxide to
Chronic granulomatous disease H2O2; catalase* (in peroxisomes) decomposes H2O2;
Diabetes mellitus glutathione peroxidase* decomposes OH· and H2O2
Eye disorders
*These enzymes are important in modulating the cellular destructive
Macular degeneration
effects of free radicals, also released in inflammation.
Cataracts
Inflammatory disorders
Iron overload
Lung disorders Humans are constantly exposed to a variety of compounds termed
Asbestosis xenobiotics (Greek xenos, “foreign;” bios, “life”) that include toxic,
Oxygen toxicity mutagenic, and carcinogenic chemicals (Figure 3-11). Some of these
Emphysema chemicals are found in the human diet. Most xenobiotics are trans-
Nutritional deficiencies ported in the blood by lipoproteins and penetrate lipid membranes.
Radiation injury These chemicals can react with cellular macromolecules, such as pro-
Reperfusion injury teins and DNA, or can react directly with cell structures to cause cell
Rheumatoid arthritis damage.12 The body has two defense systems for counteracting these
Skin disorders effects: (1) detoxification enzymes and (2) antioxidant systems (see
Toxic states p. 67). Detoxification enzymes are located predominantly in the liver
Xenobiotics (CCl4, paraquat, cigarette smoke, etc.) and provide clearance of compounds through the portal circulation,
Metal irons (Ni, Cu, Fe, etc.) thereby preventing the potentially carcinogenic agent(s) from enter-
ing the body through the gastrointestinal tract and portal circulation.
Adapted from Knight JA: Review: free radicals, antioxidants, and the
immune system, Ann Clin Lab Sci 30(2):145, 2000.
These enzymes also occur in the skin epithelia and can be induced in
other extrahepatic tissue, such as the lung.

age (timing of exposure), genetics, and complex interactions among Chemical Agents Including Drugs
various pollutants. For example, combinations of chemicals may not Numerous chemical agents cause cellular injury. Because chemical
be just additive (1 + 2 = 3) but rather synergistic (1 + 2 = 5). Chemicals injury remains a constant problem in clinical settings, it is a major
can act at the site of entry or at other sites following transport in the limitation to drug therapy. The site of injury is frequently the liver,
circulation. where many chemicals and drugs are metabolized (Figure 3-12).
 CHAPTER 3  Altered Cellular and Tissue Biology 69

Exposure to CCl4

Smooth endoplasmic reticulum

CCl3 O2

Lipid radicals

Air Water Soil Lipid peroxidation

Destruction of rough Destruction of

endoplasmic plasma membrane
reticulum membrane
HUMAN EXPOSURE
↑ Membrane permeability
↓ Protein synthesis

GI tract Na+, H2O, Ca++ influx

Skin Lung ↓ Lipoprotein secretion
Cellular swelling
↑ Triglyceride content
of liver cells
Massive influx of Ca++
↑ Fatty liver

Injury to mitochondria
↑
ATP
↓
Influx of calcium in
mitochondria
Absorption into ↑
bloodstream Oxidative metabolism
↓
Glycolysis

↓ pH

Lysosomal swelling

Release of
lysosomal enzymes
Toxicity Distribution to tissues Storage (hydrolases)

Cellular digestion
METABOLISM Excretion (autodigestion)

FIGURE 3-11  Human Exposure to Pollutants. Pollutants FIGURE 3-12  Chemical Injury of Liver Cells Induced by Carbon
­contained in air, water, and soil are absorbed through the lungs, Tetrachloride (CCl4) Poisoning. Light blue boxes are mechanisms
gastrointestinal tract, and skin. In the body they may act at the unique to chemical injury, purple boxes involve hypoxic injury, and
site of absorption but are generally transported through the blood- green boxes are clinical manifestations.
stream to various organs where they can be stored or metabolized.
Metabolism of xenobiotics may result in the formation of water-
soluble compounds that are excreted, or a toxic metabolite may and the birth defect attributed to thalidomide.13 Importantly, another
be created by activation of the agent. (From Kumar V et al, editors: example includes common drugs of abuse (Table 3-5). Drug abuse can
­Robbins and Cotran pathologic basis of disease, ed 8, St Louis, involve mind-altering substances beyond therapeutic or social norms
2010, Saunders.) (Table 3-6). Drug addiction and overdose are serious public health
issues.
Most toxic chemicals are not biologically active in their parent
The mechanisms by which drug actions, chemicals, and toxins pro- (native) form but must be converted to reactive metabolites, which
duce injury include (1) direct damage, also called on-target toxicity; then act on target molecules. This conversion is usually performed by
(2) exaggerated response at the target, including overdose; (3) biologic the cytochrome P-450 oxidase enzymes in the smooth endoplasmic
activation to toxic metabolites, including free radicals; (4) hypersen- reticulum of the liver and other organs. These toxic metabolites cause
sitivity and related immunologic reactions; and (5) rare toxicities.13 membrane damage and cell injury mostly from formation of free radi-
These mechanisms are not mutually exclusive; thus several may be cals and subsequent membrane damage called lipid peroxidation. For
operating concurrently. example, acetaminophen (paracetamol) is converted to a toxic metab-
Direct damage is when chemicals and drugs injure cells by combin- olite in the liver, causing cell injury (Figure 3-13). Acetaminophen is
ing directly with critical molecular substances. For example, cyanide one of the most common causes of poisoning world-wide.14 Hyper-
is highly toxic (e.g., poison) because it inhibits mitochondrial cyto- sensitivity reactions are a common drug toxicity and range from mild
chrome oxidase and hence blocks electron transport. Many chemo- skin rashes to immune-mediated organ failure.13 One type of hyper-
therapeutic drugs, known as antineoplastic agents, induce cell damage sensitivity reaction is the delayed-onset reaction, which occurs after
by direct cytotoxic effects. Exaggerated pharmacologic responses at the multiple doses of a drug are administered. Some protein drugs and
target include tumors caused by industrial chemicals and estrogens, large polypeptide drugs (e.g., insulin) can directly stimulate antibody
70 CHAPTER 3  Altered Cellular and Tissue Biology

production (see Chapter 7). Most drugs, however, act as haptens and
TABLE 3-5 COMMON DRUGS OF ABUSE
bind covalently to serum or cell-bound proteins. The binding makes
CLASS MOLECULAR TARGET EXAMPLE the protein immunogenic, stimulating antidrug antibody production,
Opioid narcotics Mu opioid receptor Heroin, hydromorphone T-cell responses against the drug, or both. For example, penicillin itself
(agonist) (Dilaudid) is not antigenic but its metabolic degradation products can become
Oxycodone (Percodan, antigenic and cause an allergic reaction. Rare toxicities simply mean
­Percocet, OxyContin) infrequent occurrences described by the other four mechanisms. These
Methadone (Dolophine) toxicities reflect individual genetic predispositions that affect drug or
Meperidine (Demerol) chemical metabolism, disposition, and immune responses.
Sedative-­ GABAA receptor Barbiturates Chronic exposure to air pollutants, insecticides, and herbicides
hypnotics (agonist) Ethanol can cause cellular injury. Carbon monoxide, carbon tetrachloride, and
Methaqualone social drugs, such as alcohol, can significantly alter cellular function
(Quaalude) and injure cellular structures. Accidental or suicidal poisonings by
Glutethimide (Doriden) chemical agents cause numerous deaths. The injurious effects of some
Ethchlorvynol (Placidyl) agents—lead, carbon monoxide, ethyl alcohol, mercury—are com-
Psychomotor Dopamine transporter Cocaine mon cellular injuries. Acetaminophen and common drugs of abuse
stimulants (antagonist) Amphetamines were discussed earlier (see p. 69).
Serotonin receptors 3,4-Methylenedioxy- Lead. Lead is a heavy metal that persists in the environment.
(toxicity) methamphetamine Despite efforts to reduce exposure through government regulation,
(MDMA, ecstasy) lead toxicity is still a primary hazard for children.15 Compared to
Phencyclidine-like NMDA glutamate receptor Phencyclidine (PCP, adults, children absorb lead more readily through the intestines. If
drugs channel (antagonist) angel dust) nutrition is compromised, especially if dietary intake of iron, cal-
Ketamine cium, zinc, and vitamin D is insufficient, lead’s toxic effects are
Cannabinoids CB1 cannabinoid receptors Marijuana enhanced.16,17 Particularly worrisome is lead exposure during preg-
(agonist) Hashish nancy because the developing fetal nervous system is especially vul-
Hallucinogens Serotonin 5-HT2 receptors Lysergic acid nerable; lead exposure can result in learning disorders, hyperactivity,
(agonist) ­diethylamide (LSD) and attention problems.15
Mescaline Lead-based paint has a sweet taste and is often ingested by children.
Psilocybin Common sources of lead are included in Table 3-7.
The organ systems primarily affected by lead ingestion include the
From Kumar V et al: Cellular responses to stress and toxic insults: nervous system, the hematopoietic system (tissues that produce blood
adaptation, injury, and death. In Kumar V et al, editors: Robbins and
cells), and the kidneys of the urologic system. Lead affects many differ-
Cotran pathologic basis of disease, ed 8, St Louis, 2010, Saunders;
Hyman SE: A 28 year old man addicted to cocaine, JAMA 286:2586,
ent biologic activities, many of which may be related to the function of
2001. calcium.15 Lead is able to increase intracellular calcium concentrations.
CB1, Cannabinoid receptor; GABA, γ-Aminobutyric acid; 5-HT2, 5-hy- Lead inhibits several enzymes involved in hemoglobin synthesis and
droxytryptamine; NMDA, N-methyl-d-aspartate. causes anemia as a result of lysis of red blood cells (hemolysis). Other

TABLE 3-6 SOCIAL OR STREET DRUGS AND THEIR EFFECTS

TYPE OF DRUG DESCRIPTION AND EFFECTS
Marijuana (pot) Active substance: Δ9-Tetrahydrocannabinol (THC), found in resin of Cannabis sativa plant
With smoking (e.g., “joints”), about 50% is absorbed through lungs; when ingested only 10% is absorbed; with heavy use the
­following adverse effects have been reported: alterations of sensory perception; cognitive and psychomotor impairment
(e.g., inability to judge time, speed, distance); smoking 3 or 4 joints/day is similar to smoking 20 cigarettes/day; it increases
heart rate and blood pressure; increases susceptibility to laryngitis, pharyngitis, bronchitis; causes cough and hoarseness; may
contribute to lung cancer; data from animal studies only indicate reproductive changes include reduced fertility, decreased sperm
motility, and decreased levels of circulatory testosterone; fetal abnormalities include low birth weight; increased frequency of
infectious illness is thought to be result of depressed cell-mediated and humoral immunity; beneficial effects include decreased
nausea secondary to cancer chemotherapy and decreased pain in certain chronic conditions
Methamphetamine An amine derivation of amphetamine (C10H15N) used as crystalline hydrochloride
(Meth) CNS stimulant; in large doses causes irritability, aggressive (violent) behavior, anxiety, excitement, auditory hallucinations, and
paranoia (delusions and psychosis); mood changes are common and abuser can swiftly change from friendly to hostile; paranoiac
swings can result in suspiciousness, hyperactive behavior, and dramatic mood swings
Appeals to abusers because body’s metabolism is increased and produces euphoria, alertness, and perception of increased energy
Stages:
Low intensity: User is not psychologically addicted and uses methamphetamine by swallowing or snorting
Binge and high intensity: User has psychologic addiction and smokes or injects to achieve a faster, stronger high
Tweaking: Most dangerous stage; user is continually under the influence, not sleeping for 3-15 days, extremely irritated, and
paranoid
 CHAPTER 3  Altered Cellular and Tissue Biology 71

TABLE 3-6 SOCIAL OR STREET DRUGS AND THEIR EFFECTS—cont’d

TYPE OF DRUG DESCRIPTION AND EFFECTS
Cocaine and crack Extracted from leaves of cocoa plant and sold as a water-soluble powder (cocaine hydrochloride) liberally diluted with talcum
powder or other white powders; extraction of pure alkaloid from cocaine hydrochloride is “free-base” called crack because it
“cracks” when heated
Crack is more potent than cocaine; cocaine is widely used as an anesthetic, usually in procedures involving oral cavity; it is a
potent CNS stimulant, blocking reuptake of neurotransmitters norepinephrine, dopamine, and serotonin; also increases synthesis
of norepinephrine and dopamine; dopamine induces sense of euphoria, and norepinephrine causes adrenergic potentiation,
including hypertension, tachycardia, and vasoconstriction; cocaine can therefore cause severe coronary artery narrowing and
ischemia; reason cocaine increases thrombus formation is unclear; other cardiovascular effects include dysrhythmias, sudden
death, dilated cardiomyopathy, rupture of descending aorta (i.e., secondary to hypertension); effects on fetus include premature
labor, retarded fetal development, stillbirth, hyperirritability
Heroin Opiate closely related to morphine, methadone, and codeine
Highly addictive, and withdrawal causes intense fear (“I’ll die without it”); sold “cut” with similar-looking white powder; dissolved
in water it is often highly contaminated; feeling of tranquility and sedation lasts only a few hours and thus encourages repeated
intravenous or subcutaneous injections; acts on the receptors enkephalins, endorphins, and dynorphins, which are widely distrib-
uted throughout body with high affinity to CNS; effects can include infectious complications, especially Staphylococcus aureus,
granulomas of lung, septic embolism, and pulmonary edema—in addition, viral infections from casual exchange of needles and
HIV; sudden death is related to overdosage secondary to respiratory depression, decreased cardiac output, and severe pulmonary
edema

Data from Cotran RS, Kumar V, Colllins T: Robbins pathologic basis of disease, ed 7, Philadelphia, 2005, Saunders; Nahas G, Sutin K, Bennett WM:
Review of marijuana and medicine, N Engl J Med 343(7):514, 2000.
CNS, Central nervous system; HIV, human immunodeficiency virus.

Acetaminophen TABLE 3-7 COMMON SOURCES

OF LEAD EXPOSURE
95% 5%
EXPOSURE SOURCE
Environmental Lead paint, soil, or dust near roadways or lead-painted
Detoxification by CYP2E1 homes; plastic window blinds; plumbing materials
Phase II enzymes activity (from pipes or solder); pottery glazes and ceramic
ware; lead-core candle wicks; leaded gasoline;
water (pipes)
Excretion in urine Occupational Lead mining and refining, plumbing and pipe
as glucuronate or NAPQI ­fitting, auto repair, glass manufacturing, b­ attery
sulfate conjugates ­manufacturing and recycling, printing shop,
­construction work, plastic manufacturing, gas station
Conjugation attendant, firing-range attendant
No toxicity Hobbies Glazed pottery making, target shooting at firing
with GSH
ranges, lead soldering, preparing fishing sinkers,
Protein adducts ­stained-glass making, painting, car or boat repair
Lipid peroxidation Other Gasoline sniffing, costume jewelry, cosmetics,
­contaminated herbal products

Data from Sanborn MD et al: Identifying and managing adverse envi-

Liver failure
ronmental health effects, 3, lead exposure, CMAJ 166(10):1287–1292,
Hepatocyte necrosis
2002.
FIGURE 3-13  Acetaminophen Metabolism and Toxicity. CYP2E1,
a cytochrome; NAPQI, toxic byproduct; GSH, glutathione.
Carbon Monoxide. Gaseous substances can be classified according
to their ability to asphyxiate (interrupt respiration) or irritate. Toxic
manifestations of brain involvement include convulsions and delirium asphyxiants, such as carbon monoxide, hydrogen cyanide, and hydro-
and, with peripheral nerve involvement, wrist, finger, and sometimes gen sulfide, directly interfere with cellular respiration.
foot paralysis. Renal lesions can cause tubular dysfunction resulting in Carbon monoxide (CO) is an odorless, colorless, and undetectable
glycosuria (glucose in the urine), aminoaciduria (amino acids in the gas unless it is mixed with a visible or odorous pollutant. It is produced
urine), and hyperphosphaturia (excess phosphate in the urine). Gas- by the incomplete combustion of fuels such as gasoline. Although
trointestinal symptoms are less severe and include nausea, loss of appe- CO is a chemical agent, the ultimate injury it produces is a hypoxic
tite, weight loss, and abdominal cramping. injury—namely, oxygen deprivation. Normally, oxygen molecules are
72 CHAPTER 3  Altered Cellular and Tissue Biology

carried to tissues bound to hemoglobin in red blood cells (see Chapter Ethanol
26). Because CO’s affinity for hemoglobin is 300 times greater than
that of oxygen, it quickly binds with the hemoglobin, preventing oxy-
gen molecules from doing so. Minute amounts of CO can produce
a significant percentage of carboxyhemoglobin (carbon monoxide MEOS ADH Catalase
bound with hemoglobin). (Cytochrome P-450) (NAD-NADH) (H2O2)
Symptoms related to CO poisoning include headache, giddiness,
tinnitus (ringing in the ears), nausea, weakness, and vomiting. At risk
for carbon monoxide exposure are those who (1) breathe air polluted
by gasoline engines or defective furnaces; (2) work in occupations such Acetaldehyde
as coal mining, fire fighting, welding, or engine repair; and (3) smoke
cigarettes, cigars, or pipes. The fetus is especially at risk from the effects
of carbon monoxide because fetal carboxyhemoglobin levels are likely ACDH
to be 10% to 15% more than maternal levels. (NAD-NADH)
Ethanol. Alcohol (ethanol) is the primary choice among mood-
altering drugs available in the United States. It is estimated there are
more than 10 million chronic alcoholics in the United States. Alco-
Acetate Free radicals
hol contributes to more than 100,000 deaths annually with 50% of
these deaths from drunk driving accidents, alcohol-related homicides,
and suicides.18 A blood concentration of 80 mg/dl is the legal defini-
Acetyl CoA
tion for drunk driving in the United States. This level of alcohol in
an average person may be reached after consumption of three drinks
(3 12-oz bottles of beer, 15 oz of wine, and 4 to 5 oz of distilled liquor). CO2  H2O
The effects of alcohol vary by age, gender, and percent body fat; the
rate of metabolism affects the blood alcohol level. Because alcohol is
not only a psychoactive drug but also a food, it is considered part of ADH  Hepatic alcohol dehydrogenase
ACDH  Hepatic acetaldehyde dehydrogenase
the basic food supply in many societies. A large intake of alcohol has
NAD  Nicotinamide adenine dinucleotide
enormous effects on nutritional status. Liver and nutritional disorders NADH  Reduced nicotinamide adenine dinucleotide
are the most serious consequences of alcohol abuse. Major nutritional MEOS  Microsomal ethanol oxidizing system
deficiencies include magnesium, vitamin B6, thiamine, and phospho-
rus. Folic acid deficiency is a common problem in chronic alcoholic FIGURE 3-14  Major Pathways of ADH Metabolism of Alcohol
in the Liver.
populations. Ethanol alters folic acid (folate) homeostasis by decreas-
ing intestinal absorption of folate, increasing liver retention of folate,
and increasing the loss of folate through urinary and fecal excretion.19
Folic acid deficiency becomes especially serious in pregnant women Since 1997 studies have consistently validated the so-called J- or
who consume alcohol and may contribute to fetal alcohol syndrome U-shaped inverse association between alcohol and cardiovascular dis-
(see p. 73). ease. Consistent epidemiologic studies show that people who daily
Most of the alcohol in blood is metabolized to acetaldehyde in consume light-to-moderate (not excessive) amounts of alcohol reduce
the liver by three enzyme systems: alcohol dehydrogenase (ADH), the their risk of coronary heart disease (CHD) as compared to nondrink-
microsomal ethanol oxidizing system (MEOS), and catalase (Figure ers. The suggested mechanisms for cardioprotection include increase
3-14). The major pathway involves ADH, an enzyme located in the in levels of high density lipoprotein–cholesterol (HDL-C), prevention
cytosol of hepatocytes. The microsomal ethanol oxidizing system of clot formation, reduction in platelet aggregation, and increase in
(MEOS) depends on cytochrome P-450, an enzyme needed for cel- clot degradation (fibrinolysis). Alcohol also may increase insulin sen-
lular oxidation. Activation of MEOS requires a high ethanol concen- sitivity.21 Limited data suggest that the level for optimal benefit may be
tration and thus is thought to be important in the accelerated ethanol slightly lower for women; therefore the American Heart Association
metabolism (i.e., tolerance) noted in persons with chronic alcohol- recommends no more than two drinks per day for men and one drink
ism. Acetaldehyde has many toxic tissue effects and is responsible per day for women. Individuals who do not consume alcohol should
for some of the acute effects of alcohol and for development of oral not be encouraged to start drinking.22
cancers.18 Acute alcoholism affects mainly the CNS but may induce revers-
The major effects of acute alcoholism involve the central nervous ible hepatic and gastric changes.23,24 The hepatic changes, initiated by
system (CNS). After alcohol is ingested, it is absorbed, unaltered, in acetaldehyde, include inflammation, deposition of fat, enlargement of
the stomach and small intestine. Fatty foods and milk slow absorption. the liver, interruption of microtubular transport of proteins and their
Alcohol then is distributed to all tissues and fluids of the body in direct secretion, increase in intracellular water, depression of fatty acid oxida-
proportion to the blood concentration. tion in the mitochondria, increased membrane rigidity, and acute liver
Individuals differ in their capability to metabolize alcohol. Genetic cell necrosis (see Chapter 34). In the CNS alcohol is, itself, a depres-
differences in metabolism of liver alcohol, including aldehyde dehy- sant, initially affecting subcortical structures (probably the brain stem
drogenases, have been identified.20 These genetic polymorphisms reticular formation).23,24 Consequently, motor and intellectual activity
may account for ethnic and gender differences in ethanol metabo- becomes disoriented. At higher blood alcohol levels, medullary cen-
lism. Persons with chronic alcoholism develop tolerance because of ters become depressed, affecting respiration. Much investigation now
production of enzymes, leading to an increased rate of metabolism concerns the relationship of alcohol and snoring and obstructive sleep
(e.g., P-450). apnea (cessation of breathing).25,26
 CHAPTER 3  Altered Cellular and Tissue Biology 73

FIGURE 3-15  Fetal Alcohol Syndrome. When alcohol enters the FIGURE 3-16  Alcoholic Hepatitis. Chicken-wire fibrosis extending
fetal blood, the potential result can cause tragic congenital abnor- between hepatocytes (Mallory trichrome stain). (From Damjanov I, 
malities, such as microcephaly (“small head”), low birth weight, Linder J, editors: Anderson’s pathology, ed 10, St Louis, 1996,
and cardiovascular defects, as well as developmental disabilities, Mosby.)
such as physical and mental retardation, and even death. Note
the small head, thinned upper lip, small eye openings (palpebral
fissures), epicanthal folds, and receded upper jaw (retrognathia)
typical of fetal alcohol syndrome. (From Fortinash KM, Holoday growth; DNA and protein synthesis; modification of carbohydrates,
Worret PA: Psychiatric mental health nursing, ed 3, St Louis, 2004, proteins, and fats; and the flow of nutrients across the placenta.28,29
Mosby.) Alcohol also may cause fetal disturbances, even preconceptual effects,
epigenetically.30
Whatever the cause, persons with chronic alcoholism have a sig-
nificantly shortened life span related mainly to damage to the liver,
Chronic alcoholism causes structural alterations in practically all stomach, brain, and heart. Alcohol is a well-known cause of hepatic
organs and tissues in the body because most tissues contain enzymes injury, terminating in cirrhosis (Figure 3-16) (see Chapter 34), yet
capable of ethanol oxidation or nonoxidative metabolism. The most moderate amounts (e.g., 20 to 30 g/day or 250 ml of wine) of alcohol
significant activity, however, occurs in the liver.27 The following altera- may decrease the incidence of coronary heart disease.
tions occur in the liver: fatty liver, alcoholic hepatitis, and cirrhosis. Mercury. Mercury has been used medically and commercially
Cirrhosis is associated with portal hypertension and an increased risk for centuries. Today people are exposed to mercury from two major
for hepatocellular carcinoma.18 Acute gastritis is a direct toxic effect sources: fish consumption and dental amalgams. Although no cases
and chronic use can lead to acute and chronic pancreatitis. Cellular of mercury toxicity have been reported secondary to vaccination, thi-
damage is increased by reactive oxygen species (ROS) and oxidative merosal was removed from all vaccines in 2001, with the exception of
stress (see p. 66). Activation of proinflammatory cytokines from neu- inactivated influenza vaccines.31 The use of mercury as a preservative
trophils and lymphocytes mediates liver damage.27 Oxidative stress is in vaccines has been greatly decreased or eliminated. Table 3-8 sum-
associated with cell membrane phospholipid depletion, which alters marizes these sources and their health effects.
the fluidity and function of cell membranes as well as intercellular
transport. Chronic alcoholism is related to several disorders, includ-
ing injury to the myocardium (alcoholic cardiomyopathy), increased 4 QUICK CHECK 3-2
tendency to hypertension, and regressive changes in skeletal muscle 1. Discuss the possible mechanisms of cell injury related to chronic alcoholism.
(see Chapter 34). 2. What are some of the systemic effects of methamphetamine, cocaine,
Ethanol is implicated in the onset of a variety of immune defects, marijuana, and heroin use?
including effects on the production of cytokines involved in inflam-
matory responses (tumor necrosis factor, interleukin-1, interleu-
kin-6).23,24 The deleterious effects of prenatal alcohol exposure can Unintentional and Intentional Injuries
cause mental retardation and neurobehavioral disorders, as well as Unintentional and intentional injuries are an important health
fetal alcohol syndrome. Fetal alcohol syndrome includes growth problem in the United States. In 2007 there were 182,479 deaths, an
retardation, facial anomalies, cognitive impairment, and ocular mal- injury death rate of 59.30/100,000.32 Death from injury is signifi-
formations (Figure 3-15). Alcohol crosses the placenta, reaching the cantly more common for men than women; the overall rate for men
fetus rapidly.28 Research has demonstrated an unimpeded bidirec- is 84.38/100,000 versus 34.31/100,000 for women. Significant racial
tional movement of alcohol between the fetus and the mother. The differences are noted in the death rate, with whites at 59.59/100,000,
fetus may completely depend on maternal hepatic detoxification blacks at 65.15/100,000, and other racial groups at a combined rate
because the activity of alcohol dehydrogenase (ADH) in fetal liver of 35.12/100,000. There also is a bimodal age distribution for injury-
is less than 10% of that in the adult liver.28 Additionally, the amni- related deaths, with peaks in the young adult and elderly groups. Unin-
otic fluid acts as a reservoir for alcohol, prolonging fetal exposure.28 tentional injury is the leading cause of death for people between the
The specific mechanisms of injury are unknown; however, acetalde- ages of 1 and 34 years; intentional injury (suicide, homicide) ranks
hyde can alter fetal development by disrupting differentiation and between the second and fourth leading cause of death in this age
74 CHAPTER 3  Altered Cellular and Tissue Biology

TABLE 3-8 MAJOR SOURCES OF MERCURY EXPOSURE AND HEALTH EFFECTS

SOURCE COMMENTS
Dental amalgams Amalgams consist of 50% mercury combined with other metals
Controversial whether amalgams can release mercury vapors into mouth and when fillings are removed cause transient eleva-
tions
Health concerns from claims that mercury vapor can cause or worsen degenerative diseases
(e.g., Alzheimer disease); however, several epidemiologic studies have failed to provide evidence
Difficult problem is that mercury can inhibit biochemical process in vitro without same effects in vivo
Fish consumption Consumption of fish and sea mammals is major source of exposure to methyl mercury
Faroe Islands study showed methyl mercury exposure from whale consumption
U.S. study showed methyl mercury levels slightly higher than EPA guideline
FDA recommends pregnant women, nursing mothers, and young children avoid eating fish with high mercury content (>1 parts
per million [ppm]), such as shark, swordfish, tile fish, king mackerel, and whale meat
Vaccines Thimerosal, a preservative in many multidose vials of vaccines, contains ethyl mercury
Single-dose vials do not require preservatives
Several vaccines containing thimerosal were given to infants until 1999
It is presumed that mercury children receive in vaccines containing thimerosal is excreted with no accumulation during 2-month
periods between vaccinations
Since 2001 no vaccines contain thimerosal except inactivated influenza vaccines
Earlier toxicology studies and a 2007 study found no adverse effects or no support for a causal relationship between thimero-
sal and neuropyschotic functioning

Data from Centers for Disease Control and Prevention, 2004. Available at www.cdc.gov/nip/vacsafeconcerns/thimerosal/flags-thimerosal.htm#4;
Clarkson TW, Magos L, Myers GI: The toxicology of mercury—current exposures and clinical manifestations, N Engl J Med 349(18):1731–1737,
2003; Thompson WW et al: Early thimerosal exposure and neuropsychological outcomes at 7 to 10 years, N Eng J Med 357(13):1281–1292, 2007.

morbidity and disability and to cost society billions of dollars annually.

BOX 3-2 CLASSIFICATION OF The more common terms used to describe and classify unintentional
PREVENTABLE ADVERSE and intentional injuries and brief descriptions of important features of
EVENTS IN PRIMARY CARE these injuries are discussed in Table 3-9.
Diagnosis: Misdiagnosis, missed diagnosis, delayed diagnosis Asphyxial Injuries
a. Related to symptoms
Asphyxial injuries are caused by a failure of cells to receive or use oxy-
b. Related to prevention
gen. Deprivation of oxygen may be partial (hypoxia) or total (anoxia).
Treatment
Asphyxial injuries can be grouped into four general categories: suffoca-
Drug: Incorrect drug, incorrect dose, delayed administration, omitted
tion, strangulation, chemical, and drowning.
administration
Suffocation. Suffocation, or oxygen failing to reach the blood, can
Nondrug: Inappropriate, delayed, omitted, procedural complication
result from a lack of oxygen in the environment (entrapment in an
Preventive services: Inappropriate, delayed, omitted, procedural compli­cation
enclosed space or filling of the environment with a suffocating gas)
Process Errors
or blockage of the external airways. Classic examples of these types of
Clinical factors: Clinical judgment, procedural skills error
asphyxial injuries are a child who is trapped in an abandoned refrig-
Communication factors: Clinician-client, clinician, or healthcare personnel
erator or a person who commits suicide by putting a plastic bag over
Administration factors: Clinician, pharmacy, ancillary providers (physical
his or her head. A reduction in the ambient oxygen level to 16% (nor-
therapy, occupational therapy, etc.), office setting
mal is 21%) is immediately dangerous. If the level is below 5%, death
Other: Personal and family issues of clinicians and staff, insurance com-
can ensue within a matter of minutes. The diagnosis of these types of
pany regulations, government regulations, funding and employers, phys-
asphyxial injuries depends on obtaining an accurate and thorough his-
ical size and location of practice, general healthcare system
tory because there will be no specific physical findings.
Data from Elder N, Dovey S: Classification of medical errors and pre- Diagnosis and treatment in choking asphyxiation (obstruction of
ventable adverse events in primary care: a synthesis of the literature,   the internal airways) depend on locating and removing the obstructing
J Fam Pract 51(1):1079, 2002. material. Injury or disease also may cause swelling of the soft tissues of
the airway leading to partial or complete obstruction and subsequent
group. The 1999 report published by the Institute of Medicine (IOM) asphyxiation. Suffocation also may result from compression of the
indicated that between 44,000 and 98,000 unnecessary deaths per year chest or abdomen (mechanical or compressional asphyxia), prevent-
occurred in hospitals alone as a result of errors by healthcare profes- ing normal respiratory movements. Usual signs and symptoms include
sionals (see Health Alert: Unintentional Injury Errors in Healthcare). florid facial congestion and petechiae (pinpoint hemorrhages) of the
Box 3-2 lists classifications of preventable events in primary care,33 and eyes and face.
Box 3-3 contains recommendations to avoid medical errors. Despite Strangulation. Strangulation is caused by compression and closure
disagreements over the reported statistics, an accurate account is a of the blood vessels and air passages resulting from external pressure on
tremendous challenge.34 Statistics on nonfatal injuries are harder to the neck. This causes cerebral hypoxia or anoxia secondary to the alter-
document accurately, but they are known to be a significant cause of ation or cessation of blood flow to and from the brain. It is important
 CHAPTER 3  Altered Cellular and Tissue Biology 75

HEALTH ALERT
Unintentional Injury Errors in Healthcare
Errors in healthcare are an unintended event; no matter how trivial or com- are methodologically easier to study because the drug prescribing process pro-
monplace, they are errors that could or did harm individuals. Medical errors vides documentation of medical decisions, administration of drugs is recorded,
are one of the leading causes of death and injury in the United States. Medi- supplying drugs are documented, and deaths attributable to medication errors
cal errors occur because the medical plan fails or is the wrong plan. A 1999 are recorded on death certificates. According to the Agency for Healthcare
report by the Institute of Medicine (IOM) estimates that as many as 44,000 to Research and Quality (AHRQ) the rate for potential adverse drug events was
98,000 people in the United States die in hospitals each year as the result of three times higher in children and much higher for babies in neonatal intensive
medical errors. These data mean that more people die from medical errors than care units. New data show bar-code technology with an electronic medication
from motor vehicle accidents, breast cancer, or AIDS. Although these statistics administration record (eMAR) substantially reduces transcription and medica-
have been challenged, the IOM report noted that many of the errors in healthcare tion administration errors. This technology also reduces potential drug-related
result from a culture and system that are fragmented and solving this major prob- adverse events. Bar-code eMAR is a combination of technologies that ensures
lem will require extensive foundation or infrastructure building. Errors involve the correct medication is administered to the right patient at the right dose and
medicines, surgery, diagnosis, equipment, and laboratory reports. They can occur time. When nurses use these technologies, medication orders appear electroni-
anywhere in the healthcare system, including hospitals, clinics, outpatient sur- cally in the individual’s chart after pharmacist approval. Electronic alerts are sent
gery centers, physicians’ and nurse practitioners’ offices, pharmacies, and an to nurses if the medication is overdue and before administering the medication.
individual’s home. Errors can happen during the most routine of plans, such as Nurses are required to scan the bar code on the individual’s wristband and then
when an individual is prescribed a low-salt diet and is given a high-salt meal. on the medication. A warning is issued if the bar codes do not match or it is the
Research indicated that most mistakes were not due to clinicians’ negligence wrong time for administration of the medication.
but rather from inherent shortcomings in the healthcare system. Yet errors can Other errors, in addition to medication errors, include surgical injuries and
occur when clinicians and their clients have trouble communicating. wrong-site surgery; preventable suicides, restraint-related injuries, or death;
Although the literature about errors in healthcare has grown substantially over hospital-acquired or other treatment-related infections; falls; burns; pressure
the last decade, we do not yet have a compelling analysis of the epidemiology of ulcers; and mistaken identity. Studies of errors outside the hospital have begun.
error. More is known about errors in hospitals than in other healthcare delivery The IOM report has galvanized a national movement to improve client safety
settings. Medication-related error has been studied for several reasons: (1) it is and eliminate healthcare errors. “Errors and excess mortality can be eliminated
the most common type of error, (2) substantial numbers of people are affected, but only if concern and attention is shifted away from individuals and toward the
and (3) it accounts for a large increase in healthcare costs. Medication errors error-prone systems in which clinicians work” (Leape, 2000).

Data from Agency for Healthcare Research and Quality (AHRQ):  

20 tips to help prevent medical errors (Pub No. 00-P038), Washington, DC, 2000, U.S. Department of Health and Human Services; Agency for
Healthcare Research and Quality (AHRQ): Advancing patient safety (Pub No. 09(10)-0084), Washington, DC, 2009, U.S. Department of Health and
Human Services; Elder N, Dovey S: Classification of medical errors and preventable adverse events in primary care: a synthesis of the literature, J
Fam Pract 51(1):1079, 2002; Kohn LT, Corrigan JM, Donaldson M, editors: To err is human: building a safer health system, Washington, DC, 1999,
Institute of Medicine; Leape L: Institute of Medicine medical error figures are not exaggerated, J Am Med Assoc 284(1), 2000. Data from AHRQ:
AHRQ study shows using bar-code technology with eMar reduces medication administration and transcription errors, Rockville, Md, press release
May 5, 2010, Author. Available at www.ahrq.gov/news/press.pr2010/emarpr.htm; Poon EG et al: Effect of bar-code technology on the safety of
medication administration, N Engl J Med 362(18):1698–1707, 2010.

to remember that the amount of force needed to close the jugular veins the assailant or by the victim clawing at his or her own neck in an
(2 kg [4.5 lb]) or carotid arteries (5 kg [11 lb]) is significantly less than attempt to remove the assailant’s hands. Internal damage can be quite
that required to crush the trachea (15 kg [33 lb]). It is the alteration of severe, with bruising of deep structures and even fractures of the hyoid
cerebral blood flow in most types of strangulation that causes injury or bone and tracheal and cricoid cartilages. Petechiae are common.
death—not the lack of airflow. With complete blockage of the carotid Chemical Asphyxiants. Chemical asphyxiants either prevent the
arteries, unconsciousness can occur within 10 to 15 seconds. delivery of oxygen to the tissues or block its utilization. Carbon mon-
A noose is placed around the neck, and the weight of the body is oxide is the most common chemical asphyxiant (see p. 71). ­Cyanide
used to cause constriction of the noose and compression of the neck acts as an asphyxiant by combining with the ferric iron atom in cyto-
in hanging strangulations. The body does not need to be completely chrome oxidase, thereby blocking the intracellular use of oxygen.
suspended to produce severe injury or death. Depending on the type of A victim of cyanide poisoning will have the same cherry-red appear-
ligature used, there usually is a distinct mark on the neck—an inverted ance as a carbon monoxide intoxication victim because cyanide blocks
V with the base of the V pointing toward the point of suspension. Inter- the use of circulating oxyhemoglobin. An odor of bitter almonds also
nal injuries of the neck are actually quite rare in hangings, and only may be detected. (The ability to smell cyanide is a genetic trait that is
in judicial hangings, in which the body is weighted and dropped, is absent in a significant portion of the general population.) Hydrogen
significant soft tissue or cervical spinal trauma seen. Petechiae of the sulfide (sewer gas) is a chemical asphyxiant in which victims of hydro-
eyes or face may be seen, but they are rare. gen cyanide poisoning may have brown-tinged blood in addition to
In ligature strangulation, the mark on the neck is horizontal without the nonspecific signs of asphyxiation.
the inverted V pattern seen in hangings. Petechiae may be more common Drowning. Drowning is an alteration of oxygen delivery to tissues
because intermittent opening and closure of the blood vessels may occur resulting from the inhalation of fluid, usually water. In 2007 there were
as a result of the victim’s struggles. Internal injuries of the neck are rare. 4086 drowning deaths in the United States. Although research in the
Variable amounts of external trauma on the neck are found with 1940s and 1950s indicated that changes in blood electrolyte levels and
contusions and abrasions in manual strangulation caused either by volume as a result of absorption of fluid from the lungs may be an
76 CHAPTER 3  Altered Cellular and Tissue Biology

TABLE 3-9 UNINTENTIONAL AND INTENTIONAL INJURIES

TYPE OF INJURY DESCRIPTION
BLUNT-FORCE INJURIES Mechanical injury to body resulting in tearing, shearing, or crushing; most com-
mon type of injury seen in healthcare settings; caused by blows or impacts;
motor vehicle accidents and falls most common cause

Contusion (bruise): Bleeding into skin or underlying tissues; initial color will
be red-purple, then blue-black, then yellow-brown or green (see Figure 3-20);
duration of bruise depends on extent, location, and degree of vascularization;
bruising of soft tissue may be confined to deeper structures; hematoma is
collection of blood in soft tissue; subdural hematoma is blood between inner
surface of dura mater and surface of brain; can result from blows, falls, or
sudden acceleration/deceleration of head as occurs in shaken baby syndrome;
epidural hematoma is collection of blood between inner surface of skull and
dura; is most often associated with a skull fracture

Laceration: Tear or rip resulting when tensile strength of skin or tissue is

exceeded; is ragged and irregular with abraded edges; an extreme example is
avulsion, where a wide area of tissue is pulled away; lacerations of internal
organs are common in blunt-force injuries; lacerations of liver, spleen, kidneys,
and bowel occur from blows to abdomen; thoracic aorta may be lacerated in
sudden deceleration accidents; severe blows or impacts to chest may rupture
heart with lacerations of atria or ventricles

Fracture: Blunt-force blows or impacts can cause bone to break or shatter (see
Chapter 37)

SHARP-FORCE INJURIES Cutting and piercing injuries accounted for 2734 deaths in 2007; men have a
higher rate (1.37/100,000) than women (0.44/100,000); differences by race are
whites 0.71/100,000, blacks 2.12/100,000, and other groups 0.80/100,000

Incised wound: Is a wound that is longer than it is deep; wound can be straight
or jagged with sharp, distinct edges without abrasion; usually produces
significant external bleeding with little internal hemorrhage; are noted in sharp-
force injury suicides; in addition to a deep, lethal cut, there will be superficial
incisions in same area called hesitation marks

Stab wound: Is a penetrating sharp force injury that is deeper than it is long;
if a sharp instrument is used, depths of wound are clean and distinct but
can be abraded if object is inserted deeply and wider portion (e.g., hilt of
a knife) impacts skin; depending on size and location of wound, external
bleeding may be surprisingly small; after an initial spurt of blood, even if a
major vessel or heart is struck, wound may be almost completely closed by
tissue pressure, thus allowing only a trickle of visible blood despite copious
internal bleeding

Puncture wound: Instruments or objects with sharp points but without sharp edges
produce puncture wounds; classic example is wound of foot after stepping on a nail;
wounds are prone to infection, have abrasion of edges, and can be very deep

Chopping wound: Heavy, edged instruments (axes, hatchets, propeller blades)

produce wounds with a combination of sharp- and blunt-force characteristics
 CHAPTER 3  Altered Cellular and Tissue Biology 77

TABLE 3-9 UNINTENTIONAL AND INTENTIONAL INJURIES—cont’d

TYPE OF INJURY DESCRIPTION
GUNSHOT WOUNDS Accounted for more than 31,224 deaths in the United States in 2007; men more
likely to die than women (18.16 vs. 2.73/100,000); black men between ages of
15 and 24 have greatest death rate (86.95/100,000); gunshot wounds are either
penetrating (bullet remains in body) or perforating (bullet exits body); bullet
also can fragment; most important factors or appearances are whether it is an
entrance or exit wound and range of fire

Entrance wound: All wounds share some common features; overall appearance is
most affected by range of fire

Contact range entrance wound: Distinctive type of wound when gun is held so
muzzle rests on or presses into skin surface; there is searing of edges of wound
from flame and soot or smoke on edges of wound in addition to hole; hard
contact wounds of head cause severe tearing and disruption of tissue (because
of thin layer of skin and muscle overlying bone); wound is gaping and jagged,
known as blow back; can produce a patterned abrasion that mirrors weapon
used

Intermediate (distance) range entrance wound: Surrounded by gunpowder tattoo-

ing or stippling; tattooing results from fragments of burning or unburned pieces
of gunpowder exiting barrel and forcefully striking skin; stippling results when
gunpowder abrades but does not penetrate skin

Indeterminate range entrance wound: Occurs when flame, soot, or gunpowder

does not reach skin surface but bullet does; i­ndeterminate is used rather than
distant because appearance may be same regardless of distance; for example,
if an individual is shot at close range through multiple layers of clothing the
wound may look the same as if the shooting occurred at a distance

Exit wound: Has the same appearance regardless of range of fire; most important
factors are speed of projectile and degree of deformation; size cannot be used
to determine if hole is an exit or entrance wound; usually has clean edges that
can often be reapproximated to cover defect; skin is one of toughest structures
for a bullet to penetrate; thus it is not uncommon for a bullet to pass entirely
through body but stopped just beneath skin on “exit” side

Wounding potential of bullets: Most damage done by a bullet is a result of amount

of energy transferred to tissue impacted; speed of bullet has much greater effect
than increased size; some bullets are designed to expand or fragment when strik-
ing an object, for example, hollow-point ammunition; lethality of a wound depends
on what structures are damaged; wounds of brain may not be lethal; however,
they are usually immediately incapacitating and lead to significant long-term
disability; a person with a “lethal” injury (wound of heart or aorta) also may not be
immediately incapacitated
78 CHAPTER 3  Altered Cellular and Tissue Biology

BOX 3-3 RECOMMENDATIONS TO AVOID MEDICAL ERRORS

What can you do? Be Involved in Your Healthcare. Hospital Stays
1. The single most important way you can help prevent errors is to be an 10. If you have a choice, choose a hospital in which many patients have the
active member of your healthcare team. That means taking part in every same procedure or surgery you need. Research shows that patients tend
decision about your healthcare. Research shows that patients who are to have better results when they are treated in hospitals that have a great
more involved with their care tend to get better results. deal of experience with their condition.
11. If you are in a hospital, consider asking all healthcare workers who have
Medicines direct contact with you whether they have washed their hands. Handwash-
2. Make sure your healthcare providers know everything you are taking, ing is an important way to prevent the spread of infections in hospitals.
including prescription and over-the-counter medicines and dietary supple- However, it is not done regularly or thoroughly enough. A recent study found
ments such as vitamins and herbs. At least once a year, take all of your that when patients checked whether healthcare workers washed their
medications and supplements to an appointment with your healthcare pro- hands, the workers washed their hands more often and used more soap.
vider. “Brown bagging” your medications can help you and your provider 12. When you are being discharged from the hospital, ask your healthcare pro-
talk about them and determine if there are any problems. This action also vider to explain the treatment plan you will use at home. This includes
can help your provider keep your records up to date, which can help you learning about your medicines and determining when you can resume your
obtain better quality care. regular activities. Recent studies show that healthcare providers often
3. Make sure you inform your healthcare providers about any allergies and overestimate their patients’ understanding of discharge instructions.
adverse reactions you have shown to medications. This can help you avoid
exposure to a medication that can harm you. Surgery
4. When your healthcare provider writes you a prescription, make sure you 13. If you are having surgery, make sure you, your healthcare provider, and your
can read it. If you cannot read your provider’s handwriting, your pharmacist surgeon all agree and are clear on exactly what will be done. Performing
might not be able to either. surgery at the wrong site (for example, operating on the left knee instead of
5. Ask for information about your medicines in terms you can understand—both the right) is rare—but even once is too often. The good news is that wrong-
when your medications are prescribed and when you receive them. What is site surgery is 100% preventable. The American Academy of Orthopaedic
the purpose of the medicine? How am I supposed to take it and for how long? Surgeons urges its members to sign their initials directly on the operative
What side effects are likely? What should I do if side effects occur? Is this site before the surgery.
medicine safe to take with other medicines or dietary supplements I am tak-
ing? What food, drink, or activities should I avoid while taking this medicine? Other Steps You Can Take
6. When you pick up your medicine from the pharmacy ask, “Is this the medi- 14. Speak up if you have questions or concerns. You have a right to question
cine my provider prescribed?” A study conducted by the Massachusetts anyone who is involved with your care.
College of Pharmacy and Allied Health Sciences found that 88% of medi- 15. Make sure that someone, such as your personal healthcare provider, is in
cine errors involved the wrong drug or the wrong dose. charge of your care. This is especially important if you have many health
7. If you have any questions about the directions on your medicine label, ask. problems or are in a hospital.
Medicine labels can be hard to understand. For example, ask if “four doses 16. Make sure that all health professionals involved in your care have impor-
daily” means taking a dose every 6 hours around the clock or just during tant health information about you. Do not assume that everyone has the
regular waking hours. necessary information about your care.
8. Ask your pharmacist for the best device to measure your liquid medicine. 17. Ask a family member or friend to stay with you and to be your advocate
Also ask questions if you are not sure how to use it. Research shows that (someone who can help get things done and speak for you if you cannot).
many people do not understand the right way to measure liquid medicines. Even if you do not need help now, you might need it later.
For example, many use household teaspoons, which often do not hold a 18. Know that “more” is not always better. It is a good idea to find out why a
true teaspoon of liquid. Special devices, like marked syringes, help to mea- test or treatment is needed and how it can help you. You could be better off
sure the right dose. Being told how to use the devices helps even more. without it.
9. Ask for written information about the side effects your medicine could 19. If you have a test, do not assume that “no news is good news.” Ask about
cause. If you know the possible side effects of a medication, you will be the results.
better prepared if a side effect occurs; alternatively, if you have an unex- 20. Learn about your condition and treatments by asking your healthcare pro-
pected reaction, you can report the problem immediately and get help vider and nurse and by using other reliable sources. For example, treatment
before the condition worsens. A study found that written information about recommendations based on the latest scientific evidence are available from
medicines can help patients recognize problem side effects and then com- the National Guidelines Clearinghouse at www.guideline.gov. Ask your
municate that information to their healthcare provider or pharmacist. provider if your treatment is based on the latest evidence.

Data from Agency for Healthcare Research and Quality: 20 tips to help prevent medical errors (Pub No. 00-PO30), Rockville, Md, 2000, Author;
Bates DW et al: JAMA 274(1):29–34, 1995; Bates DW et al: JAMA 277(4):307–311, 1997; Centers for Disease Control and Prevention, National
Center for Health Statistics: Natl Vital Stats Rep 47 191:27, 1999; Institute of Medicine: To err is human: building a safer health system,
­Washington, DC, 1999, National Academy Press.
 CHAPTER 3  Altered Cellular and Tissue Biology 79

TABLE 3-10 MECHANISMS OF CELLULAR INJURY

MECHANISM CHARACTERISTICS EXAMPLES
Genetic Factors Alter cell’s nucleus and plasma membrane’s structure, shape, receptors, Sickle cell anemia, Huntington disease, muscular dystrophy,
or transport mechanisms abetalipoproteinemia, familial hypercholesterolemia
Epigenetic Induction of mitotically heritable alterations in gene expression without Gene silencing in cancer
Factors changing DNA
Nutritional Pathophysiologic cellular effects develop when nutrients are not consumed Protein deficiency, protein-calorie malnutrition, glucose
­Imbalances in diet and transported to body’s cells or when excessive amounts of deficiency, lipid deficiency (hypolipidemia), hyperlipidemia
nutrients are consumed and transported (increased lipoproteins in blood causing deposits of fat in
heart, liver, and muscle), vitamin deficiencies

Physical Agents
Temperature Hypothermic injury results from chilling or freezing of cells, creating high Frostbite
extremes intracellular sodium concentrations; abrupt drops in temperature lead to
vasoconstriction and increased viscosity of blood, causing ischemic injury,
infarction, and necrosis; reactive oxygen species (ROS) are important in
this process
Hyperthermic injury is caused by excessive heat and varies in severity Burns, burn blisters, heat cramps usually from vigorous
according to nature, intensity, and extent of heat exercise with water and salt loss; heat exhaustion with
salt and water loss causes heme contraction; heat stroke is
life-threatening with a clinical rectal temperature of 106° F
Tissue injury caused by compressive waves of air or fluid impinging on Blast injury (air or immersion), decompression sickness
body, followed by sudden wave of decreased pressure; changes may (caisson disease or “the bends”); recently reported in a
collapse thorax, rupture internal solid organs, and cause widespread few individuals with subdural hematomas after riding high-
­hemorrhage: carbon dioxide and nitrogen that are normally dissolved speed roller coasters
in blood precipitate from solution and form small bubbles (gas emboli),
­causing hypoxic injury and pain
Ionizing radiation Refers to any form of radiation that can remove orbital electrons from X-rays, γ-rays, and α- and β-particles cause skin redness,
atoms; source is usually environment and medical use; damage is to skin damage, chromosomal damage, cancer
DNA molecule, causing chromosomal aberrations, chromosomal
­instability, and damage to membranes and enzymes; also induces
growth factors and extracellular matrix remodeling; uncertainty exists
regarding effects of low levels of radiation
Illumination Fluorescent lighting and halogen lamps create harmful oxidative stresses; Eyestrain, obscured vision, cataracts, headaches, melanoma
ultraviolet light has been linked to skin cancer
Mechanical Injury is caused by physical impact or irritation; they may be overt or Faulty occupational biomechanics, leading to overexertion
stresses cumulative disorders
Noise Can be caused by acute loud noise or cumulative effects of various Hearing impairment or loss; tinnitus, temporary threshold
­intensities, frequencies, and duration of noise; considered a public shift (TTS), or loss can occur as a complication of critical
health threat illness, from mechanical trauma, ototoxic medications,
infections, vascular disorders, and noise

important factor in some drownings, the major mechanism of injury is submerged in very cold water. Complete submersion is not necessary
hypoxemia (low blood oxygen levels). Even in freshwater drownings, for a person to drown. An incapacitated or helpless individual (epi-
where large amounts of water can pass through the alveolar-capillary leptic, alcoholic, infant) may drown in water that is only a few inches
interface, there is no evidence that increases in blood volume cause deep.
significant electrolyte disturbances or hemolysis, or that the amount It is important to remember that no specific or diagnostic find-
of fluid loading is beyond the compensatory capabilities of the kid- ings prove that a person recovered from the water is actually a
neys and heart. Airway obstruction is the more important pathologic drowning victim. In cases where water has entered the lung, there
abnormality, underscored by the fact that in as many as 15% of drown- may be large amounts of foam exiting the nose and mouth, although
ings little or no water enters the lungs because of vagal nerve–mediated this also can be seen in certain types of drug overdoses. A body
laryngospasms. This phenomenon is called dry-lung drowning. recovered from water with signs of prolonged immersion could just
No matter what mechanism is involved, cerebral hypoxia leads to as easily be a victim of some other type of injury with the immersion
unconsciousness in a matter of minutes. Whether this progresses to acting to obscure the actual cause of death. When working with a
death depends on a number of factors, including the age and the health living victim recovered from water, it is essential to keep in mind
of the individual. One of the most important factors is the temperature that an underlying condition may have led to the person’s becom-
of the water. Irreversible injury develops much more rapidly in warm ing incapacitated and submerged—a condition that also may need
water than it does in cold water. Submersion times of up to 1 hour to be treated or corrected while correcting hypoxemia and dealing
with subsequent survival have been reported in children who were with its sequelae.
80 CHAPTER 3  Altered Cellular and Tissue Biology

4 QUICK CHECK 3-3

1
1. Correlate the changes in color of a contusion to its mechanism of injury.
Abnormal
2. Distinguish between a laceration, an abrasion, and a contusion. metabolism
3. What is the major mechanism of injury with drowning?

Infectious Injury
The pathogenicity (virulence) of microorganisms lies in their ability to
Normal cell Fatty liver
survive and proliferate in the human body, where they injure cells and
tissues. The disease-producing potential of a microorganism depends
on its ability to (1) invade and destroy cells, (2) produce toxins, and
(3) produce damaging hypersensitivity reactions. (See Chapter 7 for a Protein mutation 2
description of infection and infectious organisms.) Defect in
protein
folding,
Immunologic and Inflammatory Injury transport
Cellular membranes are injured by direct contact with cellular and
chemical components of the immune and inflammatory responses,
such as phagocytic cells (lymphocytes, macrophages) and substances
such as histamine, antibodies, lymphokines, complement, and prote-
ases (see Chapter 5). Complement is responsible for many of the mem- Accumulation of
abnormal proteins
brane alterations that occur during immunologic injury.
Membrane alterations are associated with a rapid leakage of potas-
sium (K+) out of the cell and a rapid influx of water. Antibodies can
interfere with membrane function by binding with and occupying
receptor molecules on the plasma membrane. Antibodies also can block 3
Lack of
or destroy cellular junctions, interfering with intercellular communica- enzyme
tion. Other mechanisms of cellular injury are genetic factors, nutritional
imbalances, and physical agents. These are summarized in Table 3-10.
Complex Soluble
substrate products Complex
MANIFESTATIONS OF CELLULAR INJURY: Enzyme substrate
­ACCUMULATIONS Lysosomal storage disease:
accumulation of
An important manifestation of cell injury is the intracellular accumu- endogenous materials
lation of abnormal amounts of various substances and the resultant
metabolic disturbances. Cellular accumulations, also known as infil-
trations, not only result from sublethal, sustained injury by cells but also
4
result from normal (but inefficient) cell function. Two categories of sub-
Ingestion of
stances can produce accumulations: (1) a normal cellular substance (such indigestible
as excess water, proteins, lipids, and carbohydrates) or (2) an abnormal materials
substance, either endogenous (such as a product of abnormal metabo-
lism or synthesis) or exogenous (such as infectious agents or a mineral).
These products can accumulate transiently or permanently and can be
toxic or harmless. Most accumulations are attributed to four types of
mechanisms, all abnormal (Figure 3-17). Abnormal accumulations of Accumulation of
these substances can occur in the cytoplasm (often in the lysosomes) or exogenous materials
in the nucleus if (1) the normal, endogenous substance is produced in FIGURE 3-17  Mechanisms of Intracellular Accumulations.
excess or at an increased rate, thus abnormal metabolism; (2) an abnor- (From Kumar V et al: Cellular responses to stress and toxic insults:
mal substance, often the result of a mutated gene, accumulates because adaptation, injury, and death. In Kumar V et al, editors: Robbins and
of defects in protein folding, transport, or abnormal degradation; (3) an Cotran pathologic basis of disease, ed 8, St Louis, 2010, Saunders.)
endogenous substance (normal or abnormal) is not effectively catabo-
lized, usually because of lack of a vital lysosomal enzyme; or (4) harmful and other phagocytes migrate to tissues that are producing excessive
exogenous materials, such as heavy metals, mineral dusts, or microor- metabolites, the affected tissues begin to swell. This is the mechanism
ganisms, accumulate because of inhalation, ingestion, or infection. that causes enlargement of the liver (hepatomegaly) or the spleen
In all storage diseases, the cells attempt to digest, or catabolize, (splenomegaly) as a clinical manifestation of many storage diseases.
the “stored” substances. As a result, excessive amounts of metabolites
(products of catabolism) accumulate in the cells and are expelled into Water
the extracellular matrix, where they are consumed by phagocytic cells Cellular swelling, the most common degenerative change, is caused by
called macrophages (see Chapter 5). Some of these scavenger cells cir- the shift of extracellular water into the cells. In hypoxic injury, move-
culate throughout the body, whereas others remain fixed in certain ment of fluid and ions into the cell is associated with acute failure of
tissues, such as the liver or spleen. As more and more macrophages metabolism and loss of ATP production. Normally, the pump that
 CHAPTER 3  Altered Cellular and Tissue Biology 81

Injury
Injury
Hypoxia

ATP production decreases

Sodium and water move into cell Sodium and water

Potassium moves out of cell move into cell

Potassium moves
Osmotic pressure increases out of cell

More water moves into cell Extensive

vacuolation

Cisternae of endoplasmic
reticulum distend, rupture,
Distended cisternae
and form vacuoles
in endoplasmic
reticulum
Extensive vacuolation
Cytoplasm
swelling
Hydropic degeneration
FIGURE 3-18  The Process of Oncosis (Formerly Referred to as “Hydropic Degeneration”). ATP,
Adenosine triphosphate.

transports sodium ions out of the cell is maintained by the presence

of ATP and adenosinetriphosphatase (ATPase), the active transport
enzyme. In metabolic failure caused by hypoxia, reduced levels of ATP
and ATPase permit sodium to accumulate in the cell while potassium
diffuses outward. The increased intracellular sodium concentration
increases osmotic pressure, drawing more water into the cell. The cis-
ternae of the endoplasmic reticulum become distended, rupture, and
then unite to form large vacuoles that isolate the water from the cyto-
plasm, a process called vacuolation. Progressive vacuolation results in
cytoplasmic swelling called oncosis (which has replaced the old term
hydropic [water] degeneration) or vacuolar degeneration ­(Figure 3-18).
If cellular swelling affects all the cells in an organ, the organ increases in
weight and becomes distended and pale. FIGURE 3-19  Fatty Liver. The liver appears yellow. (From Damjanov I,
Cellular swelling is reversible and is considered sublethal. It is, in Linder J: Pathology: a color atlas, St Louis, 2000, Mosby.)
fact, an early manifestation of almost all types of cellular injury, includ-
ing severe or lethal cell injury. It is also associated with high fever,
hypokalemia (abnormally low concentrations of potassium in the accumulations can cause clouding of the cornea, joint stiffness, and
blood; see Chapter 4), and certain infections. mental retardation.
Although lipids sometimes accumulate in heart and kidney cells,
Lipids and Carbohydrates the most common site of intracellular lipid accumulation, or fatty
Certain metabolic disorders result in the abnormal intracellular accu- change, is liver cells. Because hepatic metabolism and secretion of lip-
mulation of carbohydrates and lipids. These substances may accu- ids are crucial to proper body function, imbalances and deficiencies in
mulate throughout the body but are found primarily in the spleen, these processes lead to major pathologic changes. Lipid accumulation
liver, and CNS. Accumulations in cells of the CNS can cause neuro- in liver cells causes fatty liver, or fatty change (Figure 3-19). As lipids
logic dysfunction and severe mental retardation. Lipids accumulate fill the cells, vacuolation pushes the nucleus and other organelles aside.
in Tay-Sachs disease, Niemann-Pick disease, and Gaucher disease, The liver’s outward appearance is yellow and greasy. Alcohol abuse is
whereas in the diseases known as mucopolysaccharidoses, carbohy- one of the most common causes of fatty liver (see Chapter 34).
drates are in excess. The mucopolysaccharidoses are progressive dis- Lipid accumulation in liver cells occurs after cellular injury insti-
orders that usually involve multiple organs, including liver, spleen, gates one or more of the following mechanisms:
heart, and blood vessels. The accumulated mucopolysaccharides are 1. Increased movement of free fatty acids into the liver (starvation, for
found in reticuloendothelial cells, endothelial cells, intimal smooth example, increases the metabolism of triglycerides in adipose tissue,
muscle cells, and fibroblasts throughout the body. These carbohydrate releasing fatty acids that subsequently enter liver cells)
82 CHAPTER 3  Altered Cellular and Tissue Biology

2. F ailure of the metabolic process that converts fatty acids to phos- color to cells undergoing slow, regressive, and often atrophic changes.
pholipids, resulting in the preferential conversion of fatty acids to Exogenous pigments include mineral dusts containing silica and iron
triglycerides particles, lead, silver salts, and dyes for tattoos.
3. Increased synthesis of triglycerides from fatty acids (increases
in an enzyme, α-glycerophosphatase, can accelerate triglyceride Melanin
synthesis) Melanin accumulates in epithelial cells (keratinocytes) of the skin and
4. Decreased synthesis of apoproteins (lipid-acceptor proteins) retina. It is an extremely important pigment because it protects the
5. Failure of lipids to bind with apoproteins and form lipoproteins skin against long exposure to sunlight and is considered an essential
6. Failure of mechanisms that transport lipoproteins out of the cell factor in the prevention of skin cancer (see Chapters 10 and 39). Ultra-
7. Direct damage to the endoplasmic reticulum by free radicals violet light (e.g., sunlight) stimulates the synthesis of melanin, which
released by alcohol’s toxic effects probably absorbs ultraviolet rays during subsequent exposure. Mela-
Many pathologic states show accumulation of cholesterol and cho- nin also may protect the skin by trapping the injurious free radicals
lesterol esters. These states include atherosclerosis, in which atheroscle- produced by the action of ultraviolet light on skin.
rotic plaques, smooth muscle cells, and macrophages within the intimal Melanin is a brown-black pigment derived from the amino acid
layer of the aorta and large arteries are filled with lipid-rich vacuoles of tyrosine. It is synthesized by epidermal cells called melanocytes and is
cholesterol and cholesterol esters. Other states include cholesterol-rich stored in membrane-bound cytoplasmic vesicles called melanosomes.
deposits in the gallbladder and Niemann-Pick disease (type C), which Melanin also can accumulate in melanophores (melanin-­
involve genetic mutations of an enzyme affecting cholesterol transport. containing pigment cells), macrophages, or other phagocytic cells in
the dermis. Presumably these cells acquire the melanin from nearby
Glycogen melanocytes or from pigment that has been extruded from dying
Intracellular accumulations of glycogen are seen in genetic disorders epidermal cells. This is the mechanism that causes freckles. Melanin
called glycogen storage diseases and in disorders of glucose and glyco- also occurs in the benign form of pigmented moles called nevi (see
gen metabolism. As with water and lipid accumulation, glycogen accu- Chapter 39). Malignant melanoma is a cancerous skin tumor that con-
mulation results in excessive vacuolation of the cytoplasm. The most tains melanin.
common cause of glycogen accumulation is the disorder of glucose A decrease in melanin production occurs in the inherited disor-
metabolism, diabetes mellitus (see Chapter 18). der of melanin metabolism called albinism. Albinism is often diffuse,
involving all the skin, the eyes, and the hair. Albinism is also related to
Proteins phenylalanine metabolism. In classic types, the person with albinism
Proteins provide cellular structure and constitute most of the cell’s dry is unable to convert tyrosine to DOPA (3,4-dihydroxyphenylalanine),
weight. They are synthesized on ribosomes in the cytoplasm from the an intermediate in melanin biosynthesis. Melanin-producing cells are
essential amino acids lysine, threonine, leucine, isoleucine, methionine, present in normal numbers, but they are unable to make melanin.
tryptophan, valine, phenylalanine, and histidine. Protein accumula- Individuals with albinism are very sensitive to sunlight and quickly
tion probably damages cells in two ways. First, metabolites, produced become sunburned. They are also at high risk for skin cancer.
when the cell attempts to digest some proteins, are enzymes that when
released from lysosomes can damage cellular organelles. Second, exces- Hemoproteins
sive amounts of protein in the cytoplasm push against cellular organ- Hemoproteins are among the most essential of the normal endoge-
elles, disrupting organelle function and intracellular communication. nous pigments. They include hemoglobin and the oxidative enzymes,
Protein excess accumulates primarily in the epithelial cells of the the cytochromes. Central to an understanding of disorders involving
renal convoluted tubule and in the antibody-forming plasma cells these pigments is knowledge of iron uptake, metabolism, excretion,
(B lymphocytes) of the immune system. Several types of renal disorders and storage (see Chapter 19). Hemoprotein accumulations in cells
cause excessive excretion of protein molecules in the urine (proteinuria). are caused by excessive storage of iron, which is transferred to the
Normally, little or no protein is present in the urine, and its presence in cells from the bloodstream. Iron enters the blood from three primary
significant amounts indicates cellular injury and altered cellular function. sources: (1) tissue stores, (2) the intestinal mucosa, and (3) macro-
Accumulations of protein in B lymphocytes can occur during active phages that remove and destroy dead or defective red blood cells. The
synthesis of antibodies during the immune response. The excess aggregates amount of iron in blood plasma depends also on the metabolism of the
of protein are called Russell bodies (see Chapter 5). Russell bodies have major iron transport protein, transferrin.
been identified in multiple myeloma (plasma cell tumor) (see Chapter 20). Iron is stored in tissue cells in two forms: as ferritin and, when
Mutations in protein can slow protein folding, resulting in the increased levels of iron are present, as hemosiderin. Hemosiderin is
accumulation of partially folded intermediates. An example is α1- a yellow-brown pigment derived from hemoglobin. With pathologic
antitrypsin deficiency, which can cause emphysema. Certain types of states, excesses of iron cause hemosiderin to accumulate within cells,
cell injury are associated with the accumulation of cytoskeleton pro- often in areas of bruising and hemorrhage and in the lungs and spleen
teins. For example, the neurofibrillary tangle found in the brain in after congestion caused by heart failure. With local hemorrhage, the
Alzheimer disease contains these types of proteins. skin first appears red-blue and then lysis of the escaped red blood
cells occurs, causing the hemoglobin to be transformed to hemosid-
Pigments erin. The color changes noted in bruising reflect this transformation
Pigment accumulations may be normal or abnormal, endogenous (Figure 3-20).
(produced within the body) or exogenous (produced outside the Hemosiderosis is a condition in which excess iron is stored as
body). Endogenous pigments are derived, for example, from amino hemosiderin in the cells of many organs and tissues. This condition
acids (e.g., tyrosine, tryptophan). They include melanin and the blood is common in individuals who have received repeated blood transfu-
proteins porphyrins, hemoglobin, and hemosiderin. Lipid-rich pig- sions or prolonged parenteral administration of iron. Hemosiderosis
ments, such as lipofuscin (the aging pigment), give a yellow-brown is associated also with increased absorption of dietary iron, conditions
 CHAPTER 3  Altered Cellular and Tissue Biology 83

in which iron storage and transport are impaired, and hemolytic ane- Bilirubin is a normal, yellow-to-green pigment of bile derived from
mia. Excessive alcohol (wine) ingestion also can lead to hemosiderosis. the porphyrin structure of hemoglobin. Excess bilirubin within cells
Normally, absorption of excessive dietary iron is prevented by an iron and tissues causes jaundice (icterus), or yellowing of the skin. Jaundice
absorption process in the intestines. Failure of this process can lead to occurs when the bilirubin level exceeds 1.5 to 2 mg/dl of plasma, com-
total body iron accumulations in the range of 60 to 80 g, compared pared with the normal values of 0.4 to 1 mg/dl. Hyperbilirubinemia
with normal iron stores of 4.5 to 5 g. Excessive accumulations of iron, occurs with (1) destruction of red blood cells (erythrocytes), such as
such as occur in hemochromatosis (a genetic disorder of iron metabo- in hemolytic jaundice; (2) diseases affecting the metabolism and excre-
lism and the most severe example of iron overload), are associated with tion of bilirubin in the liver; and (3) diseases that cause obstruction of
liver and pancreatic cell damage. the common bile duct, such as gallstones or pancreatic tumors. Certain
drugs (specifically chlorpromazine and other phenothiazine deriva-
tives), estrogenic hormones, and halothane (an anesthetic) can cause
the obstruction of normal bile flow through the liver.
Bruising Because unconjugated bilirubin is lipid soluble, it can injure the
lipid components of the plasma membrane. Albumin, a plasma pro-
tein, provides significant protection by binding unconjugated biliru-
Extravasated bin in plasma. Unconjugated bilirubin causes two cellular outcomes:
red cells uncoupling of oxidative phosphorylation and a loss of cellular pro-
teins. These two changes could cause structural injury to the various
membranes of the cell.
Phagocytosis of
red cells by Calcium
macrophages
Calcium salts accumulate in both injured and dead tissues (Figure
3-21). An important mechanism of cellular calcification is the influx
of extracellular calcium in injured mitochondria (see p. 64). Another
Hemosiderin Iron free mechanism that causes calcium accumulation in alveoli (gas-exchange
pigments airways of the lungs), gastric epithelium, and renal tubules is the excre-
FIGURE 3-20  Hemosiderin Accumulation Is Noted as the Color
tion of acid at these sites, leading to the local production of hydroxyl
Changes in a “Black Eye.” ions. Hydroxyl ions result in precipitation of calcium hydroxide,

Calcium stores in
mitochondria and endoplasmic
reticulum pumped to
extracellular space bound to
calcium-binding proteins

Released after
cell damage

Free Ca++

Activation of
Activation of phospholipases with Activation of Activation of Activation of
protein kinases phospholipid degradation proteases endonuclease ATPases
and loss
with cell
swelling

Phosphorylation Membrane Cytoskeletal disassembly Nucleus

ATP
of protein and damage (damage) chromatin damage
chromatin fragmentation
FIGURE 3-21  Free Cytosolic Calcium: A Destructive Agent. Normally, calcium is removed from the
cytosol by adenosine triphosphate (ATP)-dependent calcium pumps. In normal cells, calcium is bound to
buffering proteins, such as calbindin or paralbumin, and is contained in the endoplasmic reticulum and the
mitochondria. If there is abnormal permeability of calcium-ion channels, direct damage to membranes, or
depletion of ATP (i.e., hypoxic injury), calcium increases in the cytosol. If the free calcium cannot be buff-
ered or pumped out of cells, uncontrolled enzyme activation takes place, causing further damage. Uncon-
trolled entry of calcium into the cytosol is an important final common pathway in many causes of cell death.
84 CHAPTER 3  Altered Cellular and Tissue Biology

Ca(OH)2, and hydroxyapatite, (Ca3[PO4]2)3.Ca(OH)2, a mixed salt. (adrenocortical insufficiency), systemic sarcoidosis, milk-alkali syn-
Damage occurs when calcium salts cluster and harden, interfering with drome, and the increased bone demineralization that results from bone
normal cellular structure and function. tumors, leukemia, and disseminated cancers. Hypercalcemia also may
Pathologic calcification can be dystrophic or metastatic. Dystro- occur in advanced renal failure with phosphate retention, resulting in
phic calcification occurs in dying and dead tissues, chronic tuberculo- hyperparathyroidism.
sis of the lungs and lymph nodes, advanced atherosclerosis (narrowing
of arteries as a result of plaque accumulation), and heart valve injury Urate
(Figure 3-22). Calcification of the heart valves interferes with their In humans, uric acid (urate) is the major end product of purine catab-
opening and closing, causing heart murmurs (see Chapter 23). Calci- olism because of the absence of the enzyme urate oxidase. Serum urate
fication of the coronary arteries predisposes them to severe narrowing concentration is, in general, stable: approximately 5 mg/dl in postpu-
and thrombosis, which can lead to myocardial infarction. Another site bertal males and 4.1 mg/dl in postpubertal females. Disturbances in
of dystrophic calcification is the center of tumors. Over time, the cen- maintaining serum urate levels result in hyperuricemia and the deposi-
ter is deprived of its oxygen supply, dies, and becomes calcified. The tion of sodium urate crystals in the tissues, leading to painful disorders
calcium salts appear as gritty, clumped granules that can become hard collectively called gout. These disorders include acute arthritis, chronic
as stone. When several layers clump together, they resemble grains of gouty arthritis, tophi (firm, nodular, subcutaneous deposits of urate
sand and are called psammoma bodies. crystals surrounded by fibrosis), and nephritis (inflammation of the
Metastatic calcification consists of mineral deposits that occur nephron). Chronic hyperuricemia results in the deposition of urate in
in undamaged normal tissues as the result of hypercalcemia (excess tissues, cell injury, and inflammation. Because urate crystals are not
calcium in the blood; see Chapter 4). Conditions that cause hypercal- degraded by lysosomal enzymes, they persist in dead cells.
cemia include hyperparathyroidism, toxic levels of vitamin D, hyper-
thyroidism, idiopathic hypercalcemia of infancy, Addison disease Systemic Manifestations
Systemic manifestations of cellular injury include a general sense of
fatigue and malaise, a loss of well-being, and altered appetite. Fever
is often present because of biochemicals produced during the inflam-
matory response. Table 3-11 summarizes the most significant systemic
manifestations of cellular injury.

TABLE 3-11 SYSTEMIC MANIFESTATIONS

OF CELLULAR INJURY
MANIFESTATION CAUSE
Fever Release of endogenous pyrogens
­(interleukin-1, tumor necrosis factor-α,
prostaglandins) from bacteria or macro-
A phages; acute inflammatory response
Increased heart rate Increase in oxidative metabolic processes
resulting from fever
Increase in leukocytes Increase in total number of white blood
Necrosis or degeneration ­(leukocytosis) cells because of infection; normal is
of tissue
5000-9000/mm3 (increase is directly
related to severity of infection)
Pain Various mechanisms, such as release of
bradykinins, obstruction, pressure
Release of enzymes Presence of cellular enzymes Release of enzymes from cells of tissue* in
extracellular fluid
Lactate dehydrogenase Release from red blood cells, liver, kidney,
(LDH) (LDH isoenzymes) skeletal muscle
Creatine kinase (CK) Release from skeletal muscle, brain, heart
Breakdown of Alteration (CK isoenzymes)
organic phosphates of pH Aspartate aminotransferase Release from heart, liver, skeletal muscle,
(AST/SGOT) kidney, pancreas
Alanine aminotransferase Release from liver, kidney, heart
(ALT/SGPT)
Alkaline phosphatase (ALP) Release from liver, bone
Increased deposition Amylase Release from pancreas
of calcium Aldolase Release from skeletal muscle, heart
B
FIGURE 3-22  Aortic Valve Calcification. A, This calcified aortic valve *The rapidity of enzyme transfer is a function of the weight of the
is an example of dystrophic calcification. B, This algorithm shows the enzyme and the concentration gradient across the cellular membrane.
dystrophic mechanism of calcification. (A from Damjanov I: Pathology The specific metabolic and excretory rates of the enzymes determine
for the health professions, ed 3, St Louis, 2006, Saunders.) how long levels of enzymes remain elevated.
 CHAPTER 3  Altered Cellular and Tissue Biology 85

NORMAL NORMAL
CELL CELL

Reversible
Recovery
injury

Condensation
of chromatin
Swelling of
endoplasmic Membrane blebs
Myelin reticulum and
figure mitochondria

Membrane blebs
Cellular
fragmentation
Progressive
injury
Apoptotic
Myelin body APOPTOSIS
Breakdown of
figure
plasma membrane,
organelles and
nucleus; leakage
of contents

Inflammation
NECROSIS
Phagocytosis
Phagocyte of apoptotic cells
Amorphous densities and fragments
in mitochondria
FIGURE 3-23  Schematic Illustration of the Morphologic Changes in Cell Injury Culminating in
Necrosis or Apoptosis. Myelin figures come from degenerating cellular membranes and are noted
within the cytoplasm or extracellularly. (From Kumar V et  al: Cellular responses to stress and toxic
insults: adaptation, injury, and death. In Kumar V et al, editors: Robbins and Cotran pathologic basis of
disease, ed 8, St Louis, 2010, Saunders.)

CELLULAR DEATH Necrosis

Cell death has historically been classified as necrosis and apoptosis. Cellular death eventually leads to cellular dissolution, or necrosis.
Necrosis is characterized by rapid loss of the plasma membrane struc- Necrosis is the sum of cellular changes after local cell death and the
ture, organelle swelling, mitochondrial dysfunction, and the lack of process of cellular self-digestion, known as autodigestion or autolysis
typical features of apoptosis.35 Apoptosis is known as a regulated or (see Figure 3-23). Cells die long before any necrotic changes are noted
programmed cell process characterized by the “dropping off” of cel- by light microscopy.37 The structural signs that indicate irreversible
lular fragments called apoptotic bodies. Until recently, necrosis was injury and progression to necrosis are dense clumping and progres-
only considered passive or accidental cell death occurring after severe sive disruption both of genetic material and of plasma and organelle
and sudden injury. It is the main outcome in several common injuries membranes. In later stages of necrosis, most organelles are disrupted,
including ischemia, exposure to toxins, certain infections, and trauma. and karyolysis (nuclear dissolution and lysis of chromatin from the
It is now understood that under certain conditions, such as activation action of hydrolytic enzymes) is under way. In some cells the nucleus
of death proteases, necrosis has been proposed to be regulated or pro- shrinks and becomes a small, dense mass of genetic material (pykno-
grammed in a well-orchestrated way as a back-up for apoptosis (apop- sis). The pyknotic nucleus eventually dissolves (by karyolysis) as a
tosis may progress to necrosis).36-37 Hence the new term programmed result of the action of hydrolytic lysosomal enzymes on DNA. Kary-
necrosis or necroptosis. Historically, programmed cell death only orrhexis means fragmentation of the nucleus into smaller particles or
referred to apoptosis. Figure 3-23 illustrates the structural changes “nuclear dust” (see Figure 3-29).
in cell injury resulting in necrosis or apoptosis. Table 3-12 compares Although necrosis still refers to death induced by nonspecific
the unique features of necrosis and apoptosis. Other forms of cell loss trauma or injury (e.g., cell stress or the heat shock response), with
include autophagy (self-eating) (see p. 89). the very recent identification of molecular mechanisms regulating the
86 CHAPTER 3  Altered Cellular and Tissue Biology

TABLE 3-12 FEATURES OF NECROSIS AND APOPTOSIS

FEATURE NECROSIS APOPTOSIS
Cell size Enlarged (swelling) Reduced (shrinkage)
Nucleus Pyknosis → ­karyorrhexis → karyolysis Fragmentation into ­nucleosome-size fragments
Plasma ­membrane Disrupted Intact; altered structure, especially orientation of lipids
Cellular contents Enzymatic digestion; may leak out of cell Intact; may be released in ­apoptotic bodies
Adjacent ­inflammation Frequent No
Physiologic or pathologic role Invariably ­pathologic ­(culmination of ­irreversible Often physiologic, means of eliminating unwanted cells; may be
cell injury) pathologic after some forms of cell injury, especially DNA damage

From Kumar V et al: Cellular responses to stress and toxic insults: adaptation, injury, and death. In Kumar V et al, editors: Robbins and Cotran
pathologic basis of disease, ed 8, St Louis, 2010, Saunders.

FIGURE 3-24  Coagulative Necrosis. A wedge-shaped kidney FIGURE 3-25  Liquefactive Necrosis of the Brain. The area of
infarct (yellow). (From Kumar V et al: Cellular responses to stress infarction is softened as a result of liquefaction necrosis. (From
and toxic insults: adaptation, injury, and death. In Kumar V et  al, Damjanov I: Pathology for the health professions, ed 3, St Louis,
editors: Robbins and Cotran pathologic basis of disease, ed 8, 2006, Saunders.)
St Louis, 2010, Saunders.)

process of necrosis, the study of necrosis has experienced a new twist. contains little connective tissue. Cells are digested by their own
Unlike apoptosis, necrosis has been viewed as passive with cell death hydrolases, so the tissue becomes soft, liquefies, and segregates
occurring in a disorganized and unregulated manner. Recently, some from healthy tissue, forming cysts. This can be caused by bacterial
molecular regulators governing programmed necrosis have been iden- infection, especially Staphylococci, Streptococci, and Escherichia coli.
tified and demonstrated to be interconnected by a large network of 3. Caseous necrosis. Usually results from tuberculous pulmonary
signaling pathways.36 Emerging evidence suggests that programmed infection, especially by Mycobacterium tuberculosis (Figure 3-26). It
necrosis is associated with pathologic diseases and provides innate is a combination of coagulative and liquefactive necroses. The dead
immune response to viral infection.36 cells disintegrate, but the debris is not completely digested by the
Different types of necroses tend to occur in different organs or tis- hydrolases. Tissues resemble clumped cheese in that they are soft
sues and sometimes can indicate the mechanism or cause of cellular and granular. A granulomatous inflammatory wall encloses areas
injury. The four major types of necroses are coagulative, liquefactive, of caseous necrosis.
caseous, and fatty. Another type, gangrenous necrosis, is not a distinc- 4. Fat necrosis. Fat necrosis is cellular dissolution caused by powerful
tive type of cell death but refers instead to larger areas of tissue death. enzymes, called lipases, that occur in the breast, pancreas, and other
These necroses are summarized as follows: abdominal structures (Figure 3-27). Lipases break down triglyc-
1. Coagulative necrosis. Occurs primarily in the kidneys, heart, and erides, releasing free fatty acids that then combine with calcium,
adrenal glands; commonly results from hypoxia caused by severe magnesium, and sodium ions, creating soaps (saponification).
ischemia or hypoxia caused by chemical injury, especially ingestion The necrotic tissue appears opaque and chalk-white.
of mercuric chloride. Coagulation is caused by protein denatur- 5. Gangrenous necrosis. Refers to death of tissue and results from
ation, which causes the protein albumin to change from a gelati- severe hypoxic injury, commonly occurring because of arterioscle-
nous, transparent state to a firm, opaque state (Figure 3-24). rosis, or blockage, of major arteries, particularly those in the lower
2. Liquefactive necrosis. Commonly results from ischemic injury to leg (Figure 3-28). With hypoxia and subsequent bacterial invasion,
neurons and glial cells in the brain (Figure 3-25). Dead brain tis- the tissues can undergo necrosis. Dry gangrene is usually the result
sue is readily affected by liquefactive necrosis because brain cells of coagulative necrosis. The skin becomes very dry and shrinks,
are rich in digestive hydrolytic enzymes and lipids and the brain resulting in wrinkles, and its color changes to dark brown or black.
 CHAPTER 3  Altered Cellular and Tissue Biology 87

Wet gangrene develops when neutrophils invade the site, causing

liquefactive necrosis. This usually occurs in internal organs, causing
the site to become cold, swollen, and black. A foul odor is present,
and if systemic symptoms become severe, death can ensue.
6. Gas gangrene. Refers to a special type of gangrene caused by infec-
tion of injured tissue by one of many species of Clostridium. These
anaerobic bacteria produce hydrolytic enzymes and toxins that
destroy connective tissue and cellular membranes and cause bub-
bles of gas to form in muscle cells. This can be fatal if enzymes lyse
the membranes of red blood cells, destroying their oxygen-carrying
capacity. Death is caused by shock.

Apoptosis
Apoptosis (“dropping off”) is an important distinct type of cell death
that differs from necrosis in several ways (see Figures 3-23, 3-29, and
Table 3-12). Apoptosis is an active process of cellular self-destruction
called programmed cell death and is implicated in both normal and
pathologic tissue changes. Cells need to die; otherwise, endless prolif-
FIGURE 3-26  Caseous Necrosis. Tuberculosis of the lung, with a eration would lead to gigantic bodies. The average adult may create 10
large area of caseous necrosis containing yellow-white and cheesy billion new cells every day—and destroy the same number.39
debris. (From Kumar V et  al: Cellular responses to stress and toxic Normal physiologic death by apoptosis occurs during the following
insults: adaptation, injury, and death. In Kumar V et al, editors: Robbins processes:
and Cotran pathologic basis of disease, ed 8, St Louis, 2010, Saunders.) • Embryogenesis
• Involution of hormone-dependent tissue after hormone with-
drawal (such as involution of the lactating breast after weaning)
• Cell loss in proliferating cell populations (such as immature lym-
phocytes in the bone marrow or thymus that do not express appro-
priate receptors)
• Elimination of possibly harmful lymphocytes that may be self-
reactive and cause cell death after performing useful functions (for
example, neutrophils after an acute inflammatory reaction)
Death by apoptosis causes loss of cells in many pathologic states
including (1) severe cell injury, (2) accumulation of misfolded pro-
teins, (3) infections, and (4) obstruction in tissue ducts. When cell
injury exceeds repair mechanisms, the cell triggers apoptosis. DNA
can be damaged either by direct assault or by production of free radi-
cals. Accumulation of misfolded proteins may result from genetic
mutations or free radicals. Excessive accumulation of misfolded pro-
teins in the endoplasmic reticulum (ER) leads to a condition known
as endoplasmic stress (ER stress). ER stress results in apoptotic cell
FIGURE 3-27  Fat Necrosis of Pancreas. Interlobular adipocytes
are necrotic; acute inflammatory cells surround these. (From death and this mechanism has been linked to several degenerative
­Damjanov I, Linder J, editors: Anderson’s pathology, ed 10, diseases of the CNS and other organs. Infections, particularly viral
St Louis, 1996, Mosby.) (e.g., adenovirus and human immunodeficiency virus [HIV]), lead to

Thrombosis or embolism Strangulated hernia Volvulus Intussusception Gangrene

FIGURE 3-28  Gangrene, a Complication of Necrosis. In certain circumstances, necrotic tissue will
be invaded by putrefactive organisms that are both saccharolytic and proteolytic. Foul-smelling gases
are produced, and the tissue becomes green or black as a result of breakdown of hemoglobin. Obstruc-
tion of the blood supply to the bowel almost inevitably is followed by gangrene.
88 CHAPTER 3  Altered Cellular and Tissue Biology

Exogenous Suicide gene

injury activation

NECROSIS APOPTOSIS
(group of cells) (single cell)

Normal cell Normal cell

Nuclear
clumping
Swollen Liver cells Nuclear changes
mitochondria
and RER Cytoplasmic
Ruptured cell fragmentation
membrane
Macrophage

Nuclear
fragments Apoptotic
bodies

FIGURE 3-29  Necrosis and Apoptosis in Liver Cells. Necrosis is caused by exogenous injury whereby
cells are swollen and have nuclear changes in ruptured cell membrane. Apoptosis is single cell death. It
is genetically programmed (suicide genes) and depends on energy. Apoptotic bodies contain part of the
nucleus and cytoplasmic organelles, which are ultimately engulfed by macrophages or adjacent cells.
RER, Rough endoplasmic reticulum. (Redrawn from Damjanov I: Pathology for the health professions,
ed 3, St Louis, 2006, Saunders.)

apoptosis. The virus may directly induce apoptosis, or cell death can the death receptor pathway (Figure 3-30). Cells that die by apoptosis
occur indirectly as a result of the host immune response. Cytotoxic T release chemical factors that recruit phagocytes that quickly engulf the
lymphocytes respond to viral infections by inducing apoptosis and, remains of the dead cell, thus reducing chances of inflammation. With
therefore, eliminating the infectious cells. The tissue damage caused necrosis, cell death is not tidy because cells that die as a result of acute
by this process is the same both for cell death in tumors and for rejec- injury swell, burst, and spill their contents all over their neighbors,
tion of tissue transplants. In organs with duct obstruction, including causing a likely damaging inflammatory response.
the pancreas, kidney, and parotid gland, the pathologic atrophy is
caused by apoptosis. Autophagy
Excessive or insufficient apoptosis is known as dysregulated apop- The Greek term autophagy means “eating of self.” Autophagy, as a
tosis. A low rate of apoptosis can permit the survival of abnormal “recycling factory,” is a self-destructive process and a survival mecha-
cells, for example, mutated cells that can increase cancer risk. Defec- nism. When cells are starved or nutrient deprived, the autophagic pro-
tive apoptosis may not eliminate lymphocytes that react against host cess institutes cannibalization and recycles the digested contents.18,41
tissue (self-antigens), leading to autoimmune disorders. Excessive Autophagy can maintain cellular metabolism under starvation con-
apoptosis is known to occur in several neurodegenerative diseases, ditions and remove damaged organelles under stress conditions,
from ischemic injury (such as myocardial infarction and stroke), improving the survival of cells. Autophagy begins with a membrane,
and from death of virus-infected cells (such as seen in many viral also known as a phagophore (although controversial), likely derived
infections). from the lipid bilayer from either the endoplasmic reticulum or the
Apoptosis depends on a tightly regulated cellular program for Golgi apparatus (Figure 3-31).41 This phagophore expands and engulfs
its initiation and execution.39 This death program involves enzymes intracellular cargo—organelles, ribosomes, proteins—forming a dou-
that divide other proteins—proteases, which are activated by pro- ble membrane autophagosome. The cargo-laden autophagosome fuses
teolytic activity in response to signals that induce apoptosis. These with the lysosome, now called an autophagolysosome, which promotes
proteases are called caspases, a family of aspartic acid–specific prote- the degradation of the autophagosome by lysosomal acid proteases.
ases. The activated suicide caspases cleave and, thereby, activate other Lysosomal transporters export amino acids and other by-products
members of the family, resulting in an amplifying “suicide” cascade. of degradation out of the cytoplasm where they can be reused for the
The activated caspases then cleave other key proteins in the cell, kill- synthesis of macromolecules and for metabolism.42 ATP is generated
ing the cell quickly and neatly. The two different pathways that con- and cellular damage reduced during autophagy that removes nonfunc-
verge on caspase activation are called the mitochondrial pathway and tional proteins and organelles.41 Autophagy is considered a mechanism
 MITOCHONDRIAL (INTRINSIC) PATHWAY DEATH RECEPTOR (EXTRINSIC) PATHWAY

Receptor-ligand interactions
• Fas
• TNF receptor

Mitochondria

Cell injury Adapter proteins

• Growth factor Cytochrome c
withdrawal and other Initiator caspases
• DNA damage Bcl-2 family apoptotic proteins
(by radiation, effectors
toxin, free Pro-apoptotic
proteins Executioner
radicals) caspases
• Protein Bcl-2 regulators
misfolding Bcl-2 family
(ER stress) sensors
Breakdown of
Endonuclease cytoskeleton
activation

DNA fragmentation

Cytoplasmic bleb
Phagocyte

Ligands for
phagocytic
cell receptors

FIGURE 3-30  Mechanisms of Apoptosis. The two pathways of apoptosis differ in their induction and
regulation, and both culminate in the activation of “executioner” caspases. The induction of apoptosis
by the mitochondrial pathway involves the Bcl-2 family, which causes leakage of mitochondrial proteins.
The regulators of the death receptor pathway involve the proteases, called caspases. (From Kumar V,
Abbas A, Fausto N: Robbins and Cotran pathologic basis of disease, ed 8, Philadelphia, 2007, Saunders.)

Nutrient depletion

Formation of autophagic vacuole

Autophagy
signal

Cytoplasmic
organelles

Lysosome
Used as sources Degradation
of nutrients

FIGURE 3-31  Autophagy. Cellular stresses, such as nutrient deprivation, activate autophagy genes
that create vacuoles in which cellular organelles are sequestered and then degraded following fusion
of the vesicles with lysosomes. The digested materials are recycled to provide nutrients for the cell.
90 CHAPTER 3  Altered Cellular and Tissue Biology

of cell loss in various diseases, including degenerative diseases of the

TABLE 3-13 THEORIES OF AGING
nervous system and muscle, and there is pathologic evidence in these
disorders of damaged cells containing an abundance of autophagic THEORY YEAR PROPONENT
vacuoles.18 Waste product theory 1923 Carrell & Ebeling
Investigators are excited about the utilization of autophagy for Wear-and-tear theory 1924 Pearl
therapeutic strategies. Autophagy is a critical garbage collecting and Rate of living theory* 1928 Pearl
recycling process in healthy cells, and this process becomes less effi- Endocrine theory 1947 Korenchevsky & Jones
cient and less discriminating as the cell ages. Consequently, harmful Free radical theory† 1955 Harman
agents accumulate in cells, damaging cells and leading to aging: for Collagen theory‡ 1957 Verzar
example, failure to clear protein products in neurons of the CNS can Metabolic theory* 1957; 1961 Carlson et al; Johnson et al
cause dementia; failure to clear ROS-producing mitochondria can lead Somatic mutation theory 1959 Sziliard
to nuclear DNA mutations and cancer. Thus these processes may even Error-catastrophe theory 1963; 1970 Orgel
partially define aging. Therefore normal autophagy may potentially Cross-linking theory‡ 1968 Bjorksten
rejuvenate an organism and prevent cancer development as well as Programmed senescence theory 1969 Hayflick
other degenerative diseases.46 In addition, autophagy may be the last Immunologic theory 1969 Walform
immune defense against infectious microorganisms that penetrate Evolution theory 1977 Kirkwood
intracellularly.43 Mitochondrial theory 1980 Miguel & Fleming

Data from Schneider EL: Theories of aging: a perspective. In Warner HR 

4 QUICK CHECK 3-4 et al, editors: Modern biological theories of aging, New York, 1987,
Raven; Melov S: Mitochondrial oxidative stress: physiologic conse-
1. Why is an increase in the concentration of intracellular calcium injurious?
2. Compare and contrast necrosis and apoptosis. quences and potential for a role in aging, Ann N Y Acad Sci 908:
219–225, 2000; Biesalsk HK: Free radical theory of aging, Curr Opin
3. Why is apoptosis significant?
Clin Nutr Metab Care 5(1):5–10, 2002.
4. Define autophagy.
*May represent the same theory.
†Current emphasis on mitochondrial oxidative stress and genetic

­variability for antioxidant protection.

AGING & ALTERED CELLULAR AND TISSUE ‡May represent the same theory.
BIOLOGY
Aging is usually defined as a normal physiologic process that is both
universal and inevitable. The basic mechanisms of aging depend on the Physical insults
irreversible and universal processes at the cellular and molecular levels. (heat, ultraviolet light,
Understanding aging requires the separation of irreversible processes ionizing radiation)
from potentially reversible mechanisms (i.e., those that result from
Chemical insults
disease or age-related debilities)—a very difficult task!
(toxins, free radicals,
Aging traditionally has not been considered a disease because it is
accumulated ions)
“normal”; disease is usually considered “abnormal.” Conceptually, this
distinction seems clear until the concept of injury or damage is intro- Infectious insults
duced; some pathologists have defined disease as the result of injury. (mutagenic viruses)
Aging has been defined as the time-dependent loss of structure and
Mechanical insults
function that proceeds slowly and in such small increments that it
(trauma to vessels and joints)
appears to be the result of the accumulation of small, imperceptible
injuries—a gradual result of “wear and tear.” Historical theories of
Injury to cells and tissue
aging are summarized in Table 3-13.
Injuries may result from unavoidable and universal microinsults
caused by continuous bombardment by ultraviolet light, toxins and
Repair Loss of function
chemicals, countless mechanical insults, and reactions to metabolites
(Figure 3-32).44 In this context, the distinction between aging and
disease is unclear. For example, some degree of atrophy of the brain
is considered normal in old age until it proceeds far enough to cause System failure
clinically significant disability and is then called a disease. Likewise, FIGURE 3-32  Microinsults. (Redrawn from Johnson HA, editor:
most human beings have atherosclerosis, and the plaques progress Is aging physiological or pathological? Relations between normal
with age, but at what point in this progression is atherosclerosis con- aging and a disease, New York, 1985, Raven.)
sidered abnormal?
Cellular aging is the result of increasing molecular disorder or
entropy. Molecular disorder is caused by random targeted events Normal Life Span and Life Expectancy
(i.e., stochastic) that affect cellular renewal and repair. The loss of The maximal life span of humans is between 80 and 100 years and
molecular order ultimately exceeds repair and turnover capacity does not vary significantly among populations. However, in primi-
and, thus, increases vulnerability to pathologic processes or age-­ tive societies few individuals reach the maximal life span; most die
associated disease.45 Table 3-14 includes emerging data on the biol- in infancy or the early years. In societies with improved sanitation,
ogy of aging. housing, nutrition, and healthcare, many persons do attain the
 CHAPTER 3  Altered Cellular and Tissue Biology 91

TABLE 3-14 BIOLOGY OF AGING

EMERGING FOCUS COMMENTS
Endocrine regulation Insulin-like growth factor 1 (IGF-1) signaling pathways have a role in certain tissues to regulate life span; IGF-1 is necessary for
through signaling homeostasis, growth, and survival
pathways Reduced insulin signaling (rodents and mammals) causes glucose intolerance and hyperinsulinemia, type 2 diabetes mellitus, and
shortened life span
Main factors affected by insulin-like signaling are transcription factors such as forkhead box 0 (FOXO); FOXO controls gene
­expression that regulates cell cycle, apoptosis, DNA repair, metabolism, and resistance to oxidative stress
Nuclear architecture and Cells vary in size and shape, yet all seem to age
genomic instability DNA-protein complexes, or chromatin, stabilize genome and determine gene expression; thus maintenance of chromatin dictates
nuclear architecture
DNA damage may lead to changes in gene expression to promote aging; however, epigenetic balance hypothesis is proposed to
explain gene expression changes that occur as a result of chromatic modification
Oxidative stress may lead to DNA damage that accelerates aging; confusing, however, is that aging could directly affect chromatin
structure through some unknown mechanism that then leads to DNA damage
Decline in cell renewal by Aging might be associated with a decline in replication directed by adult stem cells
adult stem cells Data suggest that as we grow older our stem cells age as a result of mechanisms that suppress development of cancer (e.g., senes-
cence, apoptosis)
Stem cell aging may occur with accumulating DNA damage or other nuclear support mechanisms, or both
Telomeres, like plastic ends of shoelaces, form the end of chromosomes; they are short, repeated sequences of DNA that are
­important for ensuring complete replication of chromosome ends and protect the end from degradation
Thus as cells age, their telomeres shorten, causing cell cycle arrest and an inability to generate new cells to replace damaged cells
Accumulation of cellular Accumulation of metabolic and genetic damage can exceed repair mechanisms
damage related to One group of particularly toxic products are reactive oxygen species (ROS)
disease and aging These free radicals cause modifications of proteins, lipids, and nucleic acids
Increased oxidative damage (stress) could result from repeated environmental exposures, for example, ionizing radiation, mitochon-
drial dysfunction, or reduction of antioxidant defense mechanisms with age
Autophagy (see p. 88) also may slow and become less discriminating; consequently, harmful agents accumulate in cells, damage
cells, and increase aging
Effect of calorie restriction on longevity appears to be modulated by a family of proteins called sirtuins; sirtuins are thought to
­promote gene expression of products that increase longevity; these products include proteins that increase metabolic activity,
reduce apoptosis, stimulate protein folding, and inhibit damaging effects of ROS
One product, resveratrol (found in grapes, mulberries, peanuts, and especially red wine), may protect against aging cells by acting as
an antioxidant, antimutagen, and anti-inflammatory

From Haigis MC, Sinclair DA: Annu Rev Pathol Mech Dis 5:253–295, 2010; Hopkiss AR: Biogerontol 9(1):49–55, 2008; Kumar A, Sharma SS:
­Biochem Biophys Res Comm 394:360–365, 2010; Kumar V et al: Cellular responses to stress and toxic insults: adaptation, injury, and death. In
Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, ed 8, St Louis, 2010, Saunders.

maximal life span. Although the maximal life span has not changed Other age-related defects in the extracellular matrix include skeletal
significantly over time, life expectancy has increased, but not for all muscle alterations (e.g., atrophy, decreased tone, loss of contrac-
Americans (see Health Alert: Decline in Life Expectancy in Some tility), cataracts, diverticula, hernias, and rupture of intervertebral
U.S. Counties). Life expectancy is the average number of years of life disks.
remaining at a given age. Free radicals of oxygen that result from oxidative cellular metabo-
lism, oxidative stress (e.g., respiratory chain, phagocytosis, prostaglan-
Degenerative Extracellular Changes din synthesis), damage tissues during the aging process. The oxygen
Extracellular factors that affect the aging process include the binding radicals produced include superoxide radical, hydroxyl radical, and
of collagen; the increase in the effects of free radicals on cells; the struc- hydrogen peroxide (see p. 66). These oxygen products are extremely
tural alterations of fascia, tendons, ligaments, bones, and joints; and reactive and can damage nucleic acids, destroy polysaccharides, oxi-
the development of peripheral vascular disease, particularly arterio- dize proteins, peroxidize unsaturated fatty acids, and kill and lyse cells.
sclerosis (see Chapter 23). Oxidant effects on target cells can lead to malignant transformation,
Aging affects the extracellular matrix with increased cross- presumably through DNA damage. That progressive and cumulative
linking (e.g., aging collagen becomes more insoluble, chemically damage from oxygen radicals may lead to harmful alterations in cellu-
stable but rigid, resulting in decreased cell permeability), decreased lar function is consistent with those alterations of aging. This hypoth-
synthesis, and increased degradation of collagen. The extracellular esis is founded on the wear-and-tear theory of aging, which states that
matrix determines the tissue’s physical properties.1 These changes, damages accumulate with time, decreasing the organism’s ability to
together with the disappearance of elastin and changes in proteogly- maintain a steady state. Because these oxygen-reactive species not only
cans and plasma proteins, cause disorders of the ground substance can permanently damage cells but also may lead to cell death, there is
that result in dehydration and wrinkling of the skin (see Chapter 39). new support for their role in the aging process.
92 CHAPTER 3  Altered Cellular and Tissue Biology

HEALTH ALERT
85% 65%
Decline in Life Expectancy in Some U.S. Counties
Continuing rise in life expectancy for all Americans is not happening. Long-
term analysis of county trends has revealed startling data. Cardiac
Between 1961 and 1999, average life expectancy in the United States Brain weight output at rest
increased from 73.5 to 79.6 years for women and from 66.9 to 74.1 years for
55%
men. However, the differences in mortality by county between the most disad- Citric 80%
vantaged populations and those with the most advantages began to widen in acid
the early 1980s. Life expectancy between 1961 and 1999 in the male advan- cycle

taged population (best-off group) rose from 70.5 to 78.7 years and from 76.9 Basal Respiratory
to 83.0 years for females. In the female disadvantaged populations (worst-off metabolic rate capacity of lungs
group) starting in the early 1980s, life expectancy remained relatively stable
(68.7 years in 1961, 74.5 years in 1983, and only 75.5 years in 1999). The 50% 65%
worst-off men had a decline, rising again in the 1990s.
The gains made, particularly for cardiovascular disease, began to plateau
in the 1980s because of rising mortality from lung cancer, chronic obstructive
Liver
pulmonary disease, and diabetes. A major contributor, which peaked later for blood flow Kidney mass
women than men, is smoking. Smoking is thought to be a significant contribu-
tor for women, as well as overweight, obesity, and hypertension. The worst-off 85%
counties also showed an increase in HIV/AIDS deaths and homicide in men. 63%
Statistically significant declines for women occurred in 180 of 3141 coun-
ties and in 11 counties for men. In addition, 783 counties for women and
Liver weight Conduction velocity
48 for men declined but this was not statistically significant. Life expectancy of nerve fiber
was worse in all Southwestern Virginia counties with a drop over the 16-year FIGURE 3-33  Some Biological Changes Associated With Aging.
period of about 6 years in women and 2.5 years in men. The greatest improve- Insets show proportion of remaining functions in the organs of a
ments occurred in Western desert counties, where life expectancy rose almost person in late adulthood compared with a 20-year-old.
5 years for women and about 7 years for men.
The life expectancy “gap” is increasing between rich and poor and high
and low educational attainment. This increase is occurring despite the gap Of much interest is the relationship between aging and the disap-
between men and women and between blacks and whites. In addition, other pearance or alteration of extracellular substances important for vessel
indices include geography and community assets. integrity. With aging, lipid, calcium, and plasma proteins are deposited
The analysis of county data demonstrates that the 1980s and 1990s were in vessel walls. These depositions cause serious basement membrane
the beginning of the era of increased inequalities in mortality in the United thickening and alterations in smooth muscle functioning, resulting
States. Dividing the United States to eight “Americas,” it is now evident that in arteriosclerosis (a progressive disease that causes such problems as
disparities in mortality affect millions of Americans. The gap is enormous. stroke, myocardial infarction, renal disease, and peripheral vascular
The eight Americas’ analysis revealed the highest levels of life expectancy on disease).
record were for U.S.-born Asian females (America 1), which was 3 years higher
Cellular Aging
than that for females in Japan. The next highest group was low-income, white
rural populations in Minnesota, the Dakotas, Iowa, Montana, and Nebraska Cellular changes characteristic of aging include atrophy, decreased
(America 2), with a life expectancy of 76.2 years for males and 81.8 years function, and loss of cells, possibly caused by apoptosis (Figure 3-33).
for females. Blacks living in high-risk urban areas (America 8) had the low- Loss of cellular function from any of these causes initiates the com-
est life expectancy, being almost four times more likely than the America 1 pensatory mechanisms of hypertrophy and hyperplasia of the remain-
(Asian) group to die before the age of 60 years and between 3.8 and 4.7 times ing cells, which can lead to metaplasia, dysplasia, and neoplasia. All
more likely to die before age 45! The excess young and middle-aged deaths of these changes can alter receptor placement and function, nutrient
in America 8 were observed to be caused by injuries, cardiovascular disease, pathways, secretion of cellular products, and neuroendocrine con-
liver cirrhosis, diabetes, HIV, and homicide. trol mechanisms. In the aged cell, DNA, RNA, cellular proteins, and
In summary, large disparities in life expectancy exist across America because membranes are most susceptible to injurious stimuli. DNA is particu-
of differences in chronic diseases and injuries with known risk factors, includ- larly vulnerable to such injuries as breaks, deletions, and additions.
ing using alcohol or tobacco, being overweight or obese, and having elevated Lack of DNA repair increases the cell’s susceptibility to mutations
blood pressure, high cholesterol levels, and uncontrolled glucose levels. that may be lethal or may promote the development of neoplasia (see
Chapter 9).
Data from Ezzati M et al: The reversal of fortunes: trends in county Mitochondria are the organelles responsible for the generation
mortality and cross-country mortality disparances in the United States, of most of the energy used by eukaryotic cells. Mitochondrial DNA
PLOS Med 5(4):e66 doi:10.1371/journal.pmed.0050066; Murray CJL (mtDNA) encodes some of the proteins of the electron transfer chain,
et al: Eight Americas: investigating mortality disparities across races, the system necessary for the conversion of adenosine diphosphate
counties, and race-counties in the United States, PLOS Med 3(9):e260
(ADP) to ATP. Mutations in mtDNA can deprive the cell of ATP,
doi:10.1371/journal.pmed.0030260.
and mutations are correlated with the aging process. The most com-
AIDS, Acquired immunodeficiency syndrome; HIV, Human immunodefi-
ciency virus.
mon age-related mtDNA mutation in humans is a large rearrange-
ment called the 4977 deletion, or common deletion, and is found in
humans older than 40 years. It is a deletion that removes all or part
 CHAPTER 3  Altered Cellular and Tissue Biology 93

of 7 of the 13 protein-encoding mtDNA genes and 5 of the 22 tRNA decreased cellular mass is accompanied by an increased extracellular
genes. Individual cells containing this deletion have a condition fluid compartment.
known as heteroplasmy. Heteroplasmy levels rise with aging and are Although some of these alterations are probably inherent in aging,
tissue-dependent.46-48 others represent consequences of the process. Advanced age increases
The production of ROS under physiologic conditions is associ- susceptibility to disease, and death occurs after an injury or insult
ated with activity of the respiratory chain in aerobic ATP production. because of diminished cellular, tissue, and organic function.
Therefore on its own accord, increased mitochondrial activity can
cause “oxidative stress” in cells. The production of ROS is markedly Frailty
increased in many pathologic conditions in which the respiratory Frailty is a common clinical syndrome in older adults, leaving a
chain is impaired. Because mtDNA, which is essential for normal oxi- person vulnerable to falls, functional decline, disability, disease, and
dative phosphorylation, is located in proximity to the ROS-generating death. Recently investigators hypothesized that the clinical manifes-
respiratory chain, it is more oxidatively damaged than is nuclear DNA. tations of frailty include a cycle of negative energy balance, sarco-
Cumulative damage of mtDNA is implicated in the aging process as penia, and diminished strength and tolerance for exertion.50,51 (For
well as in the progression of such common diseases as diabetes, cancer, research and clinical purposes the criteria indicating compromised
and heart failure. energetics include low grip strength, slowed waking speed, low
physical activity, and unintentional weight loss).51 The syndrome
Tissue and Systemic Aging is complex, involving oxidative stress, dysregulation of inflamma-
It is probably safe to say that every physiologic process functions less tory cytokines and hormones, malnutrition, physical inactivity, and
efficiently with increasing age. The most characteristic tissue change muscle apoptosis (see review).51 Additionally, the clinical condition
with age is a progressive stiffness or rigidity that affects many sys- of frailty includes decreased lean body mass (sarcopenia), osteope-
tems, including the arterial, pulmonary, and musculoskeletal systems. nia, cognitive impairment, and anemia.52 Several physiologic gender
A consequence of blood vessel and organ stiffness is a progressive differences may explain differing levels of frailty: (1) higher base-
increase in peripheral resistance to blood flow. The movement of line levels of muscle mass for men may be protective against frailty,
intracellular and extracellular substances also decreases with age, as (2) testosterone and growth hormone can provide advantages in
does the diffusion capacity of the lung. Blood flow through organs muscle mass maintenance, (3) cortisol is more dysregulated in older
also decreases. women than older men, (4) alterations in immune function and
Changes in the endocrine and immune systems include thymus immune responsiveness to sex steroids make men more vulnerable
atrophy. Although this occurs at puberty, causing a decreased immune to sepsis and infection and women vulnerable to chronic inflamma-
response to T-dependent antigens (foreign proteins), increased num- tory conditions and muscle mass loss, and (5) lower levels of activity
bers of autoantibodies and immune complexes (antibodies that are and caloric intake may influence greater susceptibility to frailty in
bound to antigens) and an overall decrease in the immunologic toler- women.53
ance for the host’s own cells further diminish the effectiveness of the
immune system later in life. In women the reproductive system loses
SOMATIC DEATH
ova, and in men spermatogenesis decreases. Responsiveness to hor-
mones decreases in the breast and endometrium. Somatic death is death of the entire person. Unlike the changes that
The stomach experiences decreases in the rate of emptying and follow cellular death in a live body, postmortem change is diffuse and
secretion of hormones and hydrochloric acid. Muscular atrophy does not involve components of the inflammatory response. Within
diminishes mobility by decreasing motor tone and contractility. minutes after death, postmortem changes appear, eliminating any
Sarcopenia, loss of muscle mass and strength, can occur into old difficulty in determining that death has occurred. The most notable
age. The skin of the aged individual is affected by atrophy and wrin- manifestations are complete cessation of respiration and circulation.
kling of the epidermis and alterations in underlying dermis, fat, and The surface of the skin usually becomes pale and yellowish; however,
muscle. the lifelike color of the cheeks and lips may persist after death that
Total body changes include a decrease in height; a reduction in cir- is caused by carbon monoxide poisoning, drowning, or chloroform
cumference of the neck, thighs, and arms; widening of the pelvis; and poisoning.53
lengthening of the nose and ears. Several of these changes are the result Body temperature falls gradually immediately after death and then
of tissue atrophy and of decreased bone mass caused by osteoporosis more rapidly (approximately 1.0° to 1.5° F/hr) until, after 24 hours,
and osteoarthritis. Although reduced growth hormone production and body temperature equals that of the environment.55 After death caused
efficacy, reflected in diminished levels of insulin-like growth factor 1, by certain infective diseases, body temperature may continue to rise
is a current hypothesis for explaining decreased bone and lean body for a short time. Postmortem reduction of body temperature is called
mass, recent research has found advancing age rather than declining algor mortis.
levels of these hormones as a major determinant.49 Blood pressure within the retinal vessels decreases, causing muscle
Body composition changes with age. With middle age, there is an tension to decrease and the pupils to dilate. The face, nose, and chin
increase in body weight (men gain until 50 years of age and women become sharp or peaked-looking as blood and fluids drain from the
until 70 years) and fat mass, followed by a decrease in stature, weight, head.53 Gravity causes blood to settle in the most dependent, or lowest,
fat-free mass (FFM) (includes all minerals, proteins, and water plus tissues, which develop a purple discoloration called livor mortis. Inci-
all other constituents except lipids), and body cell mass at older ages. sions made at this time usually fail to cause bleeding. The skin loses its
As fat increases, total body water decreases. Increased body fat and elasticity and transparency.
centralized fat distribution (abdominal) are associated with non– Within 6 hours after death, acidic compounds accumulate within
insulin-dependent diabetes (type 2 diabetes mellitus) and heart dis- the muscles because of the breakdown of carbohydrates and deple-
ease. Total body potassium levels also decrease because of decreased tion of ATP. This interferes with ATP-dependent detachment of myo-
cellular mass. An increased sodium/potassium ratio suggests that the sin from actin (contractile proteins), and muscle stiffening, or rigor
94 CHAPTER 3  Altered Cellular and Tissue Biology

mortis, develops. The smaller muscles are usually affected first, par- this, swelling or bloating of the body and liquefactive changes occur,
ticularly the muscles of the jaw. Within 12 to 14 hours, rigor mortis sometimes causing opening of the body cavities. At a microscopic level,
usually affects the entire body. putrefactive changes are associated with the release of enzymes and
Signs of putrefaction are generally obvious about 24 to 48 hours lytic dissolution called postmortem autolysis.
after death. Rigor mortis gradually diminishes, and the body becomes
flaccid at 36 to 62 hours. Putrefactive changes vary depending on the
temperature of the environment. The most visible is greenish discol-
oration of the skin, particularly on the abdomen. The discoloration
4 QUICK CHECK 3-5
1. Why are microinsults important to aging?
is thought to be related to the diffusion of hemolyzed blood into the 2. What are the body composition changes that occur with aging?
tissues and the production of sulfhemoglobin.55 Slippage or loosen- 3. Define frailty and possible endocrine-immune system involvement.
ing of the skin from underlying tissues occurs at the same time. After

DID YOU UNDERSTAND?

Cellular Adaptation 5. Free radicals cause cellular injury because they have an unpaired electron
1. Cellular adaptation is a reversible, structural, or functional response both that makes the molecule unstable. To stabilize itself, the molecule either
to normal or physiologic conditions and to adverse or pathologic conditions. donates or accepts an electron from another molecule. Therefore it forms
Cells can adapt to physiologic demands or stress to maintain a steady state injurious chemical bonds with proteins, lipids, and carbohydrates—key
called homeostasis. molecules in membranes and nucleic acids.
2. The most significant adaptive changes include atrophy, hypertrophy, hyper- 6. The damaging effects of free radicals, especially activated oxygen species
plasia, and metaplasia. such as O− 2̇
, OH·, and H2O2, called oxidative stress, include (a) peroxidation
3. Atrophy is a decrease in cellular size caused by aging, disuse, or reduced/ of lipids, (b) alteration of ion pumps and transport mechanisms, (c) fragmen-
absent blood supply, hormonal stimulation, or neural stimulation. The tation of DNA, and (d) damage to mitochondria, releasing calcium into the
amounts of endoplasmic reticulum, mitochondria, and microfilaments cytosol.
decrease. The mechanisms of atrophy probably include decreased protein 7. Restoration of oxygen, however, can cause additional injury, called reperfu-
synthesis, increased protein catabolism, or both. sion injury. Reperfusion injury results from the generation of highly reactive
4. Hypertrophy is an increase in the size of cells caused by increased work oxygen intermediates increasing cellular oxidative stress and damage.
demands or hormonal stimulation. The amounts of protein in the plasma mem- 8. The initial insult in chemical injury is damage or destruction of the plasma
brane, endoplasmic reticulum, microfilaments, and mitochondria increase. membrane. Examples of chemical agents that cause cellular injury are car-
5. Hyperplasia is an increase in the number of cells caused by an increased bon tetrachloride, lead, carbon monoxide, and ethyl alcohol.
rate of cellular division. Normal hyperplasia is stimulated by hormones or 9. Unintentional and intentional injuries are an important health problem in
the need to replace lost tissues. the United States. Death as a result of these injuries is more common for
6. Metaplasia is the reversible replacement of one mature cell type by another men than women and higher among blacks than whites and other racial
less mature cell type. groups.
7. Dysplasia, or atypical hyperplasia, is an abnormal change in the size, 10. Injuries by blunt force are the result of the application of mechanical energy to
shape, and organization of mature tissue cells. It is considered an atypical the body, resulting in tearing, shearing, or crushing of tissues. The most com-
rather than a true adaptational change. mon types of blunt-force injuries include motor vehicle accidents and falls.
11. A contusion is bleeding into the skin or underlying tissues as a conse-
Cellular Injury quence of a blow. A collection of blood in soft tissues or an enclosed space
1. Cellular injury occurs if the cell is unable to maintain homeostasis. Injured may be referred to as a hematoma.
cells may recover (reversible injury) or die (irreversible injury). Injury is 12. An abrasion (scrape) results from removal of the superficial layers of the
caused by lack of oxygen (hypoxia), free radicals, caustic or toxic chemi- skin caused by friction between the skin and injuring object. Abrasions and
cals, infectious agents, inflammatory and immune responses, genetic fac- contusions may have a patterned appearance that mirrors the shape and
tors, insufficient nutrients, or physical trauma from many causes. features of the injuring object.
2. Four biochemical themes are important to cell injury: (a) ATP depletion, 13. A laceration is a tear or rip resulting when the tensile strength of the skin
resulting in mitochondrial damage; (b) accumulation of oxygen and oxy- or tissue is exceeded.
gen-derived free radicals, causing membrane damage; (c) protein folding 14. An incised wound is a cut that is longer than it is deep. A stab wound is a
defects; and (d) increased intracellular calcium concentration and loss of penetrating sharp-force injury that is deeper than it is long.
calcium steady state. 15. Gunshot wounds may be either penetrating (bullet retained in the body) or
3. The sequence of events leading to cell death is commonly decreased ATP perforating (bullet exits the body). The most important factors determining
production, failure of active transport mechanisms (the sodium-potassium the appearance of a gunshot injury are whether it is an entrance or an exit
pump), cellular swelling, detachment of ribosomes from the endoplasmic wound and the range of fire.
reticulum, cessation of protein synthesis, mitochondrial swelling as a result 16. Asphyxial injuries are caused by a failure of cells to receive or utilize oxy-
of calcium accumulation, vacuolation, leakage of digestive enzymes from gen. These injuries can be grouped into four general categories: suffoca-
lysosomes, autodigestion of intracellular structures, lysis of the plasma tion, strangulation, chemical, and drowning.
membrane, and death. 17. Activation of inflammation and immunity, which occurs after cellular injury
4. The initial insult in hypoxic injury is usually ischemia (the cessation of blood or infection, involves powerful biochemicals and proteins capable of dam-
flow into vessels that supply the cell with oxygen and nutrients). aging normal (uninjured and uninfected) cells.
 CHAPTER 3  Altered Cellular and Tissue Biology 95

DID YOU UNDERSTAND?—cont’d

18. Genetic disorders injure cells by altering the nucleus and the plasma mem- and is characterized by “dropping off” of cellular fragments, called apop-
brane’s structure, shape, receptors, or transport mechanisms. totic bodies. It is now understood that under certain conditions necrosis is
19. Deprivation of essential nutrients (proteins, carbohydrates, lipids, vita- regulated or programmed, hence the new term “programmed necrosis” or
mins) can cause cellular injury by altering cellular structure and func- necroptosis.
tion, particularly of transport mechanisms, chromosomes, the nucleus, 2. There are four major types of necroses: coagulative, liquefactive, caseous,
and DNA. and fat necroses. Different types of necroses occur in different tissues.
20. Injurious physical agents include temperature extremes, changes in atmo- 3. Structural signs that indicate irreversible injury and progression to necrosis
spheric pressure, ionizing radiation, illumination, mechanical stresses (e.g., are the dense clumping and disruption of genetic material and the disruption
repetitive body movements), and noise. of the plasma and organelle membranes.
21. Errors in healthcare are a leading cause of injury or death in the United 4. Apoptosis, a distinct type of sublethal injury, is a process of selective cellular
States. Errors involve medicines, surgery, diagnosis, equipment, and labo- self-destruction that occurs in both normal and pathologic tissue changes.
ratory reports. They can occur anywhere in the healthcare system including 5. Death by apoptosis causes loss of cells in many pathologic states including
hospitals, clinics, outpatient surgery centers, physicians’ offices, pharma- (a) severe cell injury, (b) accumulation of misfolded proteins, (c) infections,
cies, and the individual’s home. and (d) obstruction in tissue ducts.
6. Excessive accumulation of misfolded proteins in the endoplasmic reticulum
Manifestations of Cellular Injury (ER) leads to a condition known as endoplasmic stress. ER stress results in
1. An important manifestation of cell injury is the resultant metabolic distur- apoptotic cell death and this mechanism has been linked to several degen-
bances of intracellular accumulation (infiltration) of abnormal amounts of erative diseases of the CNS and other organs.
various substances. Two categories of accumulations are (a) normal cellular 7. Excessive or insufficient apoptosis is known as dysregulated apoptosis.
substances, such as water, proteins, lipids, and carbohydrate excesses; and 8. Autophagy means “eating of self” and as a recycling factory it is a self-
(b) abnormal substances, either endogenous (e.g., from abnormal metabo- destructive process and a survival mechanism. When cells are starved or
lism) or exogenous (e.g., a virus). nutrient deprived, the autophagic process institutes cannibalization and
2. Most accumulations are attributed to four types of mechanisms, all abnor- recycles the digested contents. Autophagy can maintain cellular metabo-
mal: (a) An endogenous substance is produced in excess or at an increased lism under starvation conditions and remove damaged organelles under
rate; (b) an abnormal substance, often the result of a mutated gene, accumu- stress conditions, improving the survival of cells. Autophagy declines and
lates; (c) an endogenous substance is not effectively catabolized; and (d) a becomes less efficient as the cell ages, thus contributing to the aging
harmful exogenous substance accumulates because of inhalation, ingestion, process.
or infection. 9. Gangrenous necrosis, or gangrene, is tissue necrosis caused by hypoxia and
3. Accumulations harm cells by “crowding” the organelles and by causing the subsequent bacterial invasion.
excessive (and sometimes harmful) metabolites to be produced during their
catabolism. The metabolites are released into the cytoplasm or expelled into Aging and Altered Cellular and Tissue Biology
the extracellular matrix. 1. It is difficult to determine the physiologic (normal) from the pathologic
4. Cellular swelling, the accumulation of excessive water in the cell, is changes of aging. Cellular aging is the result of increasing molecular disorder
caused by the failure of transport mechanisms and is a sign of many types or entropy.
of cellular injury. Oncosis is a type of cellular death resulting from cellular 2. Humans have an inherent maximal life span (80 to 100 years) that is dictated
swelling. by currently unknown intrinsic mechanisms.
5. Accumulations of organic substances—lipids, carbohydrates, glycogen, proteins, 3. Although the maximal life span has not changed significantly over time, the
pigments—are caused by disorders in which (a) cellular uptake of the substance average life span, or life expectancy, has increased, but not for all Ameri-
exceeds the cell’s capacity to catabolize (digest) or use it or (b) cellular anabolism cans. Life expectancy is the average number of years of life remaining at a
(synthesis) of the substance exceeds the cell’s capacity to use or secrete it. given age.
6. Dystrophic calcification (accumulation of calcium salts) is always a sign of 4. The physiologic mechanisms of aging apparently are associated with
pathologic change because it occurs only in injured or dead cells. Meta- (a) cellular changes produced by genetic and environmental/life-style factors,
static calcification, however, can occur in uninjured cells in individuals with (b) changes in cellular regulatory or control mechanisms, and (c) degenerative
hypercalcemia. extracellular and vascular alterations.
7. Disturbances in urate metabolism can result in hyperuricemia and deposi- 5. Frailty is a common clinical syndrome in older adults, leaving a person vulner-
tion of sodium urate crystals in tissue—leading to a painful disorder called able to falls, functional decline, disability, disease, and death.
gout.
8. Systemic manifestations of cellular injury include fever, leukocytosis, Somatic Death
increased heart rate, pain, and serum elevations of enzymes in the plasma. 1. Somatic death is death of the entire organism. Postmortem change is diffuse
and does not involve the inflammatory response.
Cellular Death 2. Manifestations of somatic death include cessation of respiration and circula-
1. Cellular death has historically been classified as necrosis and apoptosis. tion, gradual lowering of body temperature, pupil dilation, loss of elasticity
Necrosis is characterized by rapid loss of the plasma membrane structure, and transparency in the skin, muscle stiffening (rigor mortis), and skin discol-
organelle swelling, mitochondrial dysfunction, and the lack of features oration (livor mortis). Signs of putrefaction are obvious about 24 to 48 hours
of apoptosis. Apoptosis is known as regulated or programmed cell death after death.
96 CHAPTER 3  Altered Cellular and Tissue Biology

 KEY TERMS
•  brasion  94
A •  thanol  72
E • M aximal life span  90
• Adaptation  59 • Exit wound  77 • Melanin  82
• Aging  90 • Fat necrosis  86 • Mesenchymal (tissue from embryonic
• Algor mortis  93 • Fat-free mass (FFM)  93 mesoderm) cells  62
• Anoxia  64 • Fatty change  81 • Metaplasia  62
• Apoptosis  87 • Fetal alcohol syndrome  73 • Metastatic calcification  84
• Asphyxial injury  74 • Frailty  93 • Mitochondrial DNA (mDNA)  66
• Atrophy  60 • Free radical  66 • Necrosis  85
• Autolysis  85 • Gangrenous necrosis  86 • Oncosis (vacuolar degeneration)  81
• Autophagic vacuole  60 • Gas gangrene  87 • Oxidative stress  66
• Autophagy  88 • Hanging strangulation  75 • Pathologic atrophy  60
• Bilirubin  83 • Hemoprotein  82 • Pathologic hyperplasia  61
• Blunt force  76 • Hemosiderin  82 • Physiologic atrophy  60
• Carbon monoxide (CO)  71 • Hemosiderosis  82 • Postmortem autolysis  94
• Carboxyhemoglobin  72 • Hormonal hyperplasia  61 • Postmortem change  93
• Caseous necrosis  86 • Hydrogen sulfide  75 • Programmed necrosis (necroptosis)  85
• Caspase  88 • Hyperplasia  61 • Proteosome  60
• Cellular accumulation (infiltration)  80 • Hypertrophy  61 • Psammoma body  84
• Cellular swelling  80 • Hypoxia  63 • Puncture wound  76
• Chemical asphyxiant  75 • Incised wound  76 • Pyknosis  85
• Choking asphyxiation  74 • Irreversible injury  62 • Reperfusion injury  65
• Chopping wound  76 • Ischemia  64 • Reversible injury  62
• Coagulative necrosis  86 • Karyolysis  85 • Rigor mortis  93
• Compensatory hyperplasia  61 • Karyorrhexis  85 • Sarcopenia  93
• Contusion (bruise)  76 • Laceration  76 • Somatic death  93
• Cyanide  75 • Lead  70 • Stab wound  76
• Cytochrome  82 • Life expectancy  91 • Strangulation  74
• Disuse atrophy  60 • Ligature strangulation  75 • Suffocation  74
• Drowning  75 • Lipid peroxidation  66 • Ubiquitin  60
• Dry-lung drowning  79 • Lipofuscin  61 • Ubiquitin-proteosome pathway  60
• Dysplasia (atypical hyperplasia)  62 • Liquefactive necrosis  86 • Urate  84
• Dystrophic calcification  84 • Livor mortis  93 • Vacuolation  65
• Endoplasmic stress (ER stress)  87 • Manual strangulation  75 • Xenobiotic  68

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CHAPTER

4
Fluids and Electrolytes, Acids and Bases
Sue E. Huether

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Distribution of Body Fluids, 98 Alterations in Sodium, Water, and Chloride Balance, 103
Maturation and the Distribution of Body Fluids, 99 Isotonic Alterations, 104
Water Movement Between Plasma and Interstitial Hypertonic Alterations, 105
Fluid, 99 Hypotonic Alterations, 105
PEDIATRIC CONSIDERATIONS: Distribution of Body Fluids, 99 Alterations in Potassium and Other Electrolytes, 106
GERIATRIC CONSIDERATIONS: Distribution of Body Fluids, 100 Potassium, 106
Water Movement Between ICF and ECF, 100 Other Electrolytes—Calcium, Magnesium, and Phosphate, 109
Alterations in Water Movement, 100 Acid-Base Balance, 109
Edema, 100 Hydrogen Ion and pH, 109
Sodium, Chloride, and Water Balance, 102 Buffer Systems, 110
Sodium and Chloride Balance, 102 Acid-Base Imbalances, 111
Water Balance, 103

The cells of the body live in a fluid environment with electrolyte and kilograms. One liter of water weighs 2.2 lb (1 kg). The rest of the body
acid-base concentrations maintained within a narrow range. Changes weight is composed of fat and fat-free solids, particularly bone.
in electrolyte concentration affect the electrical activity of nerve Body fluids are distributed among functional compartments, or
and muscle cells and cause shifts of fluid from one compartment to spaces, and provide a transport medium for cellular and tissue func-
another. Alterations in acid-base balance disrupt cellular functions. tion. Intracellular fluid (ICF) comprises all the fluid within cells, about
Fluid fluctuations also affect blood volume and cellular function. Dis- two thirds of TBW. Extracellular fluid (ECF) is all the fluid outside the
turbances in these functions are common and can be life-threatening. cells (about one third of TBW) and is divided into smaller compart-
Understanding how alterations occur and how the body compensates ments. The two main ECF compartments are the interstitial fluid (the
or corrects the disturbance is important for comprehending many space between cells and outside the blood vessels) and the intravascular
pathophysiologic conditions. fluid (blood plasma) (Table 4-2). The total volume of body water for
a 70-kg person is about 42 liters. Other ECF compartments include
lymph and transcellular fluids, such as synovial, intestinal, and cere-
DISTRIBUTION OF BODY FLUIDS brospinal fluid; sweat; urine; and pleural, peritoneal, pericardial, and
The sum of fluids within all body compartments constitutes total body intraocular fluids.
water (TBW)—about 60% of body weight in adults (Table 4-1). The Although the amount of fluid within the various compartments is
volume of TBW is usually expressed as a percentage of body weight in relatively constant, solutes (e.g., salts) and water are exchanged between

98
 CHAPTER 4  Fluids and Electrolytes, Acids and Bases 99

TABLE 4-1 TOTAL BODY WATER (%) IN RELATION TO BODY WEIGHT*

BODY BUILD ADULT MALE ADULT FEMALE CHILD (1-10 yr) INFANT (1 mo to 1 yr) NEWBORN (up to 1 mo)
Normal 60 50 65 70 70-80
Lean 70 60 50-60 80
Obese 50 42 50 60

*note: Total body water is a percentage of body weight.

TABLE 4-2 DISTRIBUTION OF BODY TABLE 4-3 NORMAL WATER GAINS

WATER (70-KG MAN) AND LOSSES (70-KG MAN)
% OF BODY DAILY INTAKE (mL) DAILY OUTPUT (mL)
FLUID COMPARTMENT WEIGHT VOLUME (L) Drinking 1400-1800 Urine 1400-1800
Intracellular fluid (ICF) 40 28 Water in 700-1000 Stool 100
Extracellular fluid (ECF) 20 14 food
Interstitial 15 11 Water of 300-400 Skin 300-500
Intravascular 5 3 oxidation
Total body water (TBW) 60 42 Lungs 600-800
total 2400-3200 total 2400-3200

compartments to maintain their unique compositions. The percentage

of TBW varies with the amount of body fat and age. Because fat is PEDIATRIC CONSIDERATIONS
water repelling (hydrophobic), very little water is contained in adipose Distribution of Body Fluids
(fat) cells. Individuals with more body fat have proportionately less
TBW and tend to be more susceptible to dehydration. Newborn Infants
At birth TBW represents about 75% to 80% of body weight and decreases to
Maturation and the Distribution of Body Fluids about 67% during the first year of life. Physiologic loss of body water amount-
The distribution and the amount of TBW change with age (see the ing to 5% of body weight occurs as an infant adjusts to a new environment.
Pediatric and Aging boxes), and although daily fluid intake may fluc- Infants are particularly susceptible to significant changes in TBW because of
tuate widely, the body regulates water volume within a relatively nar- a high metabolic rate and greater body surface area, as compared to adults.
row range. Water obtained by drinking, water ingested in food, and Consequently, they have a greater fluid intake and output in relation to their
water derived from oxidative metabolism are the primary sources of body size. Renal mechanisms of fluid and electrolyte conservation may not be
body water. Normally, the largest amounts of water are lost through mature enough to counter abnormal losses related to vomiting or diarrhea,
renal excretion, with lesser amounts lost through the stool and thereby allowing dehydration to occur. Symptoms of dehydration include
through vaporization from the skin and lungs (insensible water loss) increased thirst, decreased urine output, decreased body weight, decreased
(Table 4-3). skin elasticity, sunken fontanels, absent tears, dry mucous membranes,
increased heart rate, and irritability.
Water Movement Between Plasma and Interstitial Fluid
The distribution of water and the movement of nutrients and waste Children and Adolescents
products between the capillary and interstitial spaces occur as a TBW slowly decreases to 60% to 65% of body weight. At adolescence the per-
result of changes in hydrostatic pressure (pushes water) and osmotic centage of TBW approaches adult levels and differences according to gender
(oncotic) pressure (pulls water) at the arterial and venous ends of the appear. Males have a greater percentage of body water because of increased
capillary. Water, sodium, and glucose readily move across the capillary muscle mass, and females have more body fat because of the influence of
membrane. The plasma proteins do not cross the capillary membrane estrogen and thus less water.
and maintain effective osmolality by generating plasma oncotic pres-
sure (particularly albumin).
As plasma flows from the arterial to the venous end of the capillary, The movement of fluid back and forth across the capillary wall is
four forces determine if fluid moves out of the capillary and into the called net filtration and is best described as Starling forces:
interstitial space (filtration) or if fluid moves back into the capillary Net filtration =
from the interstitial space (reabsorption): (Forces favoring filtration) − (Forces opposing filtration)
1. Capillary hydrostatic pressure (blood pressure) facilitates the Forces favoring filtration =
outward movement of water from the capillary to the interstitial Capillary hydrostatic pressure and interstitial oncotic pressure
space. Forces opposing filtration =
2. Capillary (plasma) oncotic pressure osmotically attracts water Capillary oncotic pressure and interstitial hydrostatic pressure
from the interstitial space back into the capillary.
3. Interstitial hydrostatic pressure facilitates the inward movement At the arterial end of the capillary, hydrostatic pressure exceeds
of water from the interstitial space into the capillary. capillary oncotic pressure and fluid moves into the interstitial space
4. Interstitial oncotic pressure osmotically attracts water from the (filtration). At the venous end of the capillary, capillary oncotic pres-
capillary into the interstitial space. sure exceeds capillary hydrostatic pressure and fluids are attracted back
100 CHAPTER 4  Fluids and Electrolytes, Acids and Bases

GERIATRIC CONSIDERATIONS Capillary

(fluid movement Cell
Distribution of Body Fluids by net filtration) (fluid movement
The further decline in the percentage of TBW in the elderly is in part the result pressures by osmosis)
of a decreased free fat mass and decreased muscle mass, as well as a reduced Intracellular
ability to regulate sodium and water balance. Kidneys are less efficient in pro- Arteriole
osmotic pressure
ducing either a concentrated or dilute urine, and sodium-conserving responses
are sluggish. Thirst perception also may decline and loss of cognitive func-
Interstitial
tion can influence access to beverages. Healthy older adults can adequately Capillary osmotic pressure
maintain their hydration status. When disease is present, a decrease in TBW, hydrostatic
dehydration and hypernatremia can become life-threatening. pressure
Data from Luckey AE, Parsa CJ: Fluid and electrolytes in the aged,
Arch Surg 138(10):1055-1060, 2003; Schols JM et al: Preventing and Filtrat
ion
treating dehydration in the elderly during periods of illness and warm
weather, J Nutr Health Aging 13(2):150-157, 2009; Schlanger LE,
Bailey JL, Sands JM: Electrolytes in the aging, Adv Chronic Kidney Dis
17(4):308-319, 2010.
Interstitial
hydrostatic
into the circulation (reabsorption). Interstitial hydrostatic pressure pressure
promotes the movement of about 10% of the interstitial fluid along
with small amounts of protein into the lymphatics, which then returns
Capillary
to the circulation. Because albumin does not normally cross the cap-
oncotic
illary membrane, interstitial oncotic pressure is normally minimal.
pressure
­Figure 4-1 illustrates net filtration.
pt i on
sor
Water Movement Between ICF and ECF Reab
Water moves between ICF and ECF compartments primarily as a func-
tion of osmotic forces (see Chapter 1 for definitions). Water moves Venule Lymphatics
freely by diffusion through the lipid bilayer cell membrane and through FIGURE 4-1  Net Filtration—Fluid Movement Between Plasma
aquaporins, a family of water channel proteins that provide perme- and Interstitial Space. The movement of fluid between the vas-
ability to water.1 Sodium is responsible for the ECF osmotic balance, cular, interstitial spaces and the lymphatics is the result of net
and potassium maintains the ICF osmotic balance. The osmotic force filtration of fluid across the semipermeable capillary membrane.
of ICF proteins and other nondiffusible substances is balanced by the Capillary hydrostatic pressure is the primary force for fluid move-
active transport of ions out of the cell. Water crosses cell membranes ment out of the arteriolar end of the capillary and into the interstitial
freely, so the osmolality of TBW is normally at equilibrium. Normally space. At the venous end, capillary oncotic pressure (from plasma
the ICF is not subject to rapid changes in osmolality, but when ECF proteins) attracts water back into the vascular space. Interstitial
hydrostatic pressure promotes the movement of fluid and proteins
osmolality changes, water moves from one compartment to another
into the lymphatics. Osmotic pressure accounts for the movement
until osmotic equilibrium is reestablished (see Figure 4-7, p. 104). of fluid between the interstitial space and the intracellular space.
Normally, intracellular and extracellular fluid osmotic pressures are
ALTERATIONS IN WATER MOVEMENT equal (280 to 294 mOsm) and water is equally distributed between
the interstitial and intracellular compartments.
Edema
Edema is excessive accumulation of fluid within the interstitial spaces.
The forces favoring fluid movement from the capillaries or lymphatic oncotic pressure. Plasma proteins are lost in glomerular diseases of the
channels into the tissues are increased capillary hydrostatic pressure, kidney, serous drainage from open wounds, hemorrhage, burns, and
decreased plasma oncotic pressure, increased capillary membrane per- cirrhosis of the liver. The decreased oncotic attraction of fluid within
meability, and lymphatic channel obstruction2 (Figure 4-2). the capillary causes filtered capillary fluid to remain in the interstitial
space, resulting in edema.
PATHOPHYSIOLOGY  Hydrostatic pressure increases as a result of Capillaries become more permeable with inflammation and
venous obstruction or salt and water retention. Venous obstruction immune responses, especially with trauma such as burns or crushing
causes hydrostatic pressure to increase behind the obstruction, push- injuries, neoplastic disease, and allergic reactions. Proteins escape from
ing fluid from the capillaries into the interstitial spaces. Thrombo- the vascular space and produce edema through decreased capillary
phlebitis (inflammation of veins), hepatic obstruction, tight clothing oncotic pressure and interstitial fluid protein accumulation.
around the extremities, and prolonged standing are common causes The lymphatic system normally absorbs interstitial fluid and a
of venous obstruction. Congestive heart failure, renal failure, and cir- small amount of proteins. When lymphatic channels are blocked or
rhosis of the liver are associated with excessive salt and water retention, surgically removed, proteins and fluid accumulate in the interstitial
which cause plasma volume overload, increased capillary hydrostatic space, causing lymphedema.3 For example, lymphedema of the arm
pressure, and edema. or leg occurs after surgical removal of axillary or femoral lymph nodes,
Lost or diminished plasma albumin production (e.g., from liver respectively, for treatment of carcinoma. Inflammation or tumors may
disease or protein malnutrition) contributes to decreased plasma cause lymphatic obstruction, leading to edema of the involved tissues.4
 CHAPTER 4  Fluids and Electrolytes, Acids and Bases 101

INCREASED CAPILLARY PERMEABILITY

(burns, allergic inflammation reactions)

Decreased production Loss of plasma

of plasma proteins proteins
(cirrhosis, malnutrition)

DECREASED CAPILLARY Increased tissue

ONCOTIC PRESSURE oncotic pressure

EDEMA

Decreased transport of
capillary filtered protein
↑ Na+ H2O renal retention
LYMPH OBSTRUCTION

Fluid movement into tissue Decreased absorption of

interstitial fluid

INCREASED CAPILLARY HYDROSTATIC PRESSURE

(venous obstruction, salt and water retention, heart failure)
FIGURE 4-2  Mechanisms of Edema Formation. H2O, Water; Na+, sodium ion.

CLINICAL MANIFESTATIONS  Edema may be localized or gener-

alized. Localized edema is usually limited to a site of trauma, as in a
sprained finger. Another kind of localized edema occurs within par-
ticular organ systems and includes cerebral edema, pulmonary edema,
pleural effusion (fluid accumulation in the pleural space), pericardial
effusion (fluid accumulation within the membrane around the heart),
and ascites (accumulation of fluid in the peritoneal space). Generalized
edema is manifested by a more uniform distribution of fluid in inter-
stitial spaces. Dependent edema, in which fluid accumulates in gravity-
dependent areas of the body, might signal more generalized edema.
Dependent edema appears in the feet and legs when standing and in
the sacral area and buttocks when supine (lying on back). It can be
identified by pressing on tissues overlying bony prominences. A pit left
in the skin indicates edema (hence the term pitting edema) (Figure 4-3).
Edema usually is associated with weight gain, swelling and puffi-
ness, tight-fitting clothes and shoes, limited movement of affected
joints, and symptoms associated with the underlying pathologic condi-
tion. Fluid accumulations increase the distance required for nutrients
and waste products to move between capillaries and tissues. Blood flow
may be impaired also. Therefore wounds heal more slowly, and with
prolonged edema the risks of infection and pressure sores over bony FIGURE 4-3  Pitting Edema. (From Patton KT, Thibodeau GA: Anat-
prominences increase. Edema of specific organs, such as the brain, omy & physiology, ed 7, St Louis, 2010, Mosby.)
lung, or larynx, can be life-threatening.
As edematous fluid accumulates, it is trapped in a “third space” (i.e.,
the interstitial space, pleural space, pericardial space) and is unavail- the underlying disorder is corrected. Supportive measures include ele-
able for metabolic processes or perfusion. Dehydration can develop vating edematous limbs, using compression stockings, avoiding pro-
as a result of this sequestering. Such sequestration occurs with severe longed standing, restricting salt intake, and taking diuretics.
burns, where large amounts of vascular fluid are lost to the interstitial
spaces, reducing plasma volume and causing shock (see Chapter 23). 4 QUICK CHECK 4-1
1. How does an increase in capillary hydrostatic pressure cause edema?
EVALUATION AND TREATMENT  Specific conditions causing 2. How does a decrease in capillary oncotic pressure cause edema?
edema require diagnosis. Edema may be treated symptomatically until
102 CHAPTER 4  Fluids and Electrolytes, Acids and Bases

TABLE 4-4 REPRESENTATIVE
DISTRIBUTION OF Feedback
Loop
ELECTROLYTES IN BODY Lungs
COMPARTMENTS Angiotensin II
ELECTROLYTES ECF (mEq/L) ICF (mEq/L)
Cations
Sodium 142 12
Potassium 4.2 150 Angiotensin- 3 4
Calcium 5 0 converting
Magnesium 2 24 enzyme (ACE)
total 153.2 186
Aldosterone
Anions
Bicarbonate 24 12 5 Adrenal
Chloride 103 4 cortex
Angiotensin I 1
Phosphate 2 100
Proteins 16 65 Angiotensinogen 2
Other anions 8 6
total 153 187

ECF, Extracellular fluid; ICF, intracellular fluid. Renin

Blood vessel Kidney

SODIUM, CHLORIDE, AND WATER BALANCE
The kidneys and hormones have a central role in maintaining sodium FIGURE 4-4  The Renin-Angiotensin-Aldosterone System.
and water balance. Because water follows the osmotic gradients estab- (1) Renal juxtaglomerular cells sense decrease in blood pressure
lished by changes in salt concentration, sodium and water balance are and release renin; (2) renin activates angiotensinogen to angioten-
intimately related. Sodium is regulated by renal effects of aldosterone sin I; (3) angiotensin I is converted to angiotensin II via angiotensin-
converting enzyme (ACE) in the lung capillaries; (4) angiotensin
(see Figure 17-17, p. 442). Water balance is regulated primarily by
II promotes vasoconstriction and stimulates aldosterone secre-
antidiuretic hormone (ADH; also known as vasopressin). tion from the adrenal cortex, resulting in renal sodium and water
retention, potassium excretion, and an increase in blood pressure;
Sodium and Chloride Balance (5) aldosterone causes increased reabsorption of sodium and water
Sodium (Na+) accounts for 90% of the ECF cations (positively charged retention. (From Patton KT, Thibodeau GA: Anatomy & physiology,
ions). (The distribution of electrolytes in body compartments is sum- ed 7, St Louis, 2010, Mosby.)
marized in Table 4-4.) Along with its constituent anions (negatively
charged ions) chloride and bicarbonate, sodium regulates extracel-
lular osmotic forces and therefore regulates water balance. Sodium is of potassium, increasing blood volume (Figure 4-4). Vasoconstric-
important in other functions, including maintenance of neuromuscu- tion elevates the systemic blood pressure and restores renal perfusion
lar irritability for conduction of nerve impulses (in conjunction with (blood flow). This restoration inhibits the further release of renin.
potassium and calcium), regulation of acid-base balance (using sodium Natriuretic peptides are hormones, including atrial natriuretic
bicarbonate and sodium phosphate), participation in cellular chemical hormone (ANH), produced by the myocardial atria; brain natriuretic
reactions, and transport of substances across the cellular membrane. peptide (BNP) is produced by the myocardial ventricles and urodi-
The kidney, in conjunction with neural and hormonal mediators, latin (an ANP analogue) is synthesized within the kidney. Natri-
maintains normal serum sodium concentration within a narrow range uretic peptides are released when there is an increase in transmural
(135 to 145 mEq/L) primarily through renal tubular reabsorption. atrial pressure (increased volume), which may occur with congestive
Hormonal regulation of sodium (and potassium) balance is mediated heart failure or when there is an increase in mean arterial pressure5
by aldosterone, a mineralocorticoid synthesized and secreted from the (Figure 4-5). They are natural antagonists to the renin-angiotensin-
adrenal cortex as a component of the renin-angiotensin-aldosterone aldosterone system. Natriuretic peptides cause vasodilation and
system (see Chapters 17 and 28). Aldosterone secretion is influenced increase sodium and water excretion, decreasing blood pressure.
both by circulating blood volume and blood pressure and by plasma Natriuretic peptides are sometimes called a “third factor” in sodium
concentrations of sodium and potassium. regulation. (Increased glomerular filtration rate is thus the first factor
When circulating blood volume or blood pressure is reduced, or and aldosterone the second factor.)
sodium levels are depressed or potassium levels are increased, renin, an Chloride (Cl¯) is the major anion in the ECF and provides elec-
enzyme secreted by the juxtaglomerular cells of the kidney, is released. troneutrality, particularly in relation to sodium. Chloride transport is
Renin stimulates the formation of angiotensin I, an inactive poly- generally passive and follows the active transport of sodium so that
peptide. Angiotensin-converting enzyme (ACE) in pulmonary vessels increases or decreases in chloride concentration are proportional
converts angiotensin I to angiotensin II, which stimulates the secre- to changes in sodium concentration. Chloride concentration tends
tion of aldosterone and also causes vasoconstriction. The aldosterone to vary inversely with changes in the concentration of bicarbonate
then promotes renal sodium and water reabsorption and excretion (HCO3−), the other major anion.
 CHAPTER 4  Fluids and Electrolytes, Acids and Bases 103

↑ Plasma osmolality
Total body Na+
or
↓ Circulating fluid volume

Osmotic shift of ↑ Thirst ↑ ADH secretion

Drinking
water out of cells

↑ Fluid intake ↓ Water excretion

Plasma volume

↑ Renal water retention

Atrial stretching detected
by atrial endocrine cells
↑ Circulating fluid volume

ANH release
↓ Plasma osmolarity

Action on Inhibition of renin- Inhibition of ↓ ADH

glomerulus to angiotensin- proximal tubule
GFR aldosterone system Na+ reabsorption ↓ Thirst
FIGURE 4-6  The Antidiuretic Hormone (ADH) System.

Sodium and water excretion

TABLE 4-5 WATER AND SOLUTE
IMBALANCES
TONICITY MECHANISM
Blood volume
Blood pressure Isotonic (isoosmolar) Gain or loss of ECF* resulting in concentration
imbalance equivalent to 0.9% sodium chloride (salt) solution
FIGURE 4-5  The Atrial Natriuretic Hormone (ANH) System. GFR, (normal saline); no shrinking or swelling of cells
Glomerular filtration rate; Na+, sodium ion. Hypertonic Imbalances that result in ECF concentration >0.9%
­(hyperosmolar) salt solution (i.e., water loss or solute gain); cells
Water Balance imbalance shrink in hypertonic fluid
Hypotonic Imbalance that results in ECF <0.9% salt solution
Water balance is regulated by the secretion of ADH (also known as
­(hypoosmolar) (i.e., water gain or solute loss); cells swell in
vasopressin).6 ADH is secreted when plasma osmolality increases or
imbalance hypotonic fluid
circulating blood volume decreases and blood pressure drops (Figure
4-6). Increased plasma osmolality occurs with water deficit or sodium *ECF, Extracellular fluid.
excess in relation to total body water. The increased osmolality stimu-
lates hypothalamic osmoreceptors. In addition to causing thirst, these
osmoreceptors signal the posterior pituitary gland to release ADH.
Thirst stimulates water drinking and ADH increases water reabsorp- 4 QUICK CHECK 4-2
tion into the plasma from the distal tubules and collecting ducts of the 1. What forces promote net filtration?
kidney (see Chapter 28). The reabsorbed water decreases plasma osmo- 2. What hormones regulate salt and water balance?
lality, returning it toward normal, and urine concentration increases.
With fluid loss (dehydration) from vomiting, diarrhea, or exces-
sive sweating, a decrease in blood volume and blood pressure often ALTERATIONS IN SODIUM, WATER,
occurs. Volume-sensitive receptors and baroreceptors (nerve end-
AND CHLORIDE BALANCE
ings that are sensitive to changes in volume and pressure) also stimu-
late the release of ADH from the pituitary gland and stimulate thirst. Alterations in sodium and water balance are closely related. Water
The volume receptors are located in the right and left atria and thoracic imbalances may develop with gains or losses of salt. Likewise, sodium
vessels; baroreceptors are found in the aorta, pulmonary arteries, and imbalances occur with alterations in body water volume. Generally,
carotid sinus. ADH secretion also occurs when atrial pressure drops, as these alterations can be classified as changes in tonicity—the change
occurs with decreased blood volume. The reabsorption of water medi- in the concentration of solutes in relation to water (see Chapter 1).
ated by ADH then promotes the restoration of plasma volume and Alterations can therefore be classified as isotonic, hypertonic, or hypo-
blood pressure (Figure 4-6). tonic (Table 4-5 and Figure 4-7).
104 CHAPTER 4  Fluids and Electrolytes, Acids and Bases

Hypotonic Alteration Isotonic Alteration Hypertonic Alteration

Na+ Na+

H2O Na+ Na+

Na+ H2O Na+
H2O
Na+ Na+ Na+ Na+
RBC RBC
RBC Na+ Na+
H2O Na+
H2O Na+ Na+
H 2O Na+ Na+
Na+ Na+
H2O Na+ H2O Na+ Na+
H2O Na+
Na+
Na+ H2O
Na+
Na+ Na+
Na+
Na+
Na+
Na+ Na+
H 2O
Body cell Body cell Na+ Body cell Na+
Na+
H2O

Na+ Na+
H2O H2O Na+
H2O
Na+ H2O
Na+
Na+ Na+
Na+
Na+
Na+ H2O
H2O Na+ Na+

Neuron Neuron Neuron

A B C
FIGURE 4-7  Effects of Alterations in Extracellular Sodium Concentration in RBC, Body Cell,
and Neuron. A, Hypotonic Alteration: Decrease in ECF sodium (Na) concentration (hyponatremia)
results in ICF osmotic attraction of water with swelling and potential bursting of cells. B, Isotonic
­Alteration: Normal concentration of sodium in the ECF and no change in shifts of fluid in or out of cells.
C, Hypertonic Alteration: An increase in ECF sodium concentration (hypernatremia) results in osmotic
attraction of water out of cells with cell shrinkage. RBC, Red blood cell.

Isotonic Alterations decreased blood pressure. In severe states, hypovolemic shock can
The term isotonic refers to a solution that has the same concentration occur (see Chapter 23). Isotonic solutions of electrolytes and glu-
of solutes as the plasma. Isotonic alterations occur when TBW changes cose are given orally, intravenously or in some cases subcutaneously
are accompanied by proportional changes in the concentrations of (hypodermoclysis).
electrolytes (see Figure 4-7). Isotonic fluid excess causes hypervolemia. Common causes
Isotonic fluid loss causes hypovolemia. For example, if an indi- include excessive administration of intravenous fluids, hypersecre-
vidual loses pure plasma or ECF, fluid volume is depleted but the tion of aldosterone, or the effects of drugs such as cortisone (which
concentration and type of electrolytes and the osmolality remain in causes renal reabsorption of sodium and water). As plasma volume
the normal range (280 to 294 mOsm). Causes include hemorrhage, expands, hypervolemia develops with weight gain. The diluting effect
severe wound drainage, excessive diaphoresis (sweating), and inad- of excess plasma volume leads to decreased hematocrit and decreased
equate fluid intake. There is loss of extracellular fluid volume with plasma protein concentration. The neck veins may distend, and the
weight loss, dryness of skin and mucous membranes, decreased urine blood pressure increases. Increased capillary hydrostatic pressure leads
output, and symptoms of hypovolemia. Indicators of hypovole- to edema formation. Ultimately, pulmonary edema and heart failure
mia include a rapid heart rate, flattened neck veins, and normal or may develop. Diuretics are commonly used for treatment.
 CHAPTER 4  Fluids and Electrolytes, Acids and Bases 105

Clinical manifestations. When there is excessive sodium intake or

Hypertonic Alterations decreased sodium loss, water is redistributed to the extracellular space,
Hypertonic fluid alterations develop when the osmolality of the ECF is resulting in hypervolemia, and intracellular dehydration ensues. Clini-
elevated above normal (greater than 294 mOsm). The most common cal manifestations include weight gain, bounding pulse, and increased
causes are increased concentration of ECF sodium (hypernatremia) or blood pressure. Central nervous system symptoms are the most serious
deficit of ECF water. In both instances, ECF hypertonicity attracts water and are related to alterations in membrane potentials and shrinking
from the intracellular space, causing ICF dehydration (see Figure 4-7). of brain cells. Symptoms include muscle twitching and hyperreflexia
(hyperactive reflexes), confusion, coma, convulsions, and cerebral
Hypernatremia hemorrhage from stretching of veins.
Evaluation and treatment. The treatment of hypernatremia is to
PATHOPHYSIOLOGY  Hypernatremia occurs when serum sodium give oral fluids or isotonic salt-free fluid (5% dextrose in water) until
levels exceed 145 mEq/L. Increased levels of serum sodium may be the serum sodium level returns to normal. Fluid replacement must be
caused by retention or infusion of sodium or by decreased intake or given slowly to prevent cerebral edema. Hypervolemia or hypovolemia
increased loss of water.7 Because sodium is largely in the ECF, increases requires treatment of the underlying clinical condition.
in sodium concentration cause intracellular dehydration. The move-
ment of water to the ECF may cause hypervolemia, or with an Water Deficit
accompanying water loss both ICF and ECF dehydration may occur.
Hyperosmolality is a common result of hypernatremia. PATHOPHYSIOLOGY  Dehydration refers to water deficit but also
Increased sodium retention commonly occurs as a result of oversecre- is commonly used to indicate both sodium and water loss (isotonic
tion of aldosterone (as in primary hyperaldosteronism) or oversecretion or isoosmolar dehydration).9 Pure water deficits (hyperosmolar or
of adrenocorticotropic hormone (ACTH), which also causes increased hypertonic dehydration) are rare because most people have access to
secretion of aldosterone (as in Cushing syndrome).8 Less commonly water. Individuals who are comatose or paralyzed continue to have
there may be inappropriate administration of hypertonic saline solu- insensible water losses through the skin and lungs with a minimal
tion (e.g., as sodium bicarbonate for treatment of acidosis during cardiac obligatory formation of urine. Hyperventilation caused by fever also
arrest). High amounts of dietary sodium rarely cause hypernatremia in a may precipitate water deficit. The most common cause of water loss
healthy individual because the sodium is eliminated by the kidneys. is increased renal clearance of free water as a result of impaired tubu-
Increased sodium concentration caused by water loss or decreased lar function or inability to concentrate the urine, as occurs in diabetes
intake of water is associated with fever or respiratory tract infections, insipidus (decreased ADH) (see Chapter 18).
which increase the respiratory rate and enhance water loss from the
lungs. Diabetes insipidus (deficiency of ADH), diabetes mellitus CLINICAL MANIFESTATIONS  Marked water deficit is manifested
(hyperglycemia), polyuria (frequent urination), profuse sweating, and by symptoms of dehydration, such as headache, thirst, dry skin and
diarrhea also cause water loss in relation to sodium. Infants with severe mucous membranes, elevated temperature, weight loss, and decreased
diarrhea are particularly vulnerable. Insufficient water intake can or concentrated urine (with the exception of diabetes insipidus).
cause hypernatremia, particularly in individuals who are comatose, Skin turgor may be normal or decreased. Symptoms of hypovole-
confused, or immobilized or are receiving gastric feedings. Infants are mia include tachycardia, weak pulses, and postural hypotension
particularly at risk because they cannot communicate thirst. (a decrease in blood pressure with movement from lying or sitting to
Because chloride follows sodium, hyperchloremia (elevation of standing).
serum chloride concentration above 105 mEq/L) often accompanies
hypernatremia, as well as plasma bicarbonate deficits as in metabolic EVALUATION AND TREATMENT  An elevated hematocrit and
acidosis (see p. 111). There are no specific symptoms or treatment for increased serum sodium concentration are associated with moderate
chloride excess. water loss in addition to clinical signs and symptoms. The magnitude
of dehydration is determined from evaluation of the plasma and urine
osmolality.
HEALTH ALERT Treatment is to give water and stop fluid loss. Fluid replacement
Breast-Feeding and Hypernatremia must be administered slowly enough to prevent rapid movement of
water into brain cells, which causes cerebral edema, seizures, brain
Hypernatremic dehydration (serum sodium >150 mEq/L) is an uncommon but injury, and death. When intravenous replacement is required, 5%
serious complication of breast-fed infants, particularly those born by cesarean dextrose in water should be used because pure water lyses red blood
section. At risk are babies older than 48 hours who have lost greater than cells.
10% of body weight and have not regained original birthweight by day 10. The
most common presenting symptom is nonhemolytic jaundice. Nonmetabolic Hypotonic Alterations
symptoms include apnea or bradycardia, or both. Higher breast milk sodium Hypotonic fluid imbalances occur when the osmolality of the ECF
levels also are found. Babies with significant weight loss require maternal is less than normal (i.e., less than 280 mOsm) (see Figure 4-7). The
support to establish successful breast-feeding; daily monitoring of weight and most common causes are sodium deficit or water excess. Either leads
supplemental fluids. to intracellular overhydration (cellular edema) and cell swelling. When
there is a sodium deficit, the osmotic pressure of the ECF decreases and
Data from Konetzny G et al: Prevention of hypernatraemic dehydration in
breastfed newborn infants by daily weighing, Eur J Pediatr 168(7):815–
water moves into the cell where the osmotic pressure is greater. The
818, 2009; Kusuma S et al: Hydration status of exclusively and partially plasma volume then decreases, leading to symptoms of hypovolemia.
breastfed near-term newborns in the first week of life, J Hum Lact With water excess, increases in both the ICF and ECF volume occur,
25(3):280–286, 2009; Shroff R et al: Life-threatening hypernatraemic causing symptoms of hypervolemia and water intoxication with cere-
dehydration in breastfed babies, Arch Dis Child 91(12):1025–1026, 2006. bral and pulmonary edema.
106 CHAPTER 4  Fluids and Electrolytes, Acids and Bases

vasopressin dysregulation, also enhances water retention12 (see Chap-

Hyponatremia ter 18). Water excess is usually accompanied by hyponatremia.

PATHOPHYSIOLOGY  Hyponatremia develops when the serum CLINICAL MANIFESTATIONS  The symptoms of water excess are
sodium concentration falls below 135 mEq/L. It occurs frequently related to the rate at which water loading has occurred. Acute excesses
among hospitalized elderly individuals. This occurs when there is cause cerebral edema with confusion and convulsions. Weakness, nau-
loss of sodium, inadequate intake of sodium, or dilution of sodium sea, muscle twitching, headache, and weight gain are common symp-
by water excess.10 Sodium depletion usually causes hypoosmolality toms of chronic water accumulation.
with movement of water into cells. Pure sodium depletion is usually
caused by vomiting, diarrhea, suctioning of gastrointestinal secretions, EVALUATION AND TREATMENT  The cause and acuity of water
and burns or renal losses from use of diuretics. Inadequate intake of excess must be determined. Serum and urine osmolalities are decreased
dietary sodium is rare but possible in individuals on low-sodium diets, because water will be in excess of sodium. Urine sodium level will be
particularly when diuretics are taken. Dilutional hyponatremia occurs reduced. The hematocrit is reduced from the dilutional effect of water
when there is replacement of fluid loss with intravenous 5% dextrose excess.
in water. The glucose is metabolized to carbon dioxide and water, Fluid restriction for 24 hours is effective treatment if there are no
leaving a hypotonic solution with a diluting effect. Excessive sweat- convulsions. Small amounts of intravenous hypertonic sodium chlo-
ing may stimulate thirst and intake of large amounts of water, which ride (i.e., 3% sodium chloride) can be given when neurologic manifes-
dilute sodium. During acute oliguric renal failure, severe congestive tations are severe.13
heart failure, or cirrhosis renal excretion of water is impaired. Both
TBW and sodium levels are increased, but TBW exceeds the increase
in sodium concentration, producing hypervolemia and hyponatremia. 4 QUICK CHECK 4-3
Hypochloremia, a low level of serum chloride (less than 97 mEq/L), 1. What causes isotonic imbalance?
usually occurs with hyponatremia or an elevated bicarbonate concen- 2. Give two examples of hypertonic alterations, and explain the mechanisms
tration, as in metabolic alkalosis (see p. 112). Sodium deficit related of action for each.
to restricted intake, use of diuretics, and vomiting is accompanied by 3. What is a hypotonic imbalance? Give two examples.
chloride deficiency. Cystic fibrosis is characterized by hypochloremia
(see Chapter 27). Treatment of the underlying cause is required.
ALTERATIONS IN POTASSIUM
CLINICAL MANIFESTATIONS  A decrease in sodium concentra- AND OTHER ELECTROLYTES
tion changes the cell’s ability to depolarize and repolarize normally,
altering the action potential in neurons and muscle (see Chapter 1). Potassium
Neurologic changes characteristic of hyponatremia include lethargy, Potassium (K+) is the major intracellular electrolyte and is essential for
confusion, apprehension, depressed reflexes, seizures, and coma. normal cellular functions. Total body potassium content is about 4000
Muscle twitching and weakness are common. Pure sodium losses may mEq, with most of it (98%) located in the cells. The ICF concentration
be accompanied by loss of ECF, causing hypovolemia with symptoms of potassium is 150 to 160 mEq/L; the ECF potassium concentration
of hypotension, tachycardia, and decreased urine output. Dilutional is 3.5 to 5.0 mEq/L. The difference in concentration is maintained by
hyponatremia is accompanied by weight gain, edema, ascites, and jug- a sodium-potassium adenosinetriphosphatase active transport system
ular vein distention. Cerebral edema can be a life-threatening compli- (Na+, K+ ATPase pump) (see Chapter 1).
cation of hypervolemic hyponatremia. As the predominant ICF ion, potassium exerts a major influence on
the regulation of ICF osmolality and fluid balance as well as on intra-
EVALUATION AND TREATMENT  The cause of hyponatremia must cellular electrical neutrality in relation to hydrogen (H+) and sodium.
be determined and treatment planned accordingly. Hypertonic saline Potassium is required for glycogen and glucose deposition in liver and
solutions are used cautiously with severe symptoms, such as seizures skeletal muscle cells. It also maintains the resting membrane potential,
and must be given slowly to prevent osmotic demyelination syndrome as reflected in the transmission and conduction of nerve impulses, the
in the brain. Restriction of water intake is required in most cases of maintenance of normal cardiac rhythms, and the contraction of skel-
dilutional hyponatremia because body sodium levels may be normal etal muscle and smooth muscle.
or increased even though serum sodium levels are low. Serum sodium Dietary potassium moves rapidly into cells after ingestion. How-
concentration must be monitored.11 ever, the distribution of potassium between intracellular and extra-
cellular fluids is influenced by several factors. Insulin, aldosterone,
Water Excess epinephrine, and alkalosis facilitate the shift of potassium into cells.
Insulin deficiency, aldosterone deficiency, acidosis, cell lysis, and
PATHOPHYSIOLOGY  When the body is functioning normally, it is strenuous exercise facilitate the shift of potassium out of cells. Gluca-
almost impossible to produce an excess of TBW because water bal- gon blocks entry of potassium into cells, and glucocorticoids promote
ance is regulated by the kidneys. Some individuals with psychogenic potassium excretion. Potassium also will move out of cells along with
disorders develop water intoxication from compulsive water drinking. water when there is increased ECF osmolarity.
Acute renal failure, severe congestive heart failure, and cirrhosis can Although potassium is found in most body fluids, the kidney is
precipitate water excess during intravenous infusion of 5% dextrose in the most efficient regulator of potassium balance. Potassium is freely
water. Decreased urine formation from renal disease or decreased renal filtered by the renal glomerulus, and 90% is reabsorbed by the proxi-
blood flow contributes to water excess. The overall effect is dilution of mal tubule and loop of Henle. In the distal tubules, principal cells
the ECF, with water moving to the intracellular space by osmosis. The secrete potassium and intercalated cells reabsorb potassium. These
syndrome of inappropriate secretion of ADH (SIADH), also known as cells determine the amount of potassium excreted from the body. The
 CHAPTER 4  Fluids and Electrolytes, Acids and Bases 107

gut may also sense the amount of K+ ingested and stimulate renal K+ intake and inadequate intake of fruits and vegetables and in individuals
excretion.14 with alcoholism or anorexia nervosa. Reduced potassium intake gener-
The potassium concentration in the distal tubular cells is deter- ally becomes a problem when combined with other causes of potas-
mined primarily by the plasma concentration in the peritubular capil- sium depletion.
laries. When plasma potassium concentration increases from increased ECF hypokalemia can develop without losses of total body potas-
dietary intake or shifts of potassium from the ICF to the ECF occur, sium. For example, potassium shifts from the ECF to the ICF in
potassium is secreted into the urine by the distal tubules.15 Decreased exchange for hydrogen to maintain plasma acid-base balance during
levels of plasma potassium result in decreased distal tubular secretion, respiratory or metabolic alkalosis. Insulin promotes cellular uptake of
although approximately 5 to 15 mEq per day will continue to be lost. potassium and insulin administration may cause an ECF potassium
Changes in the rate of filtrate (urine) flow through the distal tubule deficit.
also influence the concentration gradient for potassium secretion. Potassium shifts from the ICF to the ECF in conditions such as dia-
When the flow rate is high, as with the use of diuretics, potassium con- betic ketoacidosis, in which the increased hydrogen ion concentration
centration in the distal tubular urine is lower, leading to the secretion in the ECF causes H+ to shift into the cell in exchange for potassium.
of potassium into the urine. A normal level of potassium is maintained in the plasma, but potas-
Changes in pH and thus in hydrogen ion concentration also affect sium continues to be lost in the urine, causing a deficit in the amount
potassium balance. During acute acidosis, hydrogen ions accumulate of total body potassium. Severe, even fatal, hypokalemia may occur
in the ICF and potassium shifts out of the cell to the ECF to main- if insulin is administered without also providing potassium supple-
tain a balance of cations across the cell membrane. This occurs in part ments. Thus total body potassium depletion becomes evident when
because of a decrease in sodium-potassium ATPase pump activity. insulin treatment and rehydration therapy are initiated. Potassium
Decreased ICF potassium results in decreased secretion of potassium replacement is instituted cautiously to prevent hyperkalemia.
by the distal tubular cells, contributing to hyperkalemia. In acute alka- Losses of potassium from body stores are usually caused by gastro-
losis, intracellular fluid levels of hydrogen diminish and potassium intestinal and renal disorders. Diarrhea, intestinal drainage tubes or
shifts into the cell; in addition, the distal tubular cells increase their fistulae, and laxative abuse also result in hypokalemia. Normally, only
secretion of potassium, further contributing to hypokalemia. 5 to 10 mEq of potassium and 100 to 150 ml of water are excreted in the
Besides conserving sodium, aldosterone also regulates potassium stool each day. With diarrhea, fluid and electrolyte losses can be volu-
concentration. Elevated plasma potassium concentration causes the minous, with several liters of fluid and 100 to 200 mEq of potassium
release of renin by renal juxtaglomerular cells and the adrenal secre- lost per day. Vomiting or continuous nasogastric suctioning often is
tion of aldosterone through the renin-angiotensin-aldosterone system. associated with potassium depletion, partly because of the potassium
Aldosterone then stimulates the release of potassium into the urine lost from the gastric fluid but principally because of renal compensa-
by the distal renal tubules. Aldosterone also increases the secretion of tion for volume depletion and the metabolic alkalosis (elevated bicar-
potassium from sweat glands. bonate levels) that occurs from sodium, chloride, and hydrogen ion
Insulin helps regulate plasma potassium levels by stimulating the losses. The loss of fluid and sodium stimulates the secretion of aldoste-
sodium-potassium ATPase pump, thus promoting the movement of rone, which in turn causes renal losses of potassium.
potassium into liver and muscle cells, particularly after eating. Insu- Renal potassium losses occur with increased secretion of potas-
lin can also be used to treat hyperkalemia. Dangerously low levels of sium by the distal tubule. Use of potassium-wasting diuretics, exces-
plasma potassium can result when insulin is given while potassium sive aldosterone secretion, increased distal tubular flow rate, and
levels are depressed. Potassium balance is especially significant in the low plasma magnesium concentration all may contribute to urinary
treatment of conditions requiring insulin administration, such as insu- losses of potassium. The elevated flow of bicarbonate at the distal
lin-dependent diabetes mellitus. tubule during alkalosis also contributes to renal excretion of potas-
Potassium adaptation is the ability of the body to adapt to increased sium because the increased tubular lumen electronegativity attracts
levels of potassium intake over time. A sudden increase in potassium potassium. Many diuretics inhibit the reabsorption of sodium chlo-
may be fatal, but if the intake of potassium is slowly increased by ride, causing the diuretic effect. The distal tubular flow rate then
amounts of more than 120 mEq per day, the kidney can increase the increases, promoting potassium excretion. If sodium loss is severe,
urinary excretion of potassium and maintain potassium balance. the compensating aldosterone secretion may further deplete potas-
sium stores. Primary hyperaldosteronism with excessive secretion of
Hypokalemia aldosterone from an adrenal adenoma (tumor) also causes potassium
wasting. Many kidney diseases reduce the ability to conserve sodium.
PATHOPHYSIOLOGY  Potassium deficiency, or hypokalemia, devel- The disordered sodium reabsorption produces a diuretic effect, and
ops when the serum potassium concentration falls below 3.5 mEq/L. the increased distal tubule flow rate favors the secretion of potassium.
Because cellular and total body stores of potassium are difficult to mea- Magnesium deficits increase renal potassium secretion and promote
sure, changes in potassium balance are described, although not always hypokalemia. Several antibiotics are known to cause hypokalemia by
accurately, by the plasma concentration. Generally, lowered serum increasing the rate of potassium excretion. Rare hereditary defects in
potassium level indicates loss of total body potassium. With potassium potassium transport (e.g., Bartter and Gitelman syndromes) also can
loss from the ECF, the concentration gradient change favors move- cause hypokalemia.
ment of potassium from the cell to the ECF. The ICF/ECF concentra-
tion ratio is maintained, but the amount of total body potassium is CLINICAL MANIFESTATIONS  Mild losses of potassium are usu-
depleted. ally asymptomatic. Severe loss of potassium, however, results in neu-
Factors contributing to the development of hypokalemia include romuscular and cardiac manifestations. Neuromuscular excitability
reduced intake of potassium, increased entry of potassium into cells, decreases, causing skeletal muscle weakness, smooth muscle atony,
and increased losses of body potassium. Dietary deficiency of potas- cardiac dysrhythmias, glucose intolerance and impaired urinary con-
sium is rare but may occur in elderly individuals with both low protein centrating ability.16
108 CHAPTER 4  Fluids and Electrolytes, Acids and Bases

Normokalemia TABLE 4-6 CLINICAL MANIFESTATIONS

OF POTASSIUM LEVEL
ALTERATIONS
Normal ORGAN
PR interval SYSTEM HYPOKALEMIA HYPERKALEMIA
Cardiovascular Dysrhythmias Dysrhythmias
Normal U wave shallow ECG changes (flattened ECG changes (peaked
Normal
P wave Rounded, if present T waves, U waves, ST T waves, prolonged
QRS normal-size
depression, peaked P wave, PR interval, absent P
T wave prolonged QT interval) wave with widened
Hypokalemia Cardiac arrest QRS complex)
Weak, irregular pulse rate Bradycardia
Postural hypotension Heart block
Slightly ST depression Cardiac arrest
prolonged Nervous Lethargy Anxiety
PR interval Fatigue Tingling
Confusion Numbness
Slightly Prominent Paresthesias
peaked Shallow U wave Gastrointestinal Nausea and vomiting Nausea and vomiting
P wave T wave Decreased motility Diarrhea
Distention Colicky pain
Hyperkalemia Decreased bowel sounds
Ileus
Tall, peaked Kidney Water loss Oliguria
Decreased T wave
R wave Thirst Kidney damage
amplitude Inability to concentrate urine
Kidney damage
Wide, flat Skeletal and Weakness Early: hyperactive
P wave Depressed smooth muscle Flaccid paralysis muscles
ST segment Respiratory arrest Late: weakness and
Prolonged Widened QRS Constipation flaccid paralysis
PR interval Bladder dysfunction

FIGURE 4-8  Electrocardiogram Changes With Potassium

Imbalance. A wide range of metabolic dysfunctions may result from potassium
deficiency (Table 4-6). Carbohydrate metabolism is affected because
hypokalemia depresses insulin secretion and alters hepatic and skel-
Symptoms occur in relation to the rate of potassium depletion. etal muscle glycogen synthesis. Renal function is impaired, with a
Because the body can accommodate slow losses of potassium, the decreased ability to concentrate urine. Polyuria (increased urine) and
decrease in ECF concentration may allow potassium to shift from polydipsia (increased thirst) are associated with decreased responsive-
the intracellular space, restoring the potassium concentration gradi- ness to ADH. Long-term potassium deficits lasting more than 1 month
ent toward normal, with less severe neuromuscular changes. With may damage renal tissue, with interstitial fibrosis and tubular atrophy.
acute and severe losses of potassium, changes in neuromuscular excit-
ability are more profound. Skeletal muscle weakness occurs initially EVALUATION AND TREATMENT  The diagnosis of hypokalemia is
in the larger muscles of the legs and arms and ultimately affects the significantly related to the medical history and the identification of dis-
diaphragm and depresses ventilation. Paralysis and respiratory arrest orders associated with potassium loss or shifts of extracellular potassium
can occur. Loss of smooth muscle tone is manifested by constipation, to the intracellular space. Treatment involves an estimation of total body
intestinal distention, anorexia, nausea, vomiting, and paralytic ileus potassium losses and correction of acid-base imbalances. Further losses
(paralysis of the intestinal muscles). of potassium should be prevented and the individual should be encour-
The cardiac effects of hypokalemia are related also to changes in aged to eat foods rich in potassium. The maximal rate of oral replace-
membrane excitability. Because potassium contributes to the repolar- ment is 40 to 80 mEq/day if renal function is normal. A maximal safe rate
ization phase of the action potential, hypokalemia delays ventricular of intravenous replacement is 20 mEq/hr. Because potassium is irritating
repolarization. Various dysrhythmias may occur, including sinus bra- to blood vessels, a maximal concentration of 40 mEq/L should be used.
dycardia, atrioventricular block, and paroxysmal atrial tachycardia. Serum potassium values are monitored until normokalemia is achieved.
The characteristic changes in the electrocardiogram (ECG) reflect
delayed repolarization. For instance, the amplitude of the T wave Hyperkalemia
decreases, the amplitude of the U wave increases, and the ST segment
is depressed (Figure 4-8). In severe states of hypokalemia, P waves peak PATHOPHYSIOLOGY  Elevation of ECF potassium concentration
and the QT interval is prolonged. Hypokalemia also increases the risk above 5.5 mEq/L constitutes hyperkalemia.17 Because of efficient
of digitalis toxicity. renal excretion, increases in total body potassium level are relatively
 CHAPTER 4  Fluids and Electrolytes, Acids and Bases 109

rare. Acute increases in serum potassium level are handled quickly concentration result in shifts of potassium into the cell, because the
through increased cellular uptake and renal excretion of body potas- tendency is to maintain a normal ratio of ICF to ECF potassium
sium excesses. concentrations. Acute elevations of extracellular potassium concen-
Potassium excesses may be caused by increased intake, a shift of tration affect neuromuscular irritability as this ratio is disrupted.
potassium from cells to the ECF, decreased renal excretion, or drugs Increases in extracellular fluid calcium concentration can override
that decrease renal potassium excretion (i.e., ACE inhibitors, angioten- the neuromuscular effects of hyperkalemia because calcium is also
sin receptor blockers, and aldosterone antagonists). If renal function a cation.
is normal, slow, long-term increases in potassium intake are usually
well tolerated through potassium adaptation, although short-term EVALUATION AND TREATMENT  Hyperkalemia should be investi-
potassium loading can exceed renal excretion rates. Dietary excesses gated when there is a history of renal disease, massive trauma, insulin
of potassium are uncommon but accidental ingestion of potassium deficiency, Addison disease, use of potassium salt substitutes, or meta-
salt substitutes can cause toxicity. Use of stored whole blood and bolic acidosis. The acuity of the onset of symptoms may be related to
intravenous boluses of potassium penicillin G or replacement potas- the underlying cause.
sium can precipitate hyperkalemia, particularly with impaired renal Management of hyperkalemia is related to treating the contributing
function. Potassium moves from the ICF to the ECF with cell trauma causes and correcting the potassium excess. Calcium gluconate can be
or a change in cell membrane permeability, acidosis, insulin defi- administered to restore normal neuromuscular irritability when serum
ciency, or cell hypoxia. Burns, massive crushing injuries, and exten- potassium levels are dangerously high. Administration of glucose
sive surgeries can cause loss of potassium to the ECF as a result of (which readily stimulates insulin secretion) or administration of both
cell trauma. If renal function is sustained, potassium is excreted. As glucose and insulin for diabetic individuals facilitates cellular entry of
cell repair begins, hypokalemia develops without an adequate replace- potassium. Sodium bicarbonate corrects metabolic acidosis and low-
ment of potassium. ers serum potassium concentration. Oral or rectal administration of
In acidosis, ECF hydrogen ions shift into the cells in exchange cation exchange resins, which exchange sodium for potassium in the
for ICF potassium and sodium; hyperkalemia and acidosis therefore intestine, can be effective. Dialysis effectively removes potassium when
often occur simultaneously. Because insulin promotes cellular entry renal failure has occurred.
of potassium, insulin deficits, which occur with such conditions as
diabetic ketoacidosis, are accompanied by hyperkalemia. Hypoxia
can lead to hyperkalemia by diminishing the efficiency of cell mem- 4 QUICK CHECK 4-4
brane active transport, resulting in the potassium escaping to the ECF. 1. What role does potassium play in the body? What metabolic dysfunctions
Digitalis overdose may cause hyperkalemia by inhibiting the Na+, K+ occur in potassium deficiency? In potassium excess?
ATPase pump, which maintains increased intracellular potassium and 2. Explain how a person can have normal total body potassium levels but still
extracellular sodium (see Chapter 1). exhibit hypokalemia.
Decreased renal excretion of potassium commonly is associated 3. What is the most prominent ECG change associated with hyperkalemia?
with hyperkalemia. Renal failure that results in oliguria (urine output With hypokalemia?
of 30 ml/hr or less) is accompanied by elevations of serum potassium
level. The severity of hyperkalemia is related to the amount of potas-
sium intake, the degree of acidosis, and the rate of renal cell damage. Other Electrolytes—Calcium, Magnesium,
Decreases in the secretion or renal effects of aldosterone also can cause and Phosphate
decreases in the urinary excretion of potassium. For example, Addison The specifics of balance for the other body electrolytes—calcium
disease (a disease of adrenal cortical insufficiency) results in decreased (Ca++), phosphate (P+), and magnesium (Mg++)—are summarized in
production and secretion of aldosterone (and other steroids) and thus Table 4-7. Parathyroid hormone and vitamin D are important for the
contributes to hyperkalemia. regulation of these minerals19 (see Chapter 17).

CLINICAL MANIFESTATIONS  Symptoms vary with the severity of

ACID-BASE BALANCE
hyperkalemia. During mild attacks, increased neuromuscular irritabil-
ity may be manifested as restlessness, intestinal cramping, and diar- Acid-base balance must be regulated within a narrow range for the
rhea. Severe hyperkalemia causes muscle weakness, loss of muscle body to function normally. Slight changes in amounts of hydrogen can
tone, and paralysis.18 Hyperkalemia causes decreased cardiac conduc- significantly alter biologic processes in cells and tissues.20 Hydrogen
tion and more rapid repolarization of heart muscle. In mild states of ion is needed to maintain membrane integrity and the speed of meta-
hyperkalemia, the more rapid repolarization is reflected in the ECG as bolic enzyme reactions. Most pathologic conditions disturb acid-base
narrow and taller T waves with a shortened QT interval. Severe hyper- balance, producing circumstances possibly more harmful than the dis-
kalemia depresses the ST segment, prolongs the PR interval, and wid- ease process itself.
ens the QRS complex because of decreased conduction velocity (see
Figure 4-8). Bradydysrhythmias and delayed conduction are common Hydrogen Ion and pH
in hyperkalemia; severe hyperkalemia can cause ventricular fibrillation The concentration of hydrogen ions in body fluids is very small—
or cardiac arrest. approximately 0.0000001 mg/L. This number may be expressed as
As with hypokalemia, changes in the ratio of intracellular to 10−7 mg/L, is indicated as pH 7.0. The symbol pH represents the acid-
extracellular potassium concentration contribute to the symp- ity or alkalinity of a solution. As the pH changes 1 unit (e.g., from pH
toms of hyperkalemia (see Table 4-6). The neuromuscular effects 7.0 to pH 6.0), the [H+] ([H+] = hydrogen ion concentration) changes
of hyperkalemia are related to the increase in rate of repolariza- tenfold. The greater the [H+], the more acidic the solution and the
tion and the presence of other contributing factors, such as aci- lower the pH. The lower the [H+], the more alkaline or basic the solu-
dosis and calcium balance. Long-term increases in ECF potassium tion and the higher the pH. In biologic fluids, a pH of less than 7.4 is
110 CHAPTER 4  Fluids and Electrolytes, Acids and Bases

TABLE 4-7 ALTERATIONS IN OTHER BODY ELECTROLYTES

PARAMETER CALCIUM PHOSPHATE MAGNESIUM
Normal values Serum: 8.8-10.5 mg/dl (total), 4.5-5.6 mg/dl (ion- Serum: 2.5-5.0 mg/dl, but may be as high as 6.0-7.0 Serum: 1.8-3.0 mEq/L; 40%-60%
ized); 99% in bone as hydroxyapatite; remainder mg/dl in infants and young children; mainly in bone stored in bone, 33% bound
in plasma and body cells with 50% bound to with some in ICF and ECF; exists as phospholipids, to plasma proteins; primary
plasma proteins; 40% free or ionized; ionized phosphate esters, and inorganic phosphate (ionized intracellular divalent cation
form most important physiologically form)
Function Needed for fundamental metabolic processes; Intracellular and extracellular anion buffer in Cofactor in intracellular enzy-
major cation for structure of bone and teeth; regulation of acid-base balance; provides energy matic reactions and causes
enzymatic cofactor for blood clotting; required for muscle contraction (as ATP) neuromuscular excitability;
for hormone secretion and function of cell recep- often interacts with calcium
tors; directly related to plasma membrane stabil- and potassium in reactions at
ity and permeability, as well as transmission of cellular level and has impor-
nerve impulses and contraction of muscles tant role in smooth muscle
contraction and relaxation
Excess Hypercalcemia (serum concentrations Hyperphosphatemia (serum concentrations Hypermagnesemia (serum
>10-12 mg/dl) >4.7 mg/dl) concentrations >3.0 mEq/L)
Causes Hyperparathyroidism; bone metastases with Acute or chronic renal failure with significant loss of Usually renal insufficiency or
calcium resorption from breast, prostate, renal, glomerular filtration; treatment of metastatic tumors failure; also excessive intake
and cervical cancer; sarcoidosis; excess vitamin with chemotherapy that releases large amounts of of magnesium-containing
D; many tumors that produce PTH phosphate into serum; long-term use of laxatives or antacids, adrenal insufficiency
enemas containing phosphates; hypoparathyroidism
Effects Many nonspecific; fatigue, weakness, lethargy, Symptoms primarily related to low serum calcium Skeletal smooth muscle contrac-
anorexia, nausea, constipation; impaired renal levels (caused by high phosphate levels) similar to tion; excess nerve function;
function, kidney stones; dysrhythmias, bradycar- results of hypocalcemia; when prolonged, calcifica- loss of deep tendon reflexes;
dia, cardiac arrest; bone pain, osteoporosis tion of soft tissues in lungs, kidneys, joints nausea and vomiting; muscle
weakness; hypotension; bra-
dycardia; respiratory distress
Deficit Hypocalcemia (serum calcium concentration Hypophosphatemia (serum phosphate concentration Hypomagnesemia (serum
<8.5 mg/dl) <2.0 mg/dl) magnesium concentration
<1.5 mEq/L)
Causes Related to inadequate intestinal absorption, Most commonly by intestinal malabsorption related Malnutrition, malabsorption
deposition of ionized calcium into bone or soft to vitamin D deficiency, use of magnesium- and syndromes, alcoholism,
tissue, blood administration, or decreases in PTH aluminum-containing antacids, long-term alcohol urinary losses (renal tubular
and vitamin D; nutritional deficiencies occur with abuse, and malabsorption syndromes; respiratory dysfunction, loop diuretics)
inadequate sources of dairy products or green alkalosis; increased renal excretion of phosphate
leafy vegetables associated with hyperparathyroidism
Effects Increased neuromuscular excitability; tingling, Conditions related to reduced capacity for oxygen Behavioral changes, irritability,
muscle spasm (particularly in hands, feet, and transport by red blood cells and disturbed energy increased reflexes, muscle
facial muscles), intestinal cramping, hyperactive metabolism; leukocyte and platelet dysfunction; de- cramps, ataxia, nystagmus,
bowel sounds; severe cases show convulsions ranged nerve and muscle function; in severe cases, tetany, convulsions, tachycar-
and tetany; prolonged QT interval, cardiac arrest irritability, confusion, numbness, coma, convulsions; dia, hypotension
possibly respiratory failure (because of muscle weak-
ness), cardiomyopathies, bone resorption (leading to
rickets or osteomalacia)

ATP, Adenosine triphosphate; PTH, parathyroid hormone.

defined as acidic and a pH greater than 7.4 is defined as alkaline or basic it readily dissociates into carbon dioxide (CO2) and water (H2O). The
(Table 4-8). carbon dioxide is then eliminated by pulmonary ventilation.
Body acids are formed as end products of protein, carbohydrate, Sulfuric, phosphoric, and other organic acids are nonvolatile strong
and fat metabolism. This must be balanced by the amount of basic sub- acids (i.e., they readily release their hydrogens). Nonvolatile acids are
stances in the body to maintain normal pH. The lungs, kidneys, and secreted into the urine by the renal tubules in amounts of about 60 to
bones are the major organs involved in regulating acid-base balance. 100 mEq of hydrogen per day or about 1 mEq per kilogram of body
The systems work together to regulate short- and long-term changes weight.
in acid-base status.
Body acids exist in two forms: volatile (can be eliminated as CO2 Buffer Systems
gas) and nonvolatile (can be eliminated by the kidney). The volatile Buffering occurs in response to changes in acid-base status. Buf-
acid is carbonic acid (H2CO3), a weak acid (i.e., it does not release its fers can absorb excessive hydrogen ion (H+) (acid) or hydroxyl ion
hydrogen easily). In the presence of the enzyme carbonic anhydrase, (OH−) (base) and prevent a significant change in pH. The buffer
 CHAPTER 4  Fluids and Electrolytes, Acids and Bases 111

systems are located in both the ICF and the ECF compartments, and
they function at different rates (Table 4-9). The most important Protein Buffering
plasma buffer systems are carbonic acid–bicarbonate and the pro- Both intracellular and extracellular proteins have negative charges
tein hemoglobin ­(Figure 4-9). Phosphate and protein are the most and can serve as buffers for hydrogen, but because most proteins are
important intracellular buffers. Ammonia and phosphate are impor- inside cells, they are primarily an intracellular buffer system. Hemoglo-
tant renal buffers. bin (Hb) is an excellent intracellular blood buffer because it can bind
with hydrogen ion (H+) (forming HHb) and carbon dioxide (forming
Carbonic Acid–Bicarbonate Buffering HHbCO2). Hemoglobin bound to hydrogen ion becomes a weak acid.
The carbonic acid–bicarbonate buffer pair operates in both the lung Hemoglobin not saturated with oxygen (venous blood) is a better buf-
and the kidney and is a major extracellular buffer. The lungs can fer than hemoglobin saturated with oxygen (arterial blood). The pH
decrease the amount of carbonic acid by blowing off carbon dioxide control mechanism is illustrated in Figure 4-9.
and leaving water. The kidneys can reabsorb bicarbonate or regener-
ate new bicarbonate from carbon dioxide and water. The relationship Renal Buffering
between bicarbonate and carbonic acid is usually expressed as a ratio. The distal tubule of the kidney regulates acid-base balance by secret-
Normal bicarbonate level is about 24 mEq/L, and normal carbonic ing hydrogen into the urine and reabsorbing bicarbonate. Dibasic
acid level is about 1.2 mEq/L (when the arterial CO2 partial pressure phosphate (HPO4= ) and ammonia (NH3) are two important renal
[Paco2] is 40 mm Hg), producing a 20:1 ratio and the normal pH of buffers. The renal buffering of hydrogen ions requires the use of car-
7.4. These two systems are very effective together because the lungs can bon dioxide (CO2) and water (H2O) to form carbonic acid (H2CO3).
adjust acid concentration rapidly and bicarbonate is easily reabsorbed The enzyme carbonic anhydrase catalyzes the reaction. The hydrogen
or regenerated by the kidneys. is then secreted from the tubular cell and buffered in the lumen by
Renal and respiratory adjustments to primary changes in pH are phosphate and ammonia (i.e., forms H2 PO3− and NH+4). The remain-
known as compensation. The respiratory system compensates for ing bicarbonate is reabsorbed. The end effect is the addition of new
changes in pH by increasing or decreasing the concentration of car- bicarbonate to the plasma, which contributes to the alkalinity of the
bon dioxide by changing ventilation. The renal system compensates plasma because the hydrogen ion is excreted from the body (see Figure
by producing more acidic or more alkaline urine. Correction occurs 28-13, p. 734).
when the values for both components of the buffer pair (carbonic acid
and bicarbonate) return to normal levels. Acid-Base Imbalances
Pathophysiologic changes in the concentration of hydrogen ion in the
blood lead to acid-base imbalances.20,21 In acidemia the pH of arterial
blood is less than 7.4. A systemic increase in hydrogen ion concentra-
TABLE 4-8 PH OF BODY FLUIDS tion or loss of base is termed acidosis. In alkalemia the pH of arterial
BODY FLUID pH FACTORS AFFECTING pH blood is greater than 7.4. A systemic decrease in hydrogen ion con-
Gastric juices 1.0-3.0 Hydrochloric acid production centration or excess of base is termed alkalosis. These changes may be
Urine 5.0-6.0 H+ ion excretion from waste products caused by metabolic or respiratory processes. Figure 4-10 summarizes
Arterial blood 7.35-7.45 pH is slightly higher because there is the relationship among pH, the partial pressure of carbon dioxide, and
less carbonic acid (H2CO3) the concentration of bicarbonate during different primary acid-base
Venous blood 7.37 pH is slightly lower because there is states.
more carbonic acid
Metabolic Acidosis
Cerebrospinal fluid 7.32 Decreased bicarbonate and higher
carbon dioxide content decrease pH In metabolic acidosis the concentrations of non–carbonic acids
Pancreatic fluid 7.8-8.0 Contains bicarbonate produced by increase or bicarbonate is lost from extracellular fluid or cannot be
exocrine cells regenerated by the kidney (Table 4-10). This can occur either quickly,
as in lactic acidosis caused by poor perfusion or hypoxemia, or slowly

TABLE 4-9 BUFFER SYSTEMS

BUFFER PAIRS BUFFER SYSTEM CHEMICAL REACTION RATE
HCO−3 /H2 CO3 Bicarbonate H + + HCO3− ≷ H2 O + CO2 Instantaneously
− +
Hb /HHb Hemoglobin HHb ⇌ H + Hb ¯ Instantaneously
HPO=4 / H2 PO−4 Phosphate H2 PO4− + H + + HPO4= Instantaneously
− + −
Pr /HPr Plasma proteins HPr ⇌ H + Pr Instantaneously

ORGANS PHYSIOLOGIC MECHANISM RATE

Lungs Regulates retention or elimination of CO2 and therefore H2CO3 concentration Minutes to hours
Ionic shifts Exchange of intracellular potassium and sodium for hydrogen 2-4 hours
Kidneys Bicarbonate reabsorption and regeneration, ammonia formation, phosphate buffering Hours to days
Bone Exchanges of calcium and phosphate and release of carbonate Hours to days

CO2, Carbon dioxide; Hb , hemoglobin; HCO−

− =
3 , bicarbonate; H2CO3, carbonic acid; HHb, hydrogenated hemoglobin; HPO4 , dibasic phosphate;
H2 PO−
4 , monobasic phosphate; HPr, hydrogenated protein; −, protein.
Pr 
112 CHAPTER 4  Fluids and Electrolytes, Acids and Bases

50 PaCO2 PaCO2 PaCO2

Circulation Erythrocyte
80 60 40 PaCO2
H2O ↑CO2 H2CO3 H HCO3 45 D 30
Carbonic H+ + Hb + CO HHbCO2
2
anhydrase Metabolic
40 A alkalosis
Respiratory

Plasma [HCO3] (mmole/liter)

↓pH Kidney 35 acidosis
Respiratory ↓pH
Lungs center in PaCO2
brain stem 30 20

25 x
20 B
↑Respiration rate PaCO2
and depth 15 C Respiratory 10
Metabolic alkalosis
10 acidosis

5
↑CO2 given off ↑Rate of H secretion
0
FIGURE 4-9  Integration of pH Control Mechanisms. Elevated 7 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9
carbon dioxide (CO2) levels result in increased formation of carbonic pH
acid (H2CO3) in red blood cells. The resulting increase in hydrogen FIGURE 4-10  Davenport Diagram: Classic Working Diagram for
ions (H+), coupled with elevated CO2 levels, results in HHbCO2 Studying Primary Uncompensated Acid-Base Imbalance. The
and an increase in respiratory rate and secretion of H+ by the kid- point ⊗ represents a normal pH value (7.4) and normal values for
neys, thus helping to regulate the pH of body fluids. (From Patton the partial pressure of arterial carbon dioxide (Paco2 = 40 mm Hg)
KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010, and the bicarbonate concentration (HCO3− = 24 mEq/L). Note that
Mosby.) as the Paco2 increases toward 60 mm Hg (A) the pH decreases
(respiratory acidosis), and that as it decreases toward 20 mm Hg (B)
over an extended time, as in renal failure or diabetic ketoacidosis (see the pH increases (respiratory alkalosis). Metabolic acidosis devel-
Chapter 18).22 ops as the concentration of HCO3− decreases (C), and metabolic
The buffering systems normally compensate for excess acid and alkalosis develops as the concentration of HCO3− increases (D).
maintain arterial pH within normal range. When acidosis is severe,
buffers become depleted and cannot compensate, and the ratio of the
concentrations of bicarbonate to carbonic acid decreases to less than
20:1 (Figure 4-11). The specific type of acidosis can be determined by
TABLE 4-10 CAUSES OF METABOLIC
examining the serum anion gap (see Table 4-10). ACIDOSIS
Metabolic acidosis is manifested by changes in the function of the BICARBONATE LOSS
neurologic, respiratory, gastrointestinal, and cardiovascular systems. OR HYPERCHLOREMIC
Early symptoms include headache and lethargy, which progress to INCREASED NON–CARBONIC ACIDOSIS (NORMAL
coma in severe acidosis. The respiratory system’s efforts to compensate ACIDS (ELEVATED ANION GAP*) ANION GAP)
for the increase in metabolic acids result in what are termed Kussmaul Increased H+ load Diarrhea
respirations (a form of hyperventilation), which are deep and rapid. Ketoacidosis (e.g., diabetes mellitus, Ureterosigmoidoscopy
This represents the body’s attempt to increase pH by expelling carbon ­starvation)
dioxide, which decreases carbonic acid concentration. Other symp- Lactic acidosis (e.g., shock, hypoxemia)
toms include anorexia, nausea, vomiting, diarrhea, and abdominal Ingestion (e.g., ammonium chloride, ethylene
discomfort. Death can result in the most severe and prolonged cases glycol, methanol, salicylates, paraldehyde)
preceded by dysrhythmias and hypotension. The underlying condition Decreased renal H+ excretion Renal HCO3− loss
must be diagnosed to establish effective treatment. Proximal renal tubule acidosis Decreased renal H+ secre-
Distal renal tubule acidosis tion
Metabolic Alkalosis
When excessive loss of metabolic acids occurs, bicarbonate concentra- *Anion gap refers to anions not usually measured in laboratory
tion increases, causing metabolic alkalosis.23 When acid loss is caused reports (e.g., sulfate, phosphate, and lactate). The anions usually mea-
by vomiting, renal compensation is not very effective because loss of sured are chloride (Cl−) and bicarbonate (HCO3− ). When the sum of the
concentrations of measured anions (e.g., chloride and bicarbonate) is
chloride (an anion) in hydrochloric (HCl) acid stimulates renal reten-
subtracted from the sum of the concentrations of measured cations
tion of bicarbonate (an anion), known as hypochloremic metabolic
(e.g., sodium and potassium), there is a “gap” of approximately 10 to
alkalosis. Hyperaldosteronism also can lead to alkalosis as a result of 12 mEq/L; this is the normal anion gap. An elevated anion gap provides
sodium bicarbonate retention and loss of hydrogen and potassium. clues to the cause of the acidosis (i.e., to the addition of endogenously
Diuretics may produce a mild alkalosis because they promote greater or exogenously generated acids). In a normal anion gap acidosis chlo-
excretion of sodium, potassium, and chloride than of bicarbonate ride is retained to replace lost bicarbonate.
(Figure 4-12). H+, Hydrogen ion.
 CHAPTER 4  Fluids and Electrolytes, Acids and Bases 113

1 1
Metabolic balance : Carbonic acid Metabolic balance
before onset of before onset of : Carbonic acid
acidosis : Bicarbonate ion alkalosis : Bicarbonate ion
( + • )
( +• )
( + • ) ( +• )
( ++ • ) ++ •
( )
( ++ • ) ++ •
( )
1 : 20 1 : 20

2 2
Metabolic acidosis Metabolic alkalosis

HCO 3 decreases HCO 3 increases

because of excess because of loss
presence of ketones, of chloride ions
chloride, or organic or excess ingestion
1 : 10 acid ions 1 : 40
of sodium
bicarbonate
3
3
Body’s compensation
Body’s compensation
+ +
+ +
+
+
+
+ +
+
Acidic Alkaline
0.75 : 10 urine 1.25 : 30
urine
Hypoventilation Kidneys conserve
Hyperventilation Kidneys conserve HCO 3 retains CO2 (↑H2CO3) H+ ions and
“blows off” CO2 (↓H2CO3) and eliminate H+ ions in eliminate HCO 3
acidic urine in alkaline urine
4
4 Therapy required
Therapy required to restore
to restore metabolic metabolic balance
balance
Lactate-
containing Chloride-
Lactate solution containing
solution

1 : 20 1 : 20
Lactate solution used HCO 3 ions
in therapy is converted replaced
to bicarbonate ions by Cl ions
in the liver
FIGURE 4-11  Metabolic Acidosis. (From Patton KT, Thibodeau FIGURE 4-12  Metabolic Alkalosis. (From Patton KT, Thibodeau
GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.) GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)

Some common signs and symptoms of metabolic alkalosis are Respiratory Acidosis
weakness, muscle cramps, hyperactive reflexes, tetany, confusion, con- Respiratory acidosis occurs when there is alveolar hypoventilation,
vulsions, and atrial tachycardia. Respirations may be shallow and slow resulting in an excess of carbon dioxide in the blood (hypercapnia).
ventilation as the lungs attempt to compensate by increasing carbon The arterial carbon dioxide tension (or pressure) (Paco2) is >45 mm
dioxide retention. The manifestations vary with the cause and severity Hg and the pH is less than normal. A decrease in alveolar ventilation in
of the alkalosis. The symptoms of hyperactive reflexes and tetany occur relation to the metabolic production of carbon dioxide produces respi-
because alkalosis increases binding of Ca++ to plasma proteins, thus ratory acidosis by an increase in the concentration of carbonic acid.24
decreasing ionized calcium concentration. The decreased ionized cal- Respiratory acidosis can be acute or chronic. Common causes include
cium concentration causes excitable cells to become hypopolarized, ini- depression of the respiratory center (e.g., from drugs or head injury),
tiating an action potential more easily and causing muscle contraction. paralysis of the respiratory muscles, disorders of the chest wall (e.g.,
Treatments are related to the underlying cause of the condition. With kyphoscoliosis or broken ribs), and disorders of the lung parenchyma
hypochloremic alkalosis or contraction alkalosis with volume depletion, (e.g., pneumonia, pulmonary edema, emphysema, asthma, bronchi-
a sodium chloride solution is required for correction because chloride tis). Renal compensation occurs by elimination of hydrogen ion and
must be replaced before bicarbonate can be excreted by the kidney. retention of bicarbonate (Figure 4-13).
114 CHAPTER 4  Fluids and Electrolytes, Acids and Bases

1
Metabolic balance : Carbonic acid
before onset of : Bicarbonate ion 1
acidosis Metabolic balance : Carbonic acid
( +• ) before onset of : Bicarbonate ion
alkalosis
( +• ) +•
( )
( ++ • )
( +• )
( ++ • )
1 : 20 ( ++ • )
( ++ • )
1 : 20
2
Respiratory acidosis 2
Respiratory alkalosis

2 : 20
0.5 : 20
Hypoventilation
retains CO2 (↑H2CO3) Hyperventilation
“blows off” CO2 (↓H2CO3)
3
Body’s compensation
3
Body’s compensation

+
+
Acidic Alkaline
0.5 15 urine
23 : 0 urine
Kidneys conserve
HCO Kidneys conserve H+ ions
3 ions and
and eliminate HCO
eliminate H+ ions 3
in alkaline urine
in acidic urine 4
4 Therapy required
Therapy required to
to restore metabolic Chloride-
restore metabolic balance containing
balance
solution
Lactate-
Lactate containing
solution 0. 5 10
HCO 3 ions are replaced
22 : 0 by Cl ions
FIGURE 4-13  Respiratory Acidosis. (From Patton KT, Thibodeau FIGURE 4-14  Respiratory Alkalosis. (From Patton KT, Thibodeau
GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.) GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)

The signs and symptoms seen often include headache, blurred hyperventilation. Improper use of mechanical ventilators also can
vision, breathlessness, restlessness, and apprehension followed by cause iatrogenic (treatment-related) respiratory alkalosis, and second-
lethargy, disorientation, muscle twitching, tremors, convulsions, ary alkalosis may develop as a result of hyperventilation stimulated by
and coma. Respiratory rate is rapid at first and gradually becomes metabolic or respiratory acidosis. The kidneys compensate by decreas-
depressed as the respiratory center adapts to increasing levels of car- ing hydrogen excretion and bicarbonate reabsorption (Figure 4-14).
bon dioxide. The skin may be warm and flushed because the elevated The central and peripheral nervous systems are stimulated by
carbon dioxide concentration causes vasodilation. The restoration of respiratory alkalosis, causing dizziness, confusion, tingling of extremi-
adequate alveolar ventilation removes the excess CO2 (↓H2CO3). ties (paresthesias), convulsions, and coma. Cerebral vasoconstriction
reduces cerebral blood flow. Carpopedal spasm (spasm of muscles in
Respiratory Alkalosis the fingers and toes), tetany, and other symptoms of hypocalcemia
Respiratory alkalosis occurs when there is alveolar hyperventila- (see Table 4-7, p. 110) are similar to those of metabolic alkalosis. The
tion (deep, rapid respirations). Excessive reduction in plasma carbon underlying disturbance must be treated, particularly hypoxemia.
dioxide levels (hypocapnia) decrease carbonic acid concentration.25,26
The Paco2 is <35 mm Hg and the pH is greater than normal. Respi-
ratory alkalosis can be chronic or acute. Hypoxemia (caused by
4 QUICK CHECK 4-5
1. What two chemicals are altered in metabolic acid-base disturbances?
pulmonary disease, congestive heart failure, or high altitudes), hyper- 2. How do alterations in carbon dioxide concentration influence acid-base
metabolic states (e.g., fever, anemia, thyrotoxicosis), early salicylate status?
intoxication, hysteria, cirrhosis, and gram-negative sepsis stimulate
 CHAPTER 4  Fluids and Electrolytes, Acids and Bases 115

DID YOU UNDERSTAND?

Distribution of Body Fluids 10. Water excess is rare but can be caused by compulsive water ingestion,
1. Body fluids are distributed among functional compartments and are classi- decreased urine formation, or the syndrome of inappropriate secretion of
fied as intracellular fluid (ICF) and extracellular fluid (ECF). ADH (SIADH).
2. The sum of all fluids is the total body water (TBW), which varies with age 11. Hypochloremia usually is the result of hyponatremia or elevated bicarbon-
and amount of body fat. ate concentrations.
3. Water moves between the ICF and ECF compartments principally by osmosis.
4. Water moves between the plasma and interstitial fluid by osmosis (pulling Alterations in Potassium and Other Electrolytes
of water) and hydrostatic pressure (pushing of water), which occur across 1. Potassium is the predominant ICF ion; it regulates ICF osmolality, maintains
the capillary membrane. the resting membrane potential, and is required for deposition of glycogen
5. Movement across the capillary wall is called net filtration and is described in liver and skeletal muscle cells.
according to Starling law (the balance between hydrostatic and osmotic 2. Potassium balance is regulated by the kidney, by aldosterone and insulin
forces). secretion, and by changes in pH.
3. Potassium adaptation allows the body to accommodate slowly to increased
Alterations in Water Movement levels of potassium intake.
1. Edema is a problem of fluid distribution that results in accumulation of fluid 4. Hypokalemia (serum potassium concentration less than 3.5 mEq/L) indi-
within the interstitial spaces. cates loss of total body potassium, although ECF hypokalemia can develop
2. The pathophysiologic process that leads to edema is related to an increase without losses of total body potassium, and plasma potassium levels may
in forces favoring fluid filtration from the capillaries or lymphatic channels be normal or elevated when total body potassium is depleted.
into the tissues. 5. Hypokalemia may be caused by reduced potassium intake, a shift of
3. Edema is caused by arterial dilation, venous or lymphatic obstruction, potassium from the ECF to the ICF, increased aldosterone secretion, and
increased vascular volume, or increased capillary permeability. increased renal excretion.
4. Edema may be localized or generalized and usually is associated with 6. Hyperkalemia (potassium levels that are more than 5.5 mEq/L) may be
weight gain, swelling and puffiness, tighter-fitting clothes and shoes, and caused by increased potassium intake, a shift of potassium from the ICF to
limited movement of the affected area. the ECF, or decreased renal excretion.
7. Calcium is an ion necessary for bone and teeth formation, blood coagula-
Sodium, Chloride, and Water Balance tion, hormone secretion and cell receptor function, and membrane stability.
1. There is an intimate relationship between the balance of sodium and water 8. Phosphate acts as a buffer in acid-base regulation and provides energy for
levels; chloride levels are generally proportional to changes in sodium muscle contraction.
levels. 9. Calcium and phosphate concentrations are rigidly controlled by parathyroid
2. Water balance is regulated by the sensation of thirst and by antidiuretic hormone (PTH), vitamin D, and calcitonin.
hormone (ADH), which is secreted in response to an increase in plasma 10. Hypocalcemia (serum calcium concentration less than 8.5 mg/dl) is related
osmolality or a decrease in circulating blood volume. to inadequate intestinal absorption, deposition of calcium into bone or soft
3. Sodium balance is regulated by aldosterone, which increases reabsorption tissue, blood administration, or decreased PTH and vitamin D levels.
of sodium from the urine into the blood by the distal tubule of the kidney. 11. Hypercalcemia (serum calcium concentration more than 12 mg/dl) can
4. Renin and angiotensin are enzymes that promote secretion of aldosterone be caused by a number of diseases, including hyperparathyroidism, bone
and thus regulate sodium and water balance. metastases, sarcoidosis, and excess vitamin D.
5. Atrial natriuretic hormone is involved in decreasing tubular reabsorption 12. Hypophosphatemia is usually caused by intestinal malabsorption and
and promoting urinary excretion of sodium. increased renal excretion of phosphate.
13. Hyperphosphatemia develops with acute or chronic renal failure when
Alterations in Sodium, Water, and Chloride Balance
there is significant loss of glomerular filtration.
1. Alterations in water balance may be classified as isotonic, hypertonic, or
14. Magnesium is a major intracellular cation and is regulated principally by PTH.
hypotonic.
15. Magnesium functions in enzymatic reactions and often interacts with cal-
2. Isotonic alterations occur when changes in TBW are accompanied by pro-
cium at the cellular level.
portional changes in electrolytes.
16. Hypomagnesemia (serum magnesium concentrations less than 1.5 mEq/L)
3. Hypertonic alterations develop when the osmolality of the ECF is elevated
may be caused by malabsorption syndromes.
above normal, usually because of an increased concentration of ECF sodium
17. Hypermagnesemia (serum magnesium concentrations more than 2.5 mEq/L)
or a deficit of ECF water.
is rare and usually is caused by renal failure.
4. Hypernatremia (sodium levels more than 145 mEq/L) may be caused by an
acute increase in sodium level or a loss of water. Acid-Base Balance
5. Water deficit, or hypertonic dehydration, is rare but can be caused by lack 1. Hydrogen ions, which maintain membrane integrity and the speed of enzy-
of access to water, pure water losses, hyperventilation, arid climates, and matic reactions, must be concentrated within a narrow range if the body is
increased renal elimination of water. to function normally.
6. Hyperchloremia is caused by an excess of sodium or a deficit of bicarbonate. 2. Hydrogen ion concentration, [H+], is expressed as pH, which represents the
7. Hypotonic alterations occur when the osmolality of the ECF is less than negative logarithm (i.e., 10−7) of hydrogen ions in solution (i.e., 0.0000001
normal. mg/L).
8. Hyponatremia (serum sodium concentration less than 135 mEq/L) usually 3. Different body fluids have different pH values.
causes movement of water into cells. 4. The renal and respiratory systems, together with the body’s buffer systems,
9. Hyponatremia may be caused by sodium loss, inadequate sodium intake, or are the principal regulators of acid-base balance.
dilution of the body’s sodium level with excess water.
116 CHAPTER 4  Fluids and Electrolytes, Acids and Bases

DID YOU UNDERSTAND?—cont’d

5. Buffers are substances that can absorb excessive acid or base without a 11. Metabolic acidosis is caused by an increase in the levels of non–carbonic
significant change in pH. acids or by loss of bicarbonate from the extracellular fluid.
6. Buffers exist as acid-base pairs; the principal plasma buffers are carbonic 12. Metabolic alkalosis occurs with an increase in bicarbonate concentration,
acid–bicarbonate, protein (hemoglobin), and phosphate. which is usually caused by loss of metabolic acids from conditions such as
7. The lungs and kidneys act to compensate for changes in pH by increasing or vomiting or gastrointestinal suctioning or by excessive bicarbonate intake,
decreasing ventilation and by producing more acidic or more alkaline urine. hyperaldosteronism, and diuretic therapy, which increase plasma bicarbon-
8. Correction is a process different from compensation; correction occurs ate concentration.
when the values for both components of the buffer pair return to normal. 13. Respiratory acidosis occurs with decreased alveolar ventilation, which in
9. Acid-base imbalances are caused by changes in the concentration of hydro- turn causes hypercapnia (an increase in carbon dioxide concentration) and
gen ion in the blood; an increase causes acidosis, and a decrease causes increased carbonic acid concentration.
alkalosis. 14. Respiratory alkalosis occurs with alveolar hyperventilation and excessive
10. An abnormal increase or decrease in bicarbonate concentration causes reduction of carbon dioxide level, or hypocapnia with decreases in carbonic
metabolic alkalosis or metabolic acidosis; changes in the rate of alveolar acid concentration.
ventilation and removal of carbon dioxide produce respiratory acidosis or
respiratory alkalosis.

 KEY TERMS
•  cidemia  111
A •  dema  100
E •  etabolic alkalosis  112
M
• Acidosis  111 • Extracellular fluid (ECF)  98 • Natriuretic peptide  102
• Aldosterone  102 • Hypercapnia  113 • Net filtration  99
• Alkalemia  111 • Hyperchloremia  105 • Nonvolatile  110
• Alkalosis  111 • Hyperkalemia  108 • Osmoreceptor  103
• Angiotensin I  102 • Hypernatremia  105 • Potassium (K+)  106
• Anion gap  112 • Hypocapnia  114 • Potassium adaptation  107
• Aquaporin  100 • Hypochloremia  106 • Pure water deficit  105
• Baroreceptor  103 • Hypochloremic metabolic alkalosis  112 • Renin  102
• Buffer  110 • Hypokalemia  107 • Renin-angiotensin-aldosterone system  102
• Buffering  110 • Hyponatremia  106 • Respiratory acidosis  113
• Capillary hydrostatic pressure (blood • Interstitial fluid  99 • Respiratory alkalosis  114
pressure)  99 • Interstitial hydrostatic pressure  99 • Sodium (Na+)  102
• Capillary (plasma) oncotic pressure  99 • Interstitial oncotic pressure  99 • Starling forces  99
• Carbonic acid–bicarbonate buffer  111 • Intracellular fluid (ICF)  98 • Total body water (TBW)  98
• Chloride (Cl−)  102 • Intravascular fluid  98 • Volatile  110
• Compensation  111 • Isotonic fluid excess  104 • Volume-sensitive receptor  103
• Correction  111 • Isotonic fluid loss  104 • Water intoxication  106
• Dehydration  105 • Lymphedema  100
• Dilutional hyponatremia  106 • Metabolic acidosis  111

REFERENCES 9. Thomas DR, et al: Dehydration council: understanding clinical dehydra-

tion and its treatment, J Am Med Dir Assoc 9(5):292–301, 2008.
1. Ishibashi K, et al: The evolutionary aspects of aquaporin family, Am J 10. Overgaard-Steensen C: Initial approach to the hyponatremic patient, Acta
Physiol Regal Integr Comp Physiol 300(3):R566–R576, 2011. Anesthesiol Scand 55(2):139–148, 2011.
2. O’Brien JC, Chennubhotla SA, Chennubhotla RV: Treatment of edema, 11. Vaidya C, Ho W, Freda B: Management of hyponatremia: providing treat-
Am Fam Physician 17(11):2111–2117, 2005. ment and avoiding harm, Cleve Clin J Med 77(10):715–726, 2010.
3. Linnitt N: Lymphoedema: recognition, assessment and management, Br J 12. Multz AS: Vasopressin dysregulation and hyponatremia in hospitalized
Community Nurs 10(3):S20–S26, 2005. patients, J Intensive Care Med 22(4):216–223, 2007.
4. Olszewski WL, Ambujam PJ, Zaleska M, et al: Where do lymph and tissue 13. Vaidya C, Ho EW, Freda BJ: Management of hyponatremia: providing
fluid accumulate in lymphedema of the lower limbs caused by obliteration treatment and avoiding harm, Cleve Clin J Med 77(10):715–726, 2010.
of lymphatic collectors? Lymphology 42(3):105–111, 2009. 14. Youn JH, McDonough AA: Recent advances in understanding integrative
5. Lee CY, Burnett JC Jr: Natriuretic peptides and therapeutic applications, control of potassium homeostasis, Annu Rev Physiol 71:381–401, 2009.
Heart Fail Rev 12(2):131–142, 2007. 15. Wang WH, Giebisch G: Regulation of potassium (K) handling in the renal
6. Boone M, Deen PM: Physiology and pathophysiology of the vasopressin- collecting duct, Pflugers Arch 458(1):157–168, 2009.
regulated renal water reabsorption, Pflugers Arch 456(6):1005–1024, 2008. 16. Palmer BF: A physiologic-based approach to the evaluation of a patient
7. Agrawal V, et al: Hyponatremia and hypernatremia: disorders of water with hypokalemia, Am J Kidney Dis 56(6):1184–1190, 2010.
balance, J Assoc Physicians India 56:956–964, 2008. 17. Lim S: Approach to hyperkalemia, Acta Med Indones 39(2):99–103, 2007.
8. Bagshaw SM, Townsend DR, McDermid RC: Disorders of sodium and 18. Weisberg LS: Management of severe hyperkalemia, Crit Care Med
water balance in hospitalized patients, Can J Anaesth 56(2):151–167, 2009. 36(12):L3246–L3251, 2008.
 CHAPTER 4  Fluids and Electrolytes, Acids and Bases 117

19. Moe SM: Disorders involving calcium, phosphorus and magnesium, Prim 23. Khanna A, Kurtzman NA: Metabolic alkalosis, J Nephrol 19(Suppl
Care 35(2):215–237, 2008. 9):S86–S96, 2006.
20. Palmer BF: Approach to fluid and electrolyte disorders and acid-base 24. Epstein SK, Singh N: Respiratory acidosis, Respir Care 46(4):366–383,
problems, Prim Care 35(2):195–213, 2008. 2001.
21. Edwards SL: Pathophysiology of acid base balance: the theory practice 25. Foster GT, Vaziri ND, Sassoon CS: Respiratory alkalosis, Respir Care
relationship, Intensive Crit Care Nurs 24(1):28–38, 2008. 46(4):384–391, 2001.
22. Kraut JA, Madias NE: Metabolic acidosis: pathophysiology, diagnosis and 26. Madias NE: Renal acidification responses to respiratory acid base
management, Nat Rev Nephrol 6(5):274–285, 2010. ­disorders, J Nephrol 16(Suppl 16):S85–S91, 2010.
CHAPTER

5
Innate Immunity: Inflammation
and Wound Healing
Neal S. Rote

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Human Defense Mechanisms, 118 Wound Healing, 134
Innate Immunity, 119 Phase I: Inflammation, 135
First Line of Defense: Physical and Biochemical Barriers and Phase II: Proliferation and New Tissue Formation, 135
Normal Flora, 119 Phase III: Remodeling and Maturation, 136
Second Line of Defense: Inflammation, 121 Dysfunctional Wound Healing, 136
Plasma Protein Systems and Inflammation, 122 PEDIATRIC CONSIDERATIONS: Age-Related Factors Affecting
Cellular Components of Inflammation, 125 Innate Immunity in the Newborn Child, 138
Acute and Chronic Inflammation, 132 GERIATRIC CONSIDERATIONS: Age-Related Factors Affecting
Local Manifestations of Acute Inflammation, 132 Innate Immunity in the Elderly, 138
Systemic Manifestations of Acute Inflammation, 132
Chronic Inflammation, 133

The human body is continually exposed to a large variety of condi- damage by substances in the environment and thwart infection by
tions that result in damage, such as sunlight, pollutants, agents that can pathogenic microorganisms.1 Surface barriers may also harbor a group
cause physical trauma, and infectious agents (viruses, bacteria, fungi, of microorganisms known as the “normal flora” that can protect us
parasites). Damage can also arise from within, such as cancers. The from pathogens. If the surface barriers are breached, the second line of
damage may be at the level of a single cell, which can be easily repaired, defense, the inflammatory response,2 is activated to protect the body
or may be at the level of multiple cells or tissues or organs, which can from further injury, prevent infection of the injured tissue, and pro-
result in disease and potentially the death of the individual. To protect mote healing. The inflammatory response is a rapid activation of bio-
us from these conditions, the body has developed a highly sophisti- chemical and cellular mechanisms that are relatively nonspecific, with
cated, multilevel system of interactive defense mechanisms. similar responses being initiated against a wide variety of causes of tis-
sue damage. The third line of defense, adaptive immunity (also known
as acquired or specific immunity), is induced in a relatively slower and
HUMAN DEFENSE MECHANISMS more specific process and targets particular invading microorganisms
The human body has developed several means of protecting itself for the purpose of eradicating them. Adaptive immunity also involves
from injury and infection. Innate immunity, also known as natural “memory,” which results in a more rapid response during future expo-
or native immunity, includes natural barriers (physical, mechanical, sure to the same microorganism (Table 5-1). The focus of this chapter
and biochemical) and inflammation. Innate barriers form the first line is innate immunity: barriers, the inflammatory response, and wound
of defense at the body’s surfaces and are in place at birth to prevent healing. Adaptive immunity is the focus of Chapter 6.

118
 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing 119

TABLE 5-1 OVERVIEW OF HUMAN DEFENSES

CHARACTERISTICS BARRIERS INNATE IMMUNITY ADAPTIVE (ACQUIRED) IMMUNITY
Level of defense First line of defense against infection Second line of defense; occurs as re- Third line of defense; initiated when innate
and tissue injury sponse to tissue injury or infection immune system signals cells of adaptive
immunity
Timing of defense Constant Immediate response Delay between primary exposure to antigen
and maximal response; immediate against
secondary exposure to antigen
Specificity Broadly specific Broadly specific Response is very specific toward “antigen”
Cells Epithelial cells Mast cells, granulocytes (neutrophils, T lymphocytes, B lymphocytes, macrophages,
eosinophils, basophils), monocytes/ dendritic cells
macrophages, natural killer (NK) cells,
platelets, endothelial cells
Memory No memory involved No memory involved Specific immunologic memory by T and B
lymphocytes
Active molecules Defensins, cathelicidins, collectins, Complement, clotting factors, kinins, Antibodies, complement, cytokines
lactoferrin, bacterial toxins cytokines
Protection Protection includes anatomic barriers Protection includes vascular responses, Protection includes activated T and B lympho-
(i.e., skin and mucous membranes), cellular components (e.g., mast cells, cytes, cytokines, and antibodies
cells and secretory molecules (e.g., neutrophils, macrophages), secretory
lysozymes, low pH of stomach and molecules or cytokines, and activation
urine), and ciliary activity of plasma protein systems

INNATE IMMUNITY studied are cathelicidins and defensins, which are differentiated based
on their three-dimensional chemical structures.
First Line of Defense: Physical and Biochemical Several cathelicidins have been discovered in other species, but only
Barriers and Normal Flora one is currently known to function in humans. Bacteria have choles-
Physical Barriers terol-free cell membranes into which cathelicidin can insert and dis-
The physical barriers that cover the external parts of the human body rupt the membrane, killing the bacteria. Cathelicidin is produced by
offer considerable protection from damage and infection. These barri- epithelial cells of the skin, gut, urinary tract, and respiratory tract, and
ers are composed of tightly associated epithelial cells of the skin and of is stored in neutrophils, mast cells, and monocytes and can be released
the linings of the gastrointestinal, genitourinary, and respiratory tracts during inflammation.
(Figure 5-1). When pathogens attempt to penetrate this physical bar- In contrast, many different human defensins have been identified
rier, they may be removed by mechanical means—sloughed off with thus far. Defensin molecules can be further subdivided into α (at least
dead skin cells as they are routinely replaced, expelled by coughing or 6 identified in humans) and β types (at least 6 identified, but perhaps
sneezing, vomited from the stomach, or flushed from the urinary tract up to 40 different molecules). The α-defensins often require activa-
by urine. Epithelial cells of the upper respiratory tract also produce tion by proteolytic enzymes, whereas the β-defensins are synthesized
mucus and have hair-like cilia that trap and move pathogens upward in active forms. Given the similarity in their chemical charges, defen-
to be expelled by coughing or sneezing. Additionally, the low tempera- sins may kill bacteria in the same way as cathelicidin. The α-defensins
ture, such as on the skin, and low pH, such as of the skin and stom- are particularly rich in the granules of neutrophils and may contribute
ach, generally inhibit microorganisms, most of which routinely require to the killing of bacteria by those cells. They are also found in Pan-
temperatures near 37° C (98.6° F) and pH near neutral for efficient eth cells lining the small intestine, where they protect against a variety
growth. of disease-causing microorganisms. The β-defensins are found in a
variety of epithelial cells lining the respiratory, urinary, and intestinal
Epithelial Cell–Derived Chemicals tracts, as well as in the skin.4 In addition to antibacterial properties,
Epithelial cells secrete several substances that protect against infection, β-defensins may also help protect epithelial surfaces from infection
including mucus, perspiration (or sweat), saliva, tears, and earwax. with adenovirus (one of the causes of the common cold) and human
These can trap potential invaders and contain substances that will kill immunodeficiency virus (HIV). Both classes of antimicrobial peptides
microorganisms. Perspiration, tears, and saliva contain an enzyme also can activate cells of the next levels of defense: innate and acquired
(lysozyme) that attacks the cell walls of gram-positive bacteria. Seba- immunity.
ceous glands in the skin also secrete fatty acids and lactic acid that kill The lung also produces and secretes a family of glycoproteins, col-
bacteria and fungi. These glandular secretions create an acidic (pH 3 to lectins, which includes surfactant proteins A through D and mannose-
5) and inhospitable environment for most bacteria. binding lectin. Collectins react with carbohydrates on the surface of a
Epithelial cell secretions also contain small-molecular-weight anti- wide array of pathogenic microorganisms and help cells of the innate
microbial peptides that kill or inhibit the growth of certain disease- immune system (macrophages) to recognize and kill the microor-
causing bacteria, fungi, and viruses.3 These are generally positively ganism. Mannose-binding lectin (MBL) is a powerful activator of a
charged polypeptides of approximately 15 to 95 amino acids. More plasma protein system (complement) resulting in damage to bacteria
than a thousand antimicrobial peptides have been found, but the best or increased recognition by macrophages.
120 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing

Mucosa of
High content of nasal turbinates
lysozyme in Pharyngeal tonsil
eye secretions (adenoids)
Nasal mucosa Palatine tonsil
and secretions
Pharynx
Oral mucosa
Intact skin
Tracheal mucosa
and cilia

Alveoli of lungs
Esophageal and
gastric peristalsis

Bile from liver

Acidic gastric
Gallbladder secretions
(bile)

Intestinal flora
and peristalsis

Phagocytes in
bladder wall;
Vaginal flora pH of urine
and lactic
acid

FIGURE 5-1  The Closed Barrier. The digestive, respiratory, and genitourinary tracts and skin form
closed barriers between the internal organs and the environment. (From Grimes DE: Infectious
­diseases, St Louis, 1991, Mosby.)

Normal Flora and other toxic materials) and toxic proteins (bacteriocins) that inhibit
A spectrum of nonpathogenic microorganisms, collectively called the colonization by pathogenic microorganisms. Prolonged treatment
normal flora, resides on the body’s surfaces. Each surface is colonized by with broad-spectrum antibiotics can alter the normal intestinal flora,
a combination of mostly bacteria and occasionally fungi that is unique to decreasing its protective activity, and lead to an overgrowth of patho-
the particular location, including the skin and the mucous membranes genic microorganisms, such as the yeast Candida albicans or the bacteria
of the eyes, upper and lower gastrointestinal tracts, urethra, and vagina. Clostridium difficile (overgrowth can cause pseudomembranous colitis,
Although frequently referred to as commensal (to the benefit of one an infection of the colon). Additionally, the normal flora of the gut help
organism without affecting the other) organisms, the relationship with train the adaptive immune system by inducing growth of gut-associated
humans may be more mutualistic (to the benefit of both organisms).5 lymphoid tissue (where cells of the adaptive immune system reside) and
Using the colon for an example, at birth the lower gut is relatively the development of both local and systemic adaptive immune systems.7
sterile, but colonization with bacteria begins quickly, with the num- The bacterium Lactobacillus is a major constituent of the normal
ber, diversity, and concentration increasing progressively during the vaginal flora in healthy women. This microorganism produces chemi-
first year of life. The environment of the intestine provides the needed cals (hydrogen peroxide, lactic acid, and other molecules) that help
temperature and nutrients for the growth of many bacterial species. prevent infections of the vagina and urinary tract by other bacteria and
To the benefit of humans, many of these microorganisms help digest yeast. Diminished colonization with lactobacilli (e.g., as a result of pro-
fatty acids, large polysaccharides, and other dietary substances; pro- longed antibiotic treatment) increases the risk for urologic or vaginal
duce biotin and vitamin K; and assist in the absorption of various ions, infections, such as vaginosis.
such as calcium, iron, and magnesium. It should be noted that some members of the normal bacterial flora
These bacteria contribute to our innate protection against patho- are opportunistic; opportunistic microorganisms can cause disease
genic microorganisms in the colon.6 They compete with pathogens if the individual’s defenses are compromised. These organisms are
for nutrients and block attachment to the epithelium. Members of normally controlled by the innate and acquired immune systems and
the normal flora also produce chemicals (ammonia, phenols, indoles, contribute to our defenses. For example, Pseudomonas aeruginosa is a
 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing 121

member of the normal flora of the skin and produces a toxin that pro- NORMAL
tects against infections with staphylococcal and other bacteria. How- Extracellular matrix Occasional resident
ever, severe burns compromise the integrity of the skin and may lead lymphocyte or macrophage
to life-threatening systemic pseudomonal infections.

4 QUICK CHECK 5-1

1. How do physical and mechanical barriers contribute to defense
Arteriole Venule
mechanisms?
2. What are antimicrobial peptides?
3. What two types of defensins contribute to the biochemical barrier?
4. What is the normal bacterial flora? What is its role in defense?
5. What are opportunistic microorganisms?

INFLAMED Vasodilation and increased

1
Second Line of Defense: Inflammation blood flow (erythema and warmth)
The innate immune system is programmed to respond to damage
to the body, whether the damaged tissue is septic or sterile.8 That Arteriole dilation Expansion of capillary bed Venule dilation
response rapidly initiates an interactive system of humoral (soluble in
the blood) and cellular systems, called inflammation.
Inflammation is the first response to injury. The inflammatory
response (1) occurs in tissues with a blood supply (vascularized); (2) is
activated rapidly (within seconds) after damage occurs; (3) depends on
the activity of both cellular and chemical components; and (4) is nonspe-
cific, meaning that it takes place in approximately the same way regard-
less of the type of stimulus or whether exposure to the same stimulus
has occurred in the past.
Virtually any injury to vascularized tissues will activate inflam-
mation. The classic symptoms of acute inflammation include redness
(erythema), heat, swelling, pain, and loss of function. Microscopic
inflammatory changes occur within seconds in the microcirculation
(arterioles, capillaries, and venules) near the site of an injury and
include the following processes (Figure 5-2):
1. Vasodilation (increased size of the blood vessels), which causes Leukocyte (neutrophil) 2 Leakage of plasma
3
recruitment and migration proteins edema
slower blood velocity and increases blood flow to the injured site
2. Increased vascular permeability (the blood vessels become porous FIGURE 5-2  The Major Local Changes in the Process of Inflam-
from contraction of endothelial cells) and leakage of fluid out mation. Compared to the normal circulation, inflammation is char-
of the vessel (exudation), causing swelling (edema) at the site of acterized by (1) dilation of the blood vessels and increased blood
injury; as plasma moves outward, blood in the microcirculation flow, leading to erythema and warmth; (2)  increased vascular
becomes more viscous and flows more slowly, and the increased permeability with leakage of plasma from the vessels, leading to
blood flow and increasing concentration of red cells at the site edema; and (3) movement of leukocytes from the vessels into the
of inflammation cause locally increased redness (erythema) and site of injury. (From Kumar V et al: Robbins and Cotran pathological
warmth basis of disease, ed 8, Philadelphia, 2009, Saunders.)
3. White blood cell adherence to the inner walls of vessels and their
migration through enlarged junctions between the endothelial cells
lining the vessels into the surrounding tissue (e.g., complement system, clotting system), and the influx of cells
Each of the characteristic changes associated with inflammation is (e.g., neutrophils, macrophages) that destroy cellular debris and
the direct result of the activation and interactions of a host of chemicals infectious agents
and cellular components found in the blood and tissues. The vascular 2. Limits and control the inflammatory process through the influx
changes deliver leukocytes (particularly neutrophils), plasma proteins, of plasma protein systems (e.g., clotting system), plasma enzymes,
and other biochemical mediators to the site of injury, where they act and cells (e.g., eosinophils) that prevent the inflammatory response
in concert. Some of these chemical mediators activate pain fibers. The from spreading to areas of healthy tissue
tissue injury, pain, and swelling contribute to loss of function. Figure 3. Interacts with components of the adaptive immune system to elicit
5-3 summarizes the process of inflammation. a more specific response to contaminating pathogen(s) through the
There are several benefits of inflammation, including the following: influx of macrophages and lymphocytes
1. Prevents infection and further damage by contaminating micro- 4. Prepares the area of injury for healing through removal of bacterial
organisms through the influx of plasma to dilute toxins produced products, dead cells, and other products of inflammation (e.g., by
by bacteria and released from dying cells, the influx and activation way of channels through the epithelium or drainage by lymphatic
of plasma protein systems that help contain and destroy bacteria vessels) and initiation of mechanisms of healing and repair
122 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing

Mast cell Vasodilation

degranulation (erythema, warmth)

(Figure 5-8)

Vascular
permeability
(edema)

Cellular
injury Complement
Clotting Cellular
Activation of
Kinin infiltration
plasma systems
(Figure 5-4) (pus)
Pathogenic
(Figure 5-10)
invasion

Thrombosis
(clots)

Release of Stimulation of
cellular nerve endings
products (pain)

FIGURE 5-3  Acute Inflammatory Response. Inflammation is usually initiated by cellular injury and
may be complicated by infection. Mast cell degranulation, the activation of three plasma systems,
and the release of subcellular components from the damaged cells occur as a consequence. These
systems are interdependent, so that induction of one (e.g., mast cell degranulation) can result in the
induction of the other two. The result is the development of the characteristic microscopic and clinical
hallmarks of inflammation. The figure numbers refer to additional figures in which more detailed infor-
mation may be found on that portion of the response.

Fluid and debris that accumulate at an inflamed site are drained sequential activation of other components of the system, leading to
by lymphatic vessels. This process also facilitates the development of a biologic function that helps protect the individual. This sequential
acquired immunity because microbial antigens in lymphatic fluid pass activation is referred to as a cascade. Thus, we occasionally refer to
through the lymph nodes, where they encounter lymphocytes. the complement cascade, the clotting cascade, or the kinin cascade. In
some cases, activation of a particular protein in the system may require

4 QUICK CHECK 5-2

that it be enzymatically cut into two pieces of different size. Usually the
larger fragment continues the cascade by activating the next compo-
. Why is innate immunity and inflammation described as “non-specific”?
1 nent, and the smaller fragment frequently has potent biologic activities
2. How are the five classic superficial symptoms of inflammation related to to promote inflammation.
the process of inflammation?
3. Describe the basic steps in acute inflammation. Complement System
4. What are the benefits of inflammation? The complement system consists of a large number of proteins (some-
times called complement factors) that together constitute about
10% of the total circulating serum protein. The complement system
Plasma Protein Systems and Inflammation is extremely important because activation produces factors that can
Three key plasma protein systems are essential to an effective inflam- destroy pathogens directly or can activate or increase the activity of
matory response (Figure 5-4). These are the complement system, the many other components of the inflammatory and adaptive immune
clotting system, and the kinin system. Although each system has a response.9 Factors produced during activation of the complement
unique role in inflammation, they have many similarities. Each sys- system are among the body’s most potent defenders against bacterial
tem consists of multiple proteins in the blood. They are normally in infection.
inactive forms; several are enzymes that circulate in inactive forms as The most important function of the complement cascade is acti-
proenzymes. Each system contains a few proteins that can be activated vation of C3 and C5, which results in a variety of molecules that are
during inflammation. Activation of these first components results in (1) opsonins, (2) chemotactic factors, or (3) anaphylatoxins.
 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing 123

Opsonins coat the surface of bacteria and increase their susceptibility C5a (anaphylatoxin, chemotactic factor).10 Activation of complement
to being phagocytized (eaten) and killed by inflammatory cells, such components C5b through C9 (membrane attack complex, or MAC)
as neutrophils and macrophages. Chemotactic factors diffuse from results in a complex that creates pores in the outer membranes of
a site of inflammation and attract phagocytic cells to that site. Ana- cells or bacteria. The pores disrupt the cell’s membrane and permit
phylatoxins induce rapid degranulation of mast cells (i.e., release of water to enter, causing the cell to burst and die or at least prevent its
histamine that induces vasodilation and increased capillary permeabil- reproduction.
ity), a major cellular component of inflammation. The most potent Three major pathways control the activation of complement (see
complement products are C3b (opsonin), C3a (anaphylatoxin), and Figure 5-4). The classical pathway is primarily activated by antibodies,

COMPLEMENT SYSTEM CLOTTING SYSTEM KININ SYSTEM

Classical Lectin Alternative Tissue-factor Contact activation Prekallikrein
pathway pathway pathway (extrinsic) pathway (intrinsic) pathway
Damaged vessel wall
Blood vessel
Kallikrein
injury
C3 Anaphylatoxin Hageman
Opsonin Factor XII Kininogen
Mass cell
release of
Phagocytosis C3b C3a histamine
Factor VIIa + TF XIIa Bradykinin

Factor Xa Histamine-
like effects
C5
Thrombin
Anaphylatoxin
and chemo- Increased
C5b C5a tactic factor permeability
Fibrinogen

Leukocyte
(neutrophil)
C5b, 6-9 FP
Fibrin migration
Membrane
attack Leukocyte-
complex (neutrophil)
migration Stimulates nerve
Chemotactic factor endings
Damage to Pain
Blood clot
bacterium

Increased
permeability

FIGURE 5-4  Plasma Protein Systems in Inflammation: Complement, Clotting, and Kinin Systems.
Each plasma protein system consists of a family of proteins that are activated in sequence to create potent
biologic effects. The complement system can be activated by three mechanisms, each of which results
in proteolytic activation of C3. The fragments of C3 activation, C3a and C3b, are major components of
inflammation. C3a is a potent anaphylatoxin, which induces degranulation of mast cells. C3b can bind to
the surface or cells, such as bacteria, and either serve as an opsonin for phagocytosis or proteolytically
activate the next component of the complement cascade, C5. The smaller fragment of C5 activation is C5a,
a powerful anaphylatoxin, and is also chemotactic for neutrophils, attracting them to the site of inflamma-
tion. The larger fragment, C5b, activates the components of the membrane attack complex (C5-C9), which
damage the bacterial membrane and kill the bacteria. The clotting system can be activated by the tissue
factor (extrinsic) pathway and the contact activation (intrinsic) pathway. All routes of clotting initiation lead
to activation of factor X and thrombin. Thrombin is an enzyme that proteolytically activates fibrinogen to
form fibrin and small fibrinopeptides (FPs). Fibrin polymerizes to form a clot, and the FPs are highly active as
chemotactic factors and causing increased vascular permeability. The XIIa produced by the clotting system
can also be activated by kallikrein of the kinin system (red arrow). Prekallikrein is enzymatically converted to
kininogen, which activates bradykinin. Bradykinin functions similar to histamine and increases vascular per-
meability. Bradykinin can also stimulate nerve endings to cause pain. TF, tissue factor; FPs, Fibrinopeptides.
124 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing

which are proteins of the acquired immune system. Antibodies must Kinin System
first bind to their targets, called antigens (molecules that stimulate the The third plasma protein system, the kinin system (see Figure 5-4),
production of antibodies). Antigens can be proteins or carbohydrates interacts closely with the coagulation system. Both the clotting and
from bacteria or other infectious agents. Antibodies activate the first kinin systems can be initiated through activation of Hageman factor
component of complement, C1, which leads to activation of other (factor XII) to factor XIIa.13 Another name for factor XIIa is prekal-
complement components, leading to activation of C3 and C5. Thus, likrein activator because it enzymatically activates the first compo-
antibodies of the acquired immune response can use the complement nent of the kinin system, prekallikrein. The final product of the kinin
system to kill bacteria and activate inflammation. system is a small-molecular-weight molecule, bradykinin, which is
The alternative pathway is activated by several substances found produced from a larger precursor molecule, kininogen. Bradykinin
on the surface of infectious organisms (e.g., lipopolysaccharides causes dilation of blood vessels, acts with prostaglandins to induce
[endotoxin] on the bacterial surface or yeast cell wall carbohydrates pain, causes smooth muscle cell contraction, and increases vascular
[zymosan]). This pathway uses unique proteins (factor B, factor D, and permeability.
properdin) to form a complex that activates C3. C3 activation leads to
C5 activation and convergence with the classical pathway. Thus, the Control and Interaction of Plasma Protein Systems
complement system can be directly activated by certain infectious The three plasma protein systems are highly interactive so that activa-
organisms without antibody being present. tion of one results in production of a large number of very potent,
The lectin pathway is similar to the classical pathway but is inde- biologically active substances that further activate the other systems.
pendent of antibody. It is activated by several plasma proteins, particu- Very tight regulation of these processes is essential for the following
larly mannose-binding lectin (MBL). MBL is similar to C1 and binds two reasons.
to bacterial polysaccharides containing the carbohydrate mannose. 1. The inflammatory process is critical for an individual’s survival;
Thus, infectious agents that do not activate the alternative pathway thus efficient activation must be guaranteed regardless of the cause
may be susceptible to complement through the lectin pathway. of tissue injury. Interaction among the plasma systems results in
In summary, the complement cascade can be activated by at least activation of the entire inflammatory response regardless of which
three different means, and its products have four functions: (1) opso- system is activated initially.
nization, (2) anaphylatoxic activity resulting in mast cell degranula- 2. The biochemical mediators generated during these processes are
tion, (3) leukocyte chemotaxis, and (4) cell lysis. so potent and potentially detrimental to the individual that their
actions must be strictly confined to injured or infected tissues.
Clotting System Therefore, multiple mechanisms are available to either activate or
The clotting (coagulation) system is a group of plasma proteins that, inactivate (regulate) these plasma protein systems. For instance, the
when activated sequentially, form a blood clot. A blood clot is a mesh- plasma that enters the tissues during inflammation (edema) contains
work of protein (fibrin) strands that stabilizes the platelet plug and enzymes that destroy mediators of inflammation. Carboxypeptidase
traps other cells, such as erythrocytes, phagocytes, and microorgan- inactivates the anaphylatoxic activities of C3a and C5a, and kininases
isms.11 Clots (1) plug damaged vessels and stop bleeding, (2) trap that degrade kinins. Histaminase degrades histamine and kallikrein
microorganisms and prevent their spread to adjacent tissues, and (3) and down-regulates the inflammatory response.
provide a framework for future repair and healing. Specific details and The formation of clots also activates a fibrinolytic system that is
illustrations of the clotting system are presented in Chapter 19 and only designed to limit the size of the clot and remove the clot after bleeding
the relationship between clotting and inflammation is presented here. has ceased. Thrombin of the clotting system activates plasminogen in
The clotting system can be activated by many substances that are the blood to form the enzyme plasmin. The primary activity of plas-
released during tissue injury and infection, including collagen, pro- min is to degrade fibrin polymers in clots. However, plasmin can also
teinases, kallikrein, and plasmin, as well as by bacterial products such activate the complement cascade through components C1, C3, and C5
as endotoxins. Like the complement cascade, the coagulation cascade and the kinin cascade by activating factor XII and producing prekal-
can be activated through different pathways that converge and result in likrein activator.
the formation of a clot (see Figure 5-4). These pathways are the tissue Another example of a common regulator is C1 esterase inhibi-
factor (extrinsic) pathway and the contact activation (intrinsic) path- tor (C1 inh).14 C1 inh inhibits complement activation through C1
way. The tissue factor (extrinsic) pathway is activated when there is (classical pathway), MASP-2 (lectin pathway), and C3b (alternative
tissue injury and membrane-bound or soluble tissue factor (TF) (also pathway). It is also a major inhibitor of the clotting and kinin path-
called tissue thromboplastin), a substance released by damaged endo- way components (e.g., kallikrein, factor XIIa). A genetic defect in C1
thelial cells in blood vessels, reacts with activated factor VII (VIIa). inh (C1 inh deficiency) results in hereditary angioedema, which is a
The contact activation (intrinsic) pathway is activated when there is self-limiting edema of cutaneous and mucosal layers resulting from
an abnormal vessel wall and Hageman factor (factor XII) in plasma stress, illness, or relative minor or unapparent trauma. The disease is
contacts negatively charged subendothelial substances. Kallikrein and characterized by hyperactivation of all three plasma protein systems,
kininogen can also activate factor XII. The clotting pathways converge although excessive production of bradykinin appears to be the princi-
at factor X. Activation of factor X begins a common pathway leading to pal cause of increased vascular permeability.
activation of fibrin that polymerizes to form a fibrin clot.
As with the complement cascade, activation of the clotting cas-
cade produces fragments known as fibrinopeptides (FPs) A and B that
enhance the inflammatory response.12 Fibrinopeptides are released
4 QUICK CHECK 5-3
. What are the three most important products of the complement system?
1
from fibrinogen when fibrin is produced. Both fibrinopeptides (espe- 2. How is the coagulation cascade activated? How is it related to the plasma
cially fibrinopeptide B) are chemotactic for neutrophils and increase kinin cascade?
vascular permeability by enhancing the effects of bradykinin (formed 3. What factors control the plasma protein systems of inflammation?
from the kinin system).
 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing 125

that specifically bind these molecules, resulting in activation of intra-

Erythrocyte cellular signaling pathways and activation of the cell itself. Activation
may result in the cell gaining a function critical to the inflammatory
response or induction of the release of additional cellular products that
increase inflammation, or both. Most of these inflammatory cells and
Platelet protein systems, along with the substances they produce, act at the site
of tissue injury to confine the extent of damage, kill microorganisms,
LEUKOCYTES and remove the cellular debris in preparation for healing: tissue regen-
eration (a process known as resolution) or repair.

Cellular Receptors
As will be discussed in Chapter 6, B and T lymphocytes of the acquired
immune system have evolved surface receptors (i.e., the T-cell recep-
tor, or TCR, and the B-cell receptor, or BCR) that bind a large spectrum
of antigens. Cells involved in innate resistance have evolved a different
Lymphocyte Monocyte
set of receptors that recognize a much more limited array of specific
Granulocytes molecules. These are referred to as pattern recognition receptors
(PRRs).15 PRRs recognize two types of molecular patterns: molecules
that are expressed by infectious agents, either found on their surface
or released as soluble molecules (pathogen-associated molecular pat-
terns, or PAMPs); or products of cellular damage (damage-associated
molecular patterns, or DAMPs). Thus cells of the innate immune sys-
tem can respond to both sterile (through DAMPs) or septic (through
Basophil Eosinophil Neutrophil PAMPs and DAMPs) tissue damage.
FIGURE 5-5  Cellular Components of the Blood. Cells in the PRRs are generally expressed on cells in tissues at the body’s sur-
blood can be classified as red blood cells (erythrocytes), cellular face (i.e., skin, respiratory tract, gastrointestinal tract, genitourinary
fragments (platelets), or white blood cells (leukocytes). Leukocytes tract) where they monitor the environment for products of cellular
consist of lymphocytes, monocytes, and granulocytes (neutrophils, damage and potentially infectious microorganisms. Classes of cellular
eosinophils, basophils). (Erythrocyte plate from Goldman L, Ausiello PRRs primarily differ in the specificity of ligands they bind: toll-like
DA, editors: Cecil medicine, ed 23, Philadelphia, 2007, Saunders; receptors (microbial substances), complement receptors (compo-
rest of plates from McPherson RA, Pincus MR, editors: Henry’s nents of the complement system), scavenger receptors (changes on
clinical diagnosis and management by laboratory methods, ed 21,
the surface of the damaged cell), and glucan and mannose receptors
Philadelphia, 2006, Saunders.)
(carbohydrates expressed on the surface of some microorganisms).
Although most PRRs are on the cell surface, some are in the cytoplasm
or secreted.16 An example of a secreted PRR is mannose-binding lectin
Cellular Components of Inflammation of the lectin pathway of complement activation.
Inflammation is a process in vascular tissue; thus the cellular compo- A major class of cell-surface PRRs is Toll-like receptors (TLRs),
nents of the response can be found in the blood or in tissue surround- which primarily recognize a large variety of PAMPs located on the
ing the blood vessels. The blood vessels are lined with endothelial cells, microorganism’s cell wall or surface (e.g., bacterial lipopolysaccharide
which under normal conditions actively maintain normal blood flow. [LPS], peptidoglycans, lipoproteins, yeast zymosan, viral coat pro-
During inflammation, however, the vascular endothelium becomes a teins), other surface structures (e.g., bacterial flagellin), or microbial
principal coordinator of blood clotting and the passage of cells and fluid nucleic acid (e.g., bacterial DNA, viral double-stranded RNA). Ten dif-
into the tissue. The tissues close to the vessels contain mast cells, which ferent TLRs have been described in humans. They are expressed on the
are probably the most important activators of inflammation. The tissue surface of many cells that have direct and early contact with potential
also contains dendritic cells, which connect the innate and acquired pathogenic microorganisms, including mucosal epithelial cells, mast
immune responses. The most complex mixture of cells is found in the cells, neutrophils, macrophages, dendritic cells, and some subpopula-
blood (Figure 5-5). Blood cells are divided into erythrocytes (red blood tions of lymphocytes.
cells), platelets, and leukocytes (white blood cells). Leukocytes are sub- In addition to PRRs, other receptors recognize molecules produced
divided into granulocytes, monocytes, and lymphocytes. Granulocytes by activation of plasma protein systems. For instance, complement
are the most common leukocytes and are classified by the type of stains receptors are found on many cells of the innate and acquired immune
needed to visualize enzyme-containing granules in their cytoplasm: responses (e.g., granulocytes, monocytes/macrophages, lymphocytes,
basophils, eosinophils, and neutrophils. Monocytes are precursors of mast cells, erythrocytes, platelets), as well as some epithelial cells. They
macrophages that are found in the tissue. Various forms of lympho- recognize several fragments produced through activation of the com-
cytes participate in the innate immune response (natural killer [NK] plement system, particularly C3a, C5a, and C3b.
cells) and the acquired immune response (B and T cells).
Cells of both innate and acquired immune systems respond to mol- Cellular Products
ecules produced at a site of cellular damage and are recruited to that Many different kinds of cells must cooperate during effective pro-
site to augment the protective response.8 The molecules originate from tective responses, both innate and acquired. That cooperation is
destroyed or damaged cells, contaminating microbes, activation of the achieved by the secretion of a variety of molecules (primarily pro-
plasma protein systems, or secretions by other cells of the innate or teins, but also some lipids) that affect other cells (Figure 5-6).
acquired immune systems. Each cell has a set of cell-surface receptors These factors are referred to as cytokines.8 Cytokines can be either
126 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing

Mediators (cytokines) of
inflammatory processes

Limit inflammation
IL-10 (inhibits cytokine production)
Vasodilation TGF- (inhibits macrophage proliferation)
Prostaglandins, histamine, nitric oxide ECF-A (attracts eosinophils)
Histaminase, arylsulfatase
(destroy histamine and leukotrienes)

Vascular permeability Immune response

Histamine, bradykinin, leukotrienes, PAF IL-1, IL-2, IL-4, IL-5, IL-6, IFN-

Repair and healing

IFN- (activates macrophages)
Pain
TGF- (stimulates fibroblast growth)
Prostaglandins, bradykinin
Angiogenic factors [VEGF, FGF-2] (stimulate
endothelial and fibroblast growth)

Sytemic Effects Phagocytosis

Fever Adherence and diapedesis
IL-1, IL-6, TNF- , prostaglandins IL-1, TNF- , C5a, leukotrienes
Leukocytosis
Chemotaxis
Leukocytes (IL-1, TNF- )
MCF, IL-8, ENA-78, NCF, ECF-A, kallikrein
Mast cells and eosinophils (IL-4, IL-5)
Granulocytes (G-CSF) Engulfment and phagocytosis
Monocytes (M-CSF) C3b, IgG (opsonins)
Natural killer cells (IL-2) IFN- (activates macrophages)
Acute phase reactants TNF- (increases macrophage cytokine production)
IL-1, IL-6, IL-8, TNF- , C-reactive TNF- (increases phagocytosis)
protein and other proteins

FIGURE 5-6  Principal Mediators of Inflammatory Processes. C3b, Large fragment produced from
complement component C3; C5a, small fragment produced from complement component C5; ECF-A,
eosinophil chemotactic factor of anaphylaxis; FGF, fibroblast growth factor; IFN, interferon; IgG, immu-
noglobulin G (predominant class of antibody in the blood); IL, interleukin; MCF, monocyte chemotactic
factor; NCF, neutrophil chemotactic factor; PAF, platelet-activating factor; TGF, T-cell growth factor;
TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

proinflammatory or anti-inflammatory in nature, depending on Perhaps the most important proinflammatory ILs are interleu-
whether they tend to induce or inhibit the inflammatory response. kin-1 and interleukin-6, which cooperate closely with another cyto-
Cytokines usually diffuse over short distances, bind to the appropriate kine, tumor necrosis factor-alpha.18 Interleukin-1 (IL-1) is produced
target cells, and affect the function of the target cell. Some effects occur mainly by macrophages.19 It activates monocytes, other macrophages,
over long distances, such as the induction of fever by some cytokines and lymphocytes, thereby enhancing both the innate and acquired
(i.e., endogenous pyrogens) that are produced at an inflammatory site. immunity, and acts as a growth factor for many cells. It has several
Cytokines affect other cells through specific cell-surface receptors and effects on neutrophils, including induction of proliferation (resulting
activation of intracellular signaling pathways. The affected cell may in an increase in the number of circulating neutrophils), attraction
become activated and produce other cytokines to further enhance the to an inflammatory site (chemotaxis), and increased cellular respira-
response. tion and lysosomal enzyme activity (both effects resulting in increased
To date more than 100 different cytokines have been discovered.17 cellular killing of bacteria).20 IL-1 is an endogenous pyrogen (i.e.,
The majority of important cytokines are classified as interleukins or fever-causing cytokine) that reacts with receptors on cells of the hypo-
interferons. Interleukins (ILs) are produced predominantly by mac- thalamus and affects the body’s thermostat, resulting in fever.
rophages and lymphocytes in response to stimulation of PRRs or by Interleukin-6 (IL-6) is produced by macrophages, lymphocytes,
other cytokines. More than 30 interleukins have been identified. Their fibroblasts, and other cells.18 IL-6 directly induces hepatocytes (liver
effects include the following: cells) to produce many of the proteins needed in inflammation (acute-
1. Alteration of adhesion molecule expression on many types of cells phase reactants, discussed later in this chapter). IL-6 also stimulates
2. Attraction of leukocytes to a site of inflammation (chemotaxis) growth and differentiation of blood cells in the bone marrow and the
3. Induction of proliferation and maturation of leukocytes in the growth of fibroblasts (required for wound healing).
bone marrow Tumor necrosis factor-alpha (TNF-α) is secreted by macrophages
4. General enhancement or suppression of inflammation. and other cells (e.g., mast cells) in response to stimulation of TLRs.
 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing 127

Interferon
molecules Antiviral
protein
Virus
Viral
interferon

Cell infected with virus Interferon binds to Antiviral protein

produces interferon uninfected cell and blocks viral nucleic
induces synthesis acid synthesis
of antiviral protein
FIGURE 5-7  The Action of Interferon. See text for details.

TNF-α induces a multitude of proinflammatory effects, particularly on (e.g., monocyte/macrophage chemotactic proteins [MCP-1, MCP-2,
the vascular endothelium and macrophages. When secreted in large and MCP-3], macrophage inflammatory proteins [MIP-1α and MIP-
amounts, TNF-α has systemic effects that include the following: 1β]) or attract neutrophils (e.g., interleukin 8 [IL-8]).
1. Inducing fever by acting as an endogenous pyrogen
2. Causing increased synthesis of inflammation-related serum pro- Mast Cells and Basophils
teins by the liver The mast cell is probably the most important cellular activator of
3. Causing muscle wasting (cachexia) and intravascular thrombosis in the inflammatory response.21 Mast cells are filled with granules and
cases of severe infection and cancer located in the loose connective tissues close to blood vessels near the
Very high levels of TNF-α can be lethal and are probably responsible body’s outer surfaces (i.e., in the skin and lining the gastrointestinal
for fatalities from shock caused by gram-negative bacterial infections. and respiratory tracts). Basophils are found in the blood and prob-
Some cytokines are anti-inflammatory and diminish the inflam- ably function in the same way as tissue mast cells.22 A great number of
matory response. The most important are interleukin-10 and trans- stimuli activate mast cells to release potent soluble inducers of inflam-
forming growth factor-beta (TGF-β). Interleukin-10 (IL-10) is mation. These are released by (1) degranulation (the release of the
primarily produced by lymphocytes and suppresses the growth of contents of mast cell granules) and (2) synthesis (the new production
lymphocytes and the production of proinflammatory cytokines by and release of mediators in response to a stimulus) (Figure 5-8).
macrophages, leading to down-regulation of both inflammatory and Degranulation. In response to a stimulus, biologically active mol-
acquired immune responses. Transforming growth factors, includ- ecules are released from the mast cell granules within seconds and exert
ing transforming growth factor-beta (TGF-β), are produced by their effects immediately. These molecules include histamine and che-
many types of cells in response to inflammation and induce cell divi- motactic factors.
sion and differentiation of other cell types, such as immature blood Histamine is a small-molecular-weight molecule with potent
cells. Interferons (IFNs) are members of a family of cytokines that effects on many other cells, particularly those that control the cir-
protect against viral infections. The principal interferons are IFN-α, culation. Histamine, along with serotonin (found in many cells, but
IFN-β, and IFN-γ. Macrophages and cells that become infected with not human mast cells), is called a vasoactive amine. These molecules
viruses produce and secrete both IFN-α and IFN-β, which bind to cause temporary, rapid constriction of smooth muscle and dilation
specific receptors on neighboring cells and induce those cells to pro- of the postcapillary venules, which results in increased blood flow
duce antiviral proteins (Figure 5-7). Thus, IFN-α and IFN-β protect into the microcirculation. Histamine also causes increased vascular
the surrounding cells from infection and limit the spread of the virus. permeability resulting from retraction of endothelial cells lining the
IFN-γ is produced by lymphocytes; it activates macrophages, result- capillaries and increased adherence of leukocytes to the endothelium.
ing in increased capacity to kill infectious agents (including viruses Histamine affects cells by binding to histamine H1 and H2 receptors
and bacteria), and enhances the development of acquired immune on the target cell surface (Figure 5-9).23 Antihistamines are drugs that
responses against viruses. block the binding of histamine to its receptors, resulting in decreased
Chemokines are members of a special family of low-molecular- inflammation.
weight (8 to 12 kilodaltons [kDa]) peptide cytokines that primarily Mast cell granules also contain chemotactic factors, two of which
attract leukocytes to sites of inflammation. Chemokines are synthesized are neutrophil chemotactic factor (NCF) and eosinophil chemotactic
by many cell types, including macrophages, fibroblasts, and endothe- factor of anaphylaxis (ECF-A).24 Neutrophils are the predominant cell
lial cells, in response to proinflammatory cytokines, such as TNF- needed to kill bacteria in the early stages of inflammation. Eosinophils
α. To date, more than 50 different human chemokines have been help regulate the inflammatory response. Both cells are discussed in
described. Examples include those that primarily attract macrophages more detail later in this chapter.
128 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing

Mast cell

Degranulation Synthesis

A Chemotactic Histamine Phospholipase A2

factors Vascular
effects

Arachidonic Platelet activating

Neutrophil Eosinophil acid factor
chemotactic chemotactic
factor factor Vascular effects
Platelet activation
Attracts Attracts
neutrophils eosinophils
Cyclooxygenase 5-Lipoxygenase

Prostaglandins Leukotrienes
Vascular effects Vascular
Pain effects
B
FIGURE 5-8  Mast Cell and Mast Cell Degranulation and Synthesis of Biologic Mediators Dur-
ing Inflammation. (A) Colorized photomicrograph of mast cell; dense red granules contain histamine
and other biologically active substances. Among these are histamine, which is a major initiator of
vascular changes, and a variety of chemotactic factors. (B) Mast cell degranulation (left) and synthesis
(right). Histamine and biologically active substances are released immediately after stimulation of mast
cells. Other substances are synthesized in response to mast cell stimulation. These include lipid-based
molecules that originate from plasma membrane phospholipids as a result of the action of phospho-
lipase A2. These include platelet-activating factor and a variety of prostaglandins and leukotrienes.  
(A from Patton KT and Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)

Target cell Effect of histamine

H1 Smooth muscle cell Contraction

receptor Endothelial cell Contraction (retraction at
endothelial junctions)
Increasing
level Neutrophil Increased chemotaxis
GTP Mast cell Prostaglandin synthesis
Histamine Converted Cell
to cGMP activation

Increasing
level
ATP Cell
inactivation Parietal cell of Secretion of gastric acid
Converted stomach mucosa
H2 to cAMP
receptor Lymphocyte Decreased activity
Eosinophil Decreased activity
Neutrophil Decreased chemotaxis
Mast cell Decreased degranulation
FIGURE 5-9  Effects of Histamine Through H1 and H2 Receptors. The effects depend on (1) the
density and affinity of H1 or H2 receptors on the target cell and (2) the identity of the target cell. ATP,
Adenosine triphosphate; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophos-
phate; GTP, guanosine triphosphate.
 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing 129

Synthesis of Mediators. Activated mast cells begin new synthesis of

other mediators of inflammation, which are released later than those in Platelets
the granules. These include leukotrienes, prostaglandins, and platelet- Platelets are cytoplasmic fragments formed from megakaryocytes. They
activating factor, which are produced from lipids (arachidonic acid) circulate in the bloodstream until vascular injury occurs. After injury,
in the plasma membrane. Leukotrienes (slow-reacting substances of platelets are activated by many products of tissue destruction and inflam-
anaphylaxis [SRS-A]) are sulfur-containing lipids that produce hista- mation, including collagen, thrombin, and platelet-activating factor.26
mine-like effects: smooth muscle contraction and increased vascular Activation results in (1) their interaction with components of the coagu-
permeability. Leukotrienes appear to be important in the later stages lation cascade to stop bleeding11 and (2) degranulation, releasing bio-
of the inflammatory response because they stimulate slower and more chemical mediators such as serotonin, which has vascular effects similar
prolonged responses than do histamines. to those of histamine. Platelets also release growth factors that promote
Prostaglandins cause increased vascular permeability, neutro- wound healing. (Platelet function is described in detail in Chapter 19.)
phil chemotaxis, and pain by direct effects on nerves. They are long-
chain, unsaturated fatty acids produced by the action of the enzyme Phagocytes
cyclooxygenase on arachidonic acid from membrane phospholipids; Neutrophils. The neutrophil, or polymorphonuclear neutrophil
prostaglandins are classified into groups (E, D, A, F, and B) according (PMN), is a member of the granulocytic series of white blood cells and
to their structure. Prostaglandins E1 and E2 cause increased vascular is named for the characteristic staining pattern of its granules as well as
permeability and smooth muscle contraction. Aspirin and some other its multilobed nucleus. Neutrophils are the predominant phagocytes in
nonsteroidal anti-inflammatory drugs (NSAIDs) block the synthesis of the early inflammatory site, arriving within 6 to 12 hours after the ini-
prostaglandins of the E series and other arachidonic acid derivatives, tial injury. Several inflammatory mediators (e.g., some bacterial pro-
thereby inhibiting inflammation.25 teins, complement fragments C3a and C5a, and mast cell neutrophil
Platelet-activating factor (PAF) is produced by removal of a fatty chemotactic factor) specifically and rapidly attract neutrophils from
acid from the plasma membrane phospholipid by phospholipase A2. the circulation and activate them.
Although mast cells are a major source of PAF, this molecule also can Because the neutrophil is a mature cell that is incapable of division
be produced during inflammation by neutrophils, monocytes, endo- and sensitive to acidic environments, it is short lived at the inflamma-
thelial cells, and platelets. The biologic activity of PAF is virtually iden- tory site and becomes a component of the purulent exudate, or pus,
tical to that of leukotrienes, namely, causing endothelial cell retraction which is removed from the body through the epithelium or drained
to increase vascular permeability, leukocyte adhesion to endothelial from the infected site via the lymphatic system. (The lymphatic system
cells, and platelet activation. is described in Chapter 22.) The primary roles of the neutrophil are
Thus, at a site of tissue damage all the hallmarks of inflamma- removal of debris and dead cells in sterile lesions, such as burns, and
tion can be caused by mast cell products. Histamine causes dilation destruction of bacteria in nonsterile lesions.
of the blood vessels and slows the circulation in nearby vessels. His- Monocytes and Macrophages. Monocytes (the immature form of
tamine also causes endothelial cells to change their shapes and open this white blood cell in the blood) and macrophages (the mature cell in
intercellular junctions, which allows fluid to leak from the blood into the tissues) have fewer and larger lysosomes in their cytoplasm than do
the surrounding tissues. Increased blood flow and vasodilation result granulocytes. Monocytes are the largest normal blood cells and have a
in increased redness and warmth, and increased vascular permeabil- nucleus that is often indented or horseshoe shaped. Monocytes are pro-
ity results in local swelling from increased fluid in the tissues. Lipid- duced in the bone marrow, enter the circulation, and migrate to the
derived mediators are released later and continue the inflammatory inflammatory site, where they develop into macrophages. Monocytes also
process through histamine-like effects and cause pain. appear to be the precursors of macrophages that are fixed in tissues (tissue
macrophages), including Kupffer’s cells in the liver, alveolar macrophages
Endothelium in the lungs, and microglia in the brain. Macrophages are generally larger
The vessel walls consist of a layer of endothelial cells that adhere to an and are more active as phagocytes than their monocytic precursors.
underlying matrix of connective tissue. The matrix contains a variety of Macrophages enter the site after 24 hours, or later, and gradually
proteins, including collagen, fibronectin, and laminins. Circulating cells replace the neutrophils. They migrate to the site after neutrophils
and platelets and components of plasma protein systems continually because they move more sluggishly and because many of the chemo-
contact endothelial cells lining the blood vessels. Endothelial cells regu- tactic factors that attract them, such as macrophage chemotactic fac-
late circulating components of the inflammatory system and maintain tor, must first be released by neutrophils.27 Macrophages are better
normal blood flow by preventing spontaneous activation of platelets suited than neutrophils to long-term defense against infectious agents
and members of the clotting system. Endothelial cells produce nitric because macrophages can survive and divide in the acidic inflamma-
oxide (NO) from arginine and prostacyclin (PGI2) from arachidonic tory site.28 Macrophages orchestrate the wound healing process by
acid. Both NO and PGI2 maintain blood flow and pressure and inhibit cleaning up the site of injury by phagocytosis, promoting angiogenesis,
platelet activation. PGI2 and NO are synergistic. NO is released continu- releasing cytokines and growth factors that promote epithelial cell divi-
ally to relax vascular smooth muscle and suppress the effects of low lev- sion, activating fibroblasts, and promoting the synthesis of extracellu-
els of cytokines, thus maintaining vascular tone. PGI2 production varies lar matrix and collagen formation.29
a great deal and is increased when additional regulation is needed. Several bacteria are resistant to killing by granulocytes and can
Damage to the endothelial cell lining of the vessel exposes the sub- even survive inside macrophages. Microorganisms, such as Mycobac-
endothelial connective tissue matrix, which is prothrombogenic and terium tuberculosis (tuberculosis), Mycobacterium leprae (leprosy),
initiates platelet activation and formation of clots (the contact activa- Salmonella typhi (typhoid fever), Brucella abortus (brucellosis), and
tion [intrinsic] clotting pathway). Proinflammatory cytokines affect Listeria monocytogenes (listeriosis), can remain dormant or multiply
the endothelium, resulting in adherence of leukocytes to the vessel sur- inside the phagolysosomes of macrophages. The bactericidal activ-
face, invasion of leukocytes into the tissue, and efflux of plasma from ity of macrophages can increase markedly with the help of inflam-
the vessel.17 matory cytokines produced by cells of the acquired immune system
130 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing

A. Tissue
Basement membrane
Normal endothelium Endothelial
cell retraction
3 Chemotactic factor
Retracted 1
Adherence 2
intercellular
margination
junction
and diapedesis Chemotaxis Splinter
Margination 2
Chemotactic
1 gradient

Wound
Neutrophils 3

Bacterium Epithelium
Capillary Connective tissue

C. Phagocytosis
B. Recognition and attachment Bacteria opsonized
by Ab and C3b

Phagosome 1
2
Bacterium

3
Lysosome

AbR 1 Recognition and

C3bR PAMP
adherence (binding)
Ab 4
C3b PRR Phagolysosome 2 Engulfment and formation
Ag of phagosome
3 Fusion with lysosome
to form phagolysosome
4 Destruction (killing)
and digestion
Phagocyte
FIGURE 5-10  Process of Phagocytosis. The process that results in phagocytosis is characterized by
three interrelated steps: adherence and diapedesis, tissue invasion by chemotaxis, and phagocytosis.
A, Adherence, margination, diapedesis, and chemotaxis. The primary phagocyte in the blood is the
neutrophil, which usually moves freely within the vessel (1). At sites of inflammation, the neutrophil
progressively develops increased adherence to the endothelium, leading to accumulation along the
vessel wall (margination or pavementing) (2). At sites of endothelial cell retraction the neutrophil exits
the blood by means of diapedesis (3). Chemotaxis. In the tissues, the neutrophil detects chemotactic
factor gradients through surface receptors (1) and migrates towards higher concentrations of the fac-
tors (2). The high concentration of chemotactic factors at the site of inflammation immobilizes the
neutrophil (3). B, Specific receptors for recognition and attachment. C, Phagocytosis. Opsonized micro-
organisms bind to the surface of a phagocyte through specific receptors (1). The microorganism is
ingested into a phagocytic vacuole, or phagosome (2). Lysosomes fuse with the phagosome, resulting
in the formation of a phagolysosome (3). During this process the microorganism is exposed to products
of the lysosomes, including a variety of enzymes and products of the hexose-monophosphate shunt
(e.g., H2O2, O2−). The microorganism is killed and digested (4). Ab, Antibody; AbR, antibody receptor;
C3b, complement component C3b; C3bR, complement C3b receptor; PAMP, pathogen-associated
molecular pattern; PRR, pattern recognition receptor.
 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing 131

(subsets of T lymphocytes) or cells activated through Toll-like recep- phagocytes are neutrophils and macrophages. Both cells are circulat-
tors. Macrophages have cell-surface receptors for these cytokines and ing in the blood and must first leave the circulation and migrate to
are further activated to become more effective killers of infectious the site of inflammation before initiating phagocytosis (Figure 5-10).
microorganisms. Many products of inflammation affect expression of surface molecules
Eosinophils. Although eosinophils are only mildly phagocytic, involved in cell-to-cell adherence. Both leukocytes and endothelial
they have two specific functions: (1) they serve as the body’s primary cells begin expressing molecules that increase adhesion, or stickiness,
defense against parasites, and (2) they help regulate vascular media- causing the leukocytes to adhere more avidly to the endothelial cells in
tors released from mast cells.24 The role of eosinophils in resistance to the walls of the capillaries and venules in a process called margination,
parasites occurs in collaboration with specific antibodies produced by or pavementing. Leukocyte-endothelial interactions lead to diapede-
the acquired immune system (discussed later in this chapter). sis, or emigration of the cells through the inter-endothelial junctions
The second function, regulation of mast cell–derived inflamma- that have loosened in response to inflammatory mediators.34
tory mediators, is a critical function of eosinophils and helps limit and Once inside the tissue, leukocytes undergo a process of directed
control inflammation. Mast cells produce eosinophil chemotactic fac- migration, called chemotaxis, by which they are attracted to the
tor-A (ECF-A), which attracts eosinophils to the site of inflammation. inflammatory site by chemotactic factors (Figure 5-11). The primary
Eosinophil lysosomes contain several enzymes that degrade vasoactive chemotactic factors include many bacterial products, neutrophil che-
molecules, thereby controlling the vascular effects of inflammation. motactic factor produced by mast cells, complement fragments C3a
These enzymes include histaminase, which mediates the degradation and C5a, and products of the clotting and kinin systems.
of histamine, and arylsulfatase B, which degrades some of the lipid- At the inflammatory site, the process of phagocytosis involves five
derived mediators produced by mast cells. steps: (1) recognition and adherence of the phagocyte to its target,
Dendritic Cells and T Lymphocytes. Dendritic cells provide one of (2) engulfment (ingestion or endocytosis), (3) formation of a phago-
the major links between the innate and acquired immune responses.30 some, (4) fusion of the phagosome with lysosomal granules within the
They are primary phagocytic cells located in the peripheral organs and phagocyte, and (5) destruction of the target. Throughout the process,
skin, where molecules released from infectious agents are encountered, both the target and digestive enzymes are isolated within membrane-
recognized through PRRs, and internalized through phagocytosis. bound vesicles. Isolation protects the phagocyte itself from the harmful
Dendritic cells then migrate through the lymphatic vessels to lymphoid effects of the target microorganisms, as well as its own enzymes.
tissue, such as lymph nodes, and interact with T lymphocytes to gener- Most phagocytes can trap and engulf bacteria using PRRs, although
ate an acquired immune response.31 Through the production of a fam- the process is relatively slow. Opsonization greatly enhances adher-
ily of cytokines, they guide development of a subset of T cells (helper ence by acting as a glue to tighten the affinity of adherence between the
cells) that coordinate the development of functional B and T cells (dis- phagocyte and the target cell. The most efficient opsonins are antibod-
cussed in Chapter 6). T lymphocytes are active during the proliferative ies and C3b produced by the complement system. Antibodies are made
phase of wound healing (see p. 135).32,33 against antigens on the surface of bacteria and are highly specific to
Phagocytosis. Phagocytosis is the process by which a cell ingests that particular microorganism. Certain bacterial and fungal polysac-
and disposes of foreign material, including microorganisms. Cells that charide coatings activate the alternative and lectin pathways of com-
perform this process are called phagocytes. The two most important plement activation, which deposits C3b on the bacterial surface and

R
R P

M
C

B
P

R
M

A D
FIGURE 5-11  Steps in Phagocytosis. These scanning electron micrographs show examples of the
progressive steps in phagocytosis. A, A leukocyte undergoes chemotactic movement (in direction of
arrow) by extending a filopodium (upper left) from the trailing body of the cell. B, Engulfment of red
blood cells by a macrophage (M) that attaches to the red blood cells (R). C, An extension of the macro-
phage membrane (P; pseudopod) starts to enclose the red cell. D, The red blood cells are almost totally
engulfed by the macrophage. (A from Kumar V et al: Robbins and Cotran pathologic basis of disease,
professional edition, ed 8, Philadelphia, 2009, Saunders; B-D modified from King DW, Fenoglio CM,
Lefkowitch JH: General pathology: principles and dynamics, Philadelphia, 1983, Lea & Febiger.)
132 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing

increases phagocytosis. The surface of phagocytes contains a variety designed to contain the infection or damaged site so it no longer poses
of specific receptors that will strongly bind to opsonins. These include any harm to the individual. The characteristics of the early (i.e., acute)
complement receptors that bind to C3b and Fc receptors that bind to inflammatory response differ from those of the later (i.e., chronic)
a site on antibody molecules. response, and each phase involves different biochemical mediators and
Engulfment (endocytosis) is carried out by small pseudopods that cells that function together. Depending on the successful containment
extend from the plasma membrane and surround the adherent micro- of tissue damage and infection, the acute and chronic phases may lead
organism, forming an intracellular phagocytic vacuole, or phagosome to healing without progression to the next phase.
(see Figures 5-10 and 5-11). After the formation of the phagosome,
lysosomes converge, fuse with the phagosome, and discharge their Local Manifestations of Acute Inflammation
contents, creating a phagolysosome. Destruction of the bacterium The cells and plasma protein systems of the inflammatory response
takes place within the phagolysosome and is accomplished by both interact to produce all the characteristics of inflammation, whether local
oxygen-dependent and oxygen-independent mechanisms. or systemic (discussed in the next section), as well as determine the dura-
Oxygen-dependent killing mechanisms result from the production of tion of inflammation, either acute or chronic. All the local characteristics
toxic oxygen species. Phagocytosis is accompanied by a burst of oxy- of acute inflammation (i.e., swelling, pain, heat, and redness [erythema])
gen uptake by the phagocyte; this is termed the respiratory burst and result from vascular changes and the subsequent leakage of circulating
results from a shift in much of the cell’s glucose metabolism to the hex- components into the tissue. The symptoms of acute inflammation were
ose-monophosphate shunt, which produces nicotinamide adenine previously described on page 121 and can be reviewed in Figure 5-3.
dinucleotide phosphate (NADPH). A membrane-associated enzyme, The exudate of inflammation varies in composition, depending on
NADPH oxidase uses NADPH to generate superoxide (O2−), hydrogen the stage of the inflammatory response and, to some extent, the inju-
peroxide (H2O2), and other reactive oxygen species that can be highly rious stimulus. In early or mild inflammation, the exudate is watery
damaging to bacteria. Hydrogen peroxide also can collaborate with the (serous exudate) with very few plasma proteins or leukocytes. An
lysosomal enzyme myeloperoxidase and halide anions (Cl− and Br−) to example of serous exudate is the fluid in a blister. In more severe or
form acids that kill bacteria and fungi. advanced inflammation, the exudate may be thick and clotted (fibrin-
Oxygen-independent mechanisms of microbial killing include (1) ous exudate), such as in the lungs of individuals with pneumonia. If a
the acidic pH (3.5 to 4.0) of the phagolysosome, (2) cationic proteins large number of leukocytes accumulate, as in persistent bacterial infec-
that bind to and damage target cell membranes, (3) enzymatic attack of tions, the exudate consists of pus and is called a purulent (suppura-
the microorganism’s cell wall by lysozyme and other enzymes, and (4) tive) exudate. Purulent exudate is characteristic of walled-off lesions
inhibition of bacterial growth by lactoferrin binding of iron. (cysts or abscesses). If bleeding occurs, the exudate is filled with eryth-
When a phagocyte dies at an inflammatory site, it frequently rocytes and is described as a hemorrhagic exudate.
lyses (breaks open) and releases its cytoplasmic contents, including
the lysosomal enzymes, into the tissue. They can digest the connec- Systemic Manifestations of Acute Inflammation
tive tissue matrix, causing much of the tissue destruction associated The three primary systemic changes associated with the acute inflam-
with inflammation. The destructive effects of many enzymes released matory response are fever, leukocytosis (a transient increase in the lev-
by dying phagocytes are minimized by natural inhibitors found in the els of circulating leukocytes), and increased levels of circulating plasma
blood, such as α1-antitrypsin, a plasma protein produced by the liver. proteins.
An inherited deficiency of α1-antitrypsin often leads to chronic lung
damage and emphysema as a result of inflammation. (The pulmo- Fever
nary effects of α1-antitrypsin deficiency are described in Chapter 25.) Fever is partially induced by specific cytokines (e.g., IL-1, released
Released lysosomal products also may contribute to inflammation by from neutrophils and macrophages). These are known as endogenous
increasing vascular permeability, attracting additional monocytes, and pyrogens to differentiate them from pathogen-produced exogenous
activating the complement and kinin systems. pyrogens. Pyrogens act directly on the hypothalamus, the portion of
the brain that controls the body’s thermostat (see Figure 13-5). (Mech-
4 QUICK CHECK 5-4 anisms of temperature regulation and fever are discussed in Chapter
13.) A fever can be beneficial because some microorganisms (e.g.,
. What are pattern recognition receptors?
1
2. What are cytokines? How do cytokines promote inflammation? syphilis, gonococcal urethritis) are highly sensitive to small increases
3. What products do the mast cells release during inflammation, and what in body temperature. On the other hand, fever may have harmful side
are their effects? effects because it may enhance the host’s susceptibility to the effects of
4. What phagocytic cell types are involved in the acute inflammatory endotoxins associated with gram-negative bacterial infections (bacte-
response? What is the role of each? rial toxins are described in Chapter 7).
5. What are the four steps in the process of phagocytosis?
Leukocytosis
Leukocytosis is an increase in the number of circulating white blood cells
(greater than 11,000/ml3 in adults). During many infections, leukocyto-
ACUTE AND CHRONIC INFLAMMATION sis may be accompanied by a left shift in the ratio of immature to mature
Inflammation can be divided into phases of acute and chronic inflam- neutrophils, so that the more immature forms of neutrophils, such as
mation. The acute inflammatory response is self-limiting—that is, it band cells, metamyelocytes, and occasionally myelocytes, are present in
continues only until the threat to the host is eliminated. This usually relatively greater than normal proportions. (Chapter 19 contains a more
takes 8 to 10 days from onset to healing. If the acute inflammatory complete discussion of the development and maturation of blood cells.)
response proves inadequate, a chronic inflammation may develop Production of immature leukocytes increases primarily from prolifera-
and persist for weeks or months. If a continued response is neces- tion and release of granulocyte and monocyte precursors in the bone
sary, inflammation may progress to a granulomatous response that is marrow, which is stimulated by several products of inflammation.
 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing 133

Plasma Protein Synthesis

TABLE 5-2 CIRCULATING LEVELS OF
The synthesis of many plasma proteins, mostly products of the liver,
ACUTE-PHASE REACTANTS is increased during inflammation. These proteins, which can be either
DURING INFLAMMATION proinflammatory or anti-inflammatory in nature, are referred to as
FUNCTION INCREASED DECREASED acute-phase reactants (Table 5-2). Acute-phase reactants reach maxi-
Coagulation Fibrinogen None mal circulating levels within 10 to 40 hours after the start of inflam-
­components mation. IL-1 is indirectly responsible for the synthesis of acute-phase
Prothrombin reactants through the induction of IL-6, which directly stimulates liver
Factor VIII cells to synthesize most of these proteins.
Plasminogen Common laboratory tests for inflammation measure levels of acute-
Protease inhibitors α1-Antitrypsin Inter-α-antitrypsin phase reactants. For example, an increase in blood levels of acute-phase
α1-Antichymotrypsin reactants, primarily fibrinogen, is associated with an increased adhe-
Transport proteins Haptoglobin Transferrin sion among erythrocytes and a corresponding increase in the sedimen-
Hemopexin tation rate. The erythrocyte sedimentation rate is a measurement of the
Ceruloplasmin rate at which red blood cells sediment in a tube over a prescribed time
Ferritin span (usually an hour). Although increased erythrocyte sedimentation
Complement C1s, C2, C3, C4, C5, C9, factor Properdin is a nonspecific reaction, it is considered a good indicator of an acute
­components B, C1 inhibitor inflammatory response.
Miscellaneous α1-Acid glycoprotein Albumin
proteins
Chronic Inflammation
Fibronectin Prealbumin Superficially, the difference between acute and chronic inflammation
Serum amyloid A (SAA) α1-Lipoprotein is duration; chronic inflammation lasts 2 weeks or longer, regardless
C-reactive protein (CRP) β-Lipoprotein of cause. Chronic inflammation is sometimes preceded by an unsuc-
cessful acute inflammatory response (Figure 5-12). For example, if
bacterial contamination or foreign objects (e.g., dirt, wood splinter,
and glass) persist in a wound, an acute response may be prolonged

Persistent
acute
inflammation

Lymphocyte and
monocyte/macrophage
infiltration (pus)
(Figure 5-10)
Neutrophil
degranulation
and death
Persistence of
infection,
antigen, or
foreign body

Lymphocyte
activation

Tissue repair
(scar)
(Figure 5-14)
Fibroblast
activation
FIGURE 5-12  The Chronic Inflammatory Response. Inflammation usually becomes chronic because
of the persistence of an infection, an antigen, or a foreign body in the wound. Chronic inflammation
is characterized by the persistence of many of the processes of acute inflammation. In addition, large
amounts of neutrophil degranulation and death, the activation of lymphocytes, and the concurrent acti-
vation of fibroblasts result in the release of mediators that induce the infiltration of more lymphocytes
and monocytes/macrophages and the beginning of wound healing and tissue repair. For more detailed
information on each portion of the response, see the figures referenced in this illustration.
134 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing

granuloma, which is surrounded by a wall of lymphocytes. The granu-

loma itself is often encapsulated by fibrous deposits of collagen and
may become cartilaginous or possibly calcified by deposits of calcium
carbonate and calcium phosphate.
L The classic granuloma associated with tuberculosis is characterized
by a wall of epithelioid cells surrounding a center of dead and decaying
tissue (caseous necrosis) and mycobacteria. Decay of cells within the
granuloma results in the release of acids and the enzymatic contents
of lysosomes from dead phagocytes. In this inhospitable environment,
the cellular debris is broken down into its basic constituents, and a
E
C clear fluid remains (liquefaction necrosis). Eventually, this fluid dif-
Langhans fuses out and leaves a hollow, thick-walled structure in the tissue that
giant cell may remain for the life of the individual.

4 QUICK CHECK 5-5

1. Describe how acute inflammation differs from chronic inflammation. What
characteristics do they share?
2. List the types of exudate produced in inflammation.

WOUND HEALING
Tissue injury is followed by a period of healing that begins during acute
inflammation. The most favorable outcome is a return to normal struc-
ture and function, and may take up to 2 years for some tissue injury. The
FIGURE 5-13  Tuberculous Granuloma. A central area of amor- repaired tissues may be close to normal if damage is minor, no complica-
phous caseous necrosis (C) is surrounded by a zone of lympho- tions occur, and destroyed tissues are capable of regeneration (Figure
cytes (L) and enlarged epithelioid cells (E). Activated macrophages 5-14). This restoration is called resolution. Resolution may not be possi-
frequently fuse to form multinucleated cells (Langhans giant cells). ble if extensive damage is present, the tissue is not capable of regeneration,
In tuberculoid granulomas the nuclei of the giant cells move to the infection results in abscess or granuloma formation, or fibrin persists in
cellular margins in a horseshoe-like formation. the lesion. In those cases, repair takes place instead of resolution. Repair
is the replacement of destroyed tissue with scar tissue. Scar tissue is com-
posed primarily of collagen that fills in the lesion and restores strength
beyond 2 weeks.35 Pus formation, suppuration (purulent discharge), but cannot carry out the physiologic functions of destroyed tissue.
and incomplete wound healing may characterize this type of chronic Wound healing involves processes that (1) fill in, (2) seal, and
inflammation. (3) shrink the wound. These characteristics of healing vary in impor-
Chronic inflammation can occur also as a distinct process with- tance and duration among different types of wounds. A clean inci-
out previous acute inflammation. Some microorganisms (e.g., myco- sion, such as a paper cut or a sutured surgical wound, heals primarily
bacteria that cause tuberculosis) have cell walls with a very high lipid through the process of collagen synthesis. Because this type of wound
and wax content, making them relatively insensitive to breakdown has minimal tissue loss and close apposition of the wound edges,
by phagocytes. Other microorganisms (e.g., those that cause leprosy, very little sealing (epithelialization) and shrinkage (contraction) are
syphilis, and brucellosis) can survive within the macrophage and avoid required. Wounds that heal under conditions of minimal tissue loss are
removal by the acute inflammatory response. Other microorganisms said to heal by primary intention (see Figure 5-14).
produce toxins that damage tissue and cause persistent inflammation Other wounds do not heal as easily. Healing of an open wound,
even after the organism is killed. Finally, chemicals, particulate mat- such as a stage IV pressure ulcer (decubitus ulcer), requires a great
ter, or physical irritants (e.g., inhaled dusts, wood splinters, and suture deal of tissue replacement so that epithelialization, scar formation, and
material) can cause a prolonged inflammatory response. contraction take longer and healing occurs through secondary inten-
Chronic inflammation is characterized by a dense infiltration of tion (see Figure 5-14). Healing by either primary or secondary inten-
lymphocytes and macrophages. If macrophages are unable to protect tion may occur at different rates for different types of tissue injury.
the host from tissue damage, the body attempts to wall off and isolate Epidermal wounds that heal by secondary intention and unsu-
the infected area, thus forming a granuloma (Figure 5-13). For exam- tured internal lesions are not completely restored by healing. At best,
ple, infections caused by some bacteria (Listeria sp., Brucella sp.), fungi repaired tissue regains 80% of its original tensile strength. Only epi-
(histoplasmosis, coccidioidomycosis), and parasites (leishmaniasis, thelial, hepatic (liver), and bone marrow cells are capable of the com-
schistosomiasis, toxoplasmosis) can result in granuloma formation. plete mitotic regeneration of the normal tissue known as compensatory
The process of granuloma formation begins when some macrophages hyperplasia. In fibrous connective tissue, such as joints and ligaments,
differentiate into large epithelioid cells, which specialize in taking up normal healing results in replacement of the original tissue with new
debris and other small particles. Other macrophages fuse into multi- tissue that does not have exactly the same structure or function as that
nucleated giant cells, which are active phagocytes that can engulf very of the original. Some tissues heal without replacement of cells. For
large particles—larger than can be engulfed by a single macrophage. example, damage resulting from myocardial infarction heals with a
These two types of differentiated macrophages form the center of the scar composed of fibrous tissue rather than with cardiac muscle.
 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing 135

HEALING BY PRIMARY INTENTION HEALING BY SECONDARY INTENTION

Coagulation
Platelets

Inflammation
Neutrophils
24 hours

Proliferation

Mitoses
Granulation tissue
Macrophage
3 to 14 days Lymphocyte
Fibroblast
New capillary

Remodeling
Maturation

Reepithelialization

Weeks Fibrous union Wound

to contraction
(Scar)
Months

FIGURE 5-14  Wound Healing by Primary and Secondary Intention and Phases of Wound Healing.
Phases of wound healing (coagulation, inflammation, proliferation, remodeling, and maturation) and
steps in wound healing by primary intention (left) and secondary intention (right). Note large amounts of
granulation tissue and wound contraction in healing by secondary intention. (From Roberts JR, Hedges J:  
Clinical procedures in emergency medicine, ed 5, Philadelphia, 2009, Saunders.)

Wound healing occurs in three overlapping phases: inflamma- proliferative phase is characterized by macrophage recruitment of
tion, proliferation and new tissue formation, and remodeling and fibroblasts (connective tissue cells) and fibroblast proliferation, fol-
maturation. lowed by fibroblast collagen synthesis, epithelialization, contraction of
the wound, and cellular differentiation.
Phase I: Inflammation Macrophages invade the dissolving clot and clear away debris and
The early phase of wound healing begins during acute inflammation dead cells and orchestrate the wound healing process.29 Macrophages
and usually lasts for 1 to 2 days. The inflammatory phase includes secrete the following biochemical mediators that promote healing:
coagulation and the infiltration of cells that participate in wound heal- 1. Transforming growth factor-beta (TGF-β) stimulates fibroblasts
ing, including platelets, neutrophils, and macrophages (Figure 5-15). entering the lesion to synthesize and secrete the collagen precursor
The fibrin mesh of the blood clot acts as a scaffold for cells that par- procollagen.
ticipate in healing. Platelets contribute to clot formation and, as they 2. Angiogenesis factors, such as vascular endothelial growth factor
degranulate, release growth factors. Neutrophils clear the wound of (VEGF) and fibroblast growth factor-2 (FGF-2), stimulate vascular
debris and bacteria and are later replaced by macrophages. Macro- endothelial cells to form capillary buds that grow into the lesion;
phages are essential to wound healing because they are phagocytic, decreased pH and decreased wound oxygen tension also promote
release wound healing mediators and growth factors, recruit fibro- angiogenesis.
blasts, and help promote angiogenesis during the proliferative phase 3. Matrix metalloproteinases (MMPs) degrade and remodel extracel-
of wound healing. lular matrix proteins (e.g., collagen and fibrin) at the site of injury.
Granulation tissue grows into the wound from surrounding
Phase II: Proliferation and New Tissue Formation healthy connective tissue. Granulation tissue is filled with new capil-
The proliferative phase begins 3 to 4 days after the injury and con- laries (angiogenesis) derived from capillaries in the surrounding tissue,
tinues for as long as 2 weeks. The wound is sealed and the fibrin clot giving the granulation tissue a red, granular appearance. New lym-
is replaced by normal tissue or scar tissue during this phase. The phatic vessels also grow into the granulation tissue by a similar process.
136 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing

Coagulation

Inflammation

Proliferation/new tissue
Relative number of cells

Remodeling/maturation
Platelets

Fibroblasts

Lymphocytes
Neutrophils Macrophages

0 2 4 6 8 10 12 14 16
Days after lesion
FIGURE 5-15  Time Course of Cells Infiltrating a Wound. Neutrophils and macrophages are the pre-
dominant cells that infiltrate a wound during inflammation. Lymphocytes appear later and peak at day
7. Fibroblasts are the predominant cells during the proliferative and remodeling phases of the healing
process. (Adapted From Townsend CM et al, editors: Satiston textbook of surgery, ed 18, St Louis,
2007, Elsevier.)

During this process the healing wound must be protected. Epithe- contract their fibers, and exert tension on the neighboring cells while
lialization is the process by which epithelial cells grow into the wound anchoring themselves to the wound bed. Wound contraction is neces-
from surrounding healthy tissue. Epithelial cells migrate under the clot sary for closure of all wounds, especially those that heal by secondary
or scab using MMPs to unravel collagen. Migrating epithelial cells con- intention. Contraction is noticeable 6 to 12 days after injury.
tact similar cells from all sides of the wound and seal it, thereby halting
migration and proliferation. The epithelial cells remain active, under- Phase III: Remodeling and Maturation
going differentiation to give rise to the various epidermal layers (see Tissue remodeling and maturation begins several weeks after injury
Chapter 39. Epithelialization of a skin wound can be hastened if the and is normally complete within 2 years. During this phase, there
wound is kept moist, preventing the fibrin clot from becoming a scab. is continuation of cellular differentiation, scar formation, and scar
Fibroblasts are important cells during healing because they secrete remodeling.36 The fibroblast is the major cell of tissue remodeling with
collagen and other connective tissue proteins. Fibroblasts are stimu- the deposition of collagen into an organized matrix. Tissue regenera-
lated by macrophage-derived TGF-β to proliferate, enter the lesion, tion and wound contraction continue in the remodeling and matura-
and deposit connective tissue proteins in débrided areas about 6 days tion phase—a phase for recovering normal tissue structure that can
after the fibroblasts have entered the lesion. Collagen is the most abun- persist for years. For wounds that heal by scarring, scar tissue is remod-
dant protein in the body. It contains high concentrations of the amino eled and capillaries disappear, leaving the scar avascular. Within 2 to 3
acids glycine, proline, and lysine, many of which are enzymatically weeks after maturation has begun, the scar tissue has gained about two
modified. Modification of proline and lysine requires several cofactors thirds of its eventual maximal strength.
that are absolutely necessary for proper collagen polymerization and
function. These include iron, ascorbic acid (vitamin C), and molecu- Dysfunctional Wound Healing
lar oxygen (O2); absence of any of these results in impaired wound Dysfunctional wound healing and impaired epithelialization may
healing. As healing progresses, collagen molecules are cross-linked by occur during any phase of the healing process. The cause of dysfunc-
intermolecular covalent bonds to form collagen fibrils that are further tional wound healing includes ischemia, excessive bleeding, excessive
cross-linked to form collagen fibers. The complete process takes sev- fibrin deposition, a predisposing disorder such as diabetes mellitus,
eral months. wound infection, inadequate nutrients, numerous drugs, and tobacco
The granulation tissue contains myofibroblasts, specialized cells smoke.37
responsible for wound contraction. Myofibroblasts have features of Oxygen-deprived (ischemic) tissue is susceptible to infection, which
both smooth muscle cells and fibroblasts. They appear microscopi- prolongs inflammation and delays healing. Ischemia reduces energy
cally similar to fibroblasts but differ in that their cytoplasm contains production and impairs collagen synthesis and the tensile strength of
bundles of parallel fibers similar to those found in smooth muscle cells. regenerating connective tissue.
Wound contraction occurs as extensions from the plasma membrane Healing is prolonged if there is excessive bleeding. Large clots
of myofibroblasts establish connections between neighboring cells, increase the amount of space that granulation tissue must fill and serve
 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing 137

as mechanical barriers to oxygen diffusion. Accumulated blood is an

excellent culture medium for bacteria and promotes infection, thereby
prolonging inflammation by increasing exudation and pus formation.
Decreased blood volume also inhibits inflammation because of vessel
constriction rather than the dilation required to deliver inflammatory
cells to the site of injury.
Excessive fibrin deposition is detrimental to healing. Fibrin released
in response to injury must eventually be reabsorbed to prevent orga-
nization into fibrous adhesions. Adhesions formed in the pleural,
pericardial, or abdominal cavities can bind organs together by fibrous
bands and distort or strangulate the affected organ.
Persons with diabetes are at risk for prolonged wound healing.
Wounds are often ischemic because of the potential for small-vessel
diseases that impair the microcirculation and alter (glycosylated)
hemoglobin, which has an increased affinity for oxygen and thus does
not readily release oxygen in tissues. Consequences of hyperglycemia
also include suppression of macrophages and increased risk for wound A
infection.
Wound infection is caused by the infiltration of pathogens. Patho-
gens damage cells, stimulate the release of inflammatory mediators,
consume nutrients, and delay wound healing.
Optimal nutrition is important during all phases of healing because
metabolic needs increase. Leukocytes need glucose to produce the ade-
nosine triphosphate (5′-ATP) needed for chemotaxis, phagocytosis,
and intercellular killing; therefore the wounds of persons with diabetes
who receive insufficient insulin heal poorly. Hypoproteinemia impairs
fibroblast proliferation and collagen synthesis. Prolonged lack of vita-
mins A and C results in poorly formed connective tissue and greatly
impaired healing because they are cofactors required for collagen syn-
thesis.38 Other nutrients, including iron, zinc, manganese, and cop-
per, are also required as cofactors for collagen synthesis. Malnutrition
increases risk for wound infection, delays healing, and reduces wound
tensile strength.39
Medications, including antineoplastic (anticancer) agents, nonste-
roidal anti-inflammatory drugs (NSAIDs), and steroids, delay wound
healing. Antineoplastic agents slow cell division and inhibit angiogen-
esis. Although NSAIDs inhibit prostaglandin production and suppress
acute inflammation and relieve pain, they also can delay wound heal-
ing, particularly bone formation, and may contribute to the formation B
of excessive scarring.40 Steroids prevent macrophages from migrating FIGURE 5-16  Hypertrophic Scar and Keloid Scar Formation.
to the site of injury and inhibit release of collagenase and plasmino- Hypertrophic scar (A) and keloid scar (B) caused by excessive syn-
gen activator. Steroids also inhibit fibroblast migration into the wound thesis of collagen at suture sites. (A from Flint PW et al: Cummings
during the proliferative phase and delay epithelialization. Toxic agents otolaryngology: head & neck surgery, ed 5, Philadelphia, 2010,
in tobacco smoke (i.e., nicotine, carbon monoxide, and hydrogen cya- Mosby; B from Damjanov I, Linder J: Anderson’s pathology, ed 10,
nide) delay wound healing and increase the risk for wound infection.41 St Louis, 1996, Mosby.)
Dysfunctional collagen synthesis may involve excessive production
of collagen, causing surface overhealing, leading to a hypertrophic scar
or keloid.42 A hypertrophic scar is raised but remains within the origi- breaking because of excessive strain. Obesity increases the risk for
nal boundaries of the wound and tends to regress over time ­(Figure dehiscence because adipose tissue is difficult to suture. Wound dehis-
5-16, A). A keloid is a raised scar that extends beyond the original cence usually is heralded by increased serous drainage from the wound
boundaries of the wound, invades surrounding tissue, and is likely to and a patient’s perception that “something gave way.” Prompt surgical
recur after surgical removal (Figure 5-16, B). A familial tendency to attention is required.
keloid formation has been observed, with a greater incidence in blacks
than whites. Impaired Contraction
Wound contraction, although necessary for healing, may become
Wound Disruption pathologic when contraction is excessive, resulting in a deformity or
A potential complication of wounds that are sutured closed is dehis- contracture of scar tissue. Burns of the skin are especially susceptible
cence, in which the wound pulls apart at the suture line. Dehiscence to contracture development, particularly at joints. Internal contrac-
generally occurs 5 to 12 days after suturing, when collagen synthesis is tures include duodenal strictures caused by dysfunctional healing of
at its peak. Approximately half of dehiscence occurrences are associ- a peptic ulcer; esophageal strictures caused by chemical burns, such as
ated with wound infection, but they also may be the result of sutures lye ingestion; or abdominal adhesions caused by surgery, infection, or
138 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing

radiation. Contracture may occur in cirrhosis of the liver, constricting

vascular flow and contributing to the development of portal hyper-
4 QUICK CHECK 5-6
. How does regeneration of tissue differ from repair of tissue?
1
tension and esophageal varices. Proper positioning, range-of-motion
2. What does it mean to heal by primary intention?
exercises, and surgery are among the physical means used to overcome
3. What is the role of fibroblasts in wound healing?
myofibroblast pull and prevent skin contractures. Surgery is performed
4. Describe various ways wound healing may be dysfunctional.
to release internal contractures.

PEDIATRIC CONSIDERATIONS
Age-Related Factors Affecting Innate Immunity in the Newborn Child
• Newborns have transiently depressed inflammatory responses. • There is a tendency for infections associated with chemotactic defects,
• Neutrophils are incapable of chemotaxis, lacking fluidity in the plasma for example, cutaneous abscesses caused by staphylococci and cutaneous
membrane. candidiasis.
• Complement levels are diminished, especially components of the alternative • There are diminished oxidative and bacterial responses in those stressed by
pathways (e.g., factor B), particularly in premature newborns. in utero infection or respiratory insufficiency.
• Monocyte/macrophage numbers are normal but chemotaxis of monocytes is • There is a tendency to develop severe overwhelming sepsis and meningitis
delayed. when infected by bacteria against which no maternal antibodies are present.

GERIATRIC CONSIDERATIONS
Age-Related Factors Affecting Innate Immunity in the Elderly
• Normal numbers of cells of innate immunity but possible diminished function • Use of medications that may interfere with healing (e.g., anti-inflammatory
(e.g., decreased phagocytic activity) steroids)
• Increased incidence of chronic inflammation, possibly related to increased • Loss of subcutaneous fat, diminishing layers of protection against injury
production of proinflammatory mediators • Atrophied epidermis, including underlying capillaries, which decreases perfu-
• At risk for impaired healing—often associated with chronic illness (e.g., sion and increases risk of hypoxia in wound bed
­diabetes mellitus, peripheral vascular disease, or cardiovascular disease)

Data from Freund A et al: Inflammatory networks during cellular senescence: causes and consequences, Trends Mol Med 16(5):238–246, 2010;
Gist S et al: Wound care in the geriatric client, Clin Interv Aging 4:269–287, 2009; Jaul E: Non-healing wounds: the geriatric approach, Arch
­Gerontol Geriatr 49(2):224–246, 2009; Shaw AC et al: Aging of the innate immune system, Curr Opin Immunol 22(4):507–513, 2010.

DID YOU UNDERSTAND?

Human Defense Mechanisms Plasma Protein Systems
1. There are three layers of human defense: barriers; innate immunity, which . Inflammation is mediated by three key plasma protein systems: the comple-
1
includes the inflammatory response; and adaptive (acquired) immunity. ment system, the clotting system, and the kinin system. The components
of all three systems are a series of inactive proteins that are activated
Physical and Mechanical Barriers sequentially.
1. Physical and mechanical barriers are the first lines of defense that prevent 2. The complement system can be activated by antigen-antibody reactions
damage to the individual and prevent invasion by pathogens; these include (through the classical pathway) or by other products, especially bacterial
the skin and mucous membranes. polysaccharides (through the lectin pathway or the alternative pathway),
resulting in the production of biologically active fragments and destruction of
Biochemical Barriers cells.
1. Antibacterial peptides in mucous secretions, perspiration, saliva, tears, 3. The most biologically potent products of the complement system are C3b
and other secretions provide a biochemical barrier against pathogenic (opsonin), C3a (anaphylatoxin), and C5a (anaphylatoxin, chemotactic factor).
microorganisms. 4. The clotting system stops bleeding, localizes microorganisms, and provides a
2. The normal bacterial flora provides protection by releasing chemicals that meshwork for repair and healing.
prevent colonization by pathogens. 5. Bradykinin is the most important product of the kinin system and causes vas-
cular permeability, smooth muscle contraction, and pain.
The Inflammatory Process
1. Inflammation is a rapid and nonspecific protective response to cellular injury Cellular Components of Inflammation
from any cause. It can occur only in vascularized tissue. 1. Many different types of cells are involved in the inflammatory process includ-
2. The macroscopic hallmarks of inflammation are redness, swelling, heat, pain, ing mast cells, endothelial cells, platelets, phagocytes (neutrophils, eosinophils,
and loss of function of the inflamed tissues. monocytes and macrophages, dendritic cells), natural killer (NK) cells, and
3. The microscopic hallmark of inflammation is an accumulation of fluid and lymphocytes.
cells at the inflammatory site.
 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing 139

DID YOU UNDERSTAND?—cont’d

2. Most cells express plasma membrane pattern recognition receptors (PRRs) 6. Opsonins, such as antibody and complement component C3b, coat microor-
that recognize molecules produced by infectious microorganisms (pathogen- ganisms and make them more susceptible to phagocytosis by binding them
associated molecular patterns, or PAMPs), or products of cellular damage more tightly to the phagocyte.
(damage-associated molecular patterns, or DAMPs).
Local Manifestations of Acute Inflammation
Cellular Products 1. Local manifestations of inflammation are the result of the vascular changes
1. The cells of the innate immune system secrete many biochemical mediators associated with the inflammatory process, including vasodilation and
(cytokines) that are responsible for activating other cells; these cytokines increased capillary permeability. The symptoms include redness, heat, swell-
include interleukins, chemokines, interferons, and other molecules. ing, and pain.
2. The most important proinflammatory cytokines are interleukin-1 (IL-1), inter-
leukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Systemic Manifestations of Acute Inflammation
3. Interferons are produced by cells that are infected by viruses. Once released 1. The principal systemic effects of inflammation are fever and increases in lev-
from infected cells, interferons can stimulate neighboring healthy cells to els of circulating leukocytes (leukocytosis) and plasma proteins (acute-phase
produce substances that prevent viral infection. reactants).
4. Chemokines are synthesized by a number of different cells and induce leuko-
cyte chemotaxis. Chronic Inflammation
1. Chronic inflammation can be a continuation of acute inflammation that lasts
Mast Cell 2 weeks or longer. It also can occur as a distinct process without much pre-
1. The most important activator of the inflammatory response is the mast cell, ceding acute inflammation.
which initiates inflammation by releasing biochemical mediators (histamine, 2. Chronic inflammation is characterized by a dense infiltration of lymphocytes
chemotactic factors) from preformed cytoplasmic granules and synthesizing and macrophages. The body may wall off and isolate the infection to protect
other mediators (prostaglandins, leukotrienes) in response to a stimulus. against tissue damage by formation of a granuloma.
2. Histamine is the major vasoactive amine released from mast cells. It causes
dilation of capillaries and retraction of endothelial cells lining the capillaries, Wound Healing
which increases vascular permeability. 1. Resolution (regeneration) is the return of tissue to nearly normal structure
and function. Repair is healing by scar tissue formation.
Endothelium and Platelets 2. Damaged tissue proceeds to resolution (restoration of the original tissue
1. The endothelial cells lining the circulatory system (vascular endothelium) structure and function) if little tissue has been lost or injured tissue is capa-
normally regulate circulating components of the inflammatory system and ble of regeneration. This is called healing by primary intention.
maintain normal blood flow by preventing spontaneous activation of plate- 3. Tissues that sustained extensive damage or those incapable of regeneration
lets and members of the clotting system. heal by the process of repair resulting in the formation of a scar. This is called
2. During inflammation the endothelium expresses receptors that help leuko- healing by secondary intention.
cytes leave the vessel and retract to allow fluid to pass into the tissues. 4. Resolution and repair occur in two separate phases: the reconstructive phase
3. Platelets interact with the coagulation cascade to stop bleeding and release in which the wound begins to heal and the maturation phase in which the
a number of mediators that promote and control inflammation. healed wound is remodeled.
5. Dysfunctional wound healing can be related to ischemia, excessive bleed-
Phagocytes ing, excessive fibrin deposition, a predisposing disorder (such as diabetes
1. The polymorphonuclear neutrophil (PMN), the predominant phagocytic cell in mellitus), wound infection, inadequate nutrients, numerous drugs, or altered
the early inflammatory response, exits the circulation by diapedesis through collagen synthesis.
the retracted endothelial cell junctions and moves to the inflammatory site 6. Dehiscence is a disruption in which the wound pulls apart at the suture
by chemotaxis. line.
2. Eosinophils release products that control the inflammatory response and are 7. A contracture is a deformity caused by the excessive shortening of collagen
the principal cell that kills parasitic organisms. in scar tissue.
3. The macrophage, the predominant phagocytic cell in the late inflammatory
response, is highly phagocytic, responsive to cytokines, and promotes wound PEDIATRIC CONSIDERATIONS: Age-Related Factors
healing. Affecting Innate Immunity in the Newborn Child
4. Dendritic cells connect the innate and acquired immune systems by collect- 1. Neonates often have transiently depressed inflammatory function, par-
ing antigens at the site of inflammation and transporting them to sites, such ticularly neutrophil chemotaxis and alternative complement pathway
as the lymph nodes, where immunocompetent B and T cells reside. activity.
5. Phagocytosis is a multistep cellular process for the elimination of pathogens
and foreign debris. The steps include recognition and attachment, engulf- GERIATRIC CONSIDERATIONS: Age-Related Factors
ment, formation of a phagosome and phagolysosome, and destruction of Affecting Innate Immunity in the Elderly
pathogens or foreign debris. Phagocytic cells engulf microorganisms and 1. Elderly persons are at risk for impaired wound healing, usually because of
enclose them in phagocytic vacuoles (phagolysosomes), within which toxic chronic illnesses.
products (especially metabolites of oxygen) and degradative lysosomal
enzymes kill and digest the microorganisms.
140 CHAPTER 5  Innate Immunity: Inflammation and Wound Healing

 KEY TERMS
•  bscess  132
A •  pithelialization  134
E • N eutrophil chemotactic factor
• Acute inflammation  132 • Epithelioid cell  134 (NCF)  127
• Acute-phase reactant  133 • Exudate  132 • Nitric oxide (NO)  129
• Adaptive immunity  118 • Fc receptor  132 • Normal flora  120
• Alternative pathway  124 • Fever  132 • Opportunistic microorganism  120
• Anaphylatoxin  123 • Fibrinolytic system  124 • Opsonin  123
• Angiogenesis factor  135 • Fibrinous exudate  132 • Opsonization  131
• Antimicrobial peptide  119 • Fibroblast  136 • Pathogen-associated molecular pattern
• α1-Antitrypsin  132 • Giant cell  134 (PAMP)  125
• Basophil  127 • Granulation tissue  135 • Pattern recognition receptor (PRR)  125
• Blood clot  124 • Granuloma  134 • Phagocyte  131
• Bradykinin  124 • Hageman factor (factor XII)  124 • Phagocytosis  131
• C1 esterase inhibitor (C1-inh)  124 • Hemorrhagic exudate  132 • Phagolysosome  132
• C1-inh deficiency  124 • Hereditary angioedema  124 • Phagosome  132
• Carboxypeptidase  124 • Hexose-monophosphate shunt  132 • Plasma protein system  122
• Cathelicidin  119 • Histaminase  124 • Plasmin  124
• Chemokine  127 • Histamine  127 • Plasminogen  124
• Chemotactic factor  123 • Hypertrophic scar  137 • Platelet  129
• Chemotaxis  131 • Inflammation  121 • Platelet-activating factor (PAF)  129
• Chronic inflammation  133 • Inflammatory phase  135 • Primary intention  134
• Classical pathway  123 • Inflammatory response  118 • Proliferative phase  135
• Clotting (coagulation) system  124 • Innate immunity  118 • Prostacyclin (PGI2)  129
• Collagen  136 • Interferon (IFN)  127 • Prostaglandin  129
• Collectin  119 • Interleukin (IL)  126 • Purulent (suppurative) exudate  132
• Complement receptor  125 • Interleukin-1 (IL-1)  126 • Pyrogen  132
• Complement system  122 • Interleukin-6 (IL-6)  126 • Regeneration  134
• Contact activation (intrinsic) • Interleukin-10 (IL-10)  127 • Repair  134
pathway  124 • Keloid  137 • Resolution  134
• Contraction  134 • Kinin system  124 • Scar tissue  134
• Contracture of scar tissue  137 • Lectin pathway  124 • Secondary intention  134
• Cyst  132 • Leukocytosis  132 • Serous exudate  132
• Cytokine  125 • Leukotriene (slow-reacting substance of • T lymphocyte  131
• Damage-associated molecular pattern anaphylaxis [SRS-A])  129 • Tissue factor (extrinsic) pathway  124
(DAMP)  125 • Lymphocyte  125 • Tissue factor (TF; tissue
• Defensin  119 • Lysozyme  119 thromboplastin)  124
• Degranulation  127 • Macrophage  129 • Toll-like receptor (TLR)  125
• Dehiscence  137 • Mannose-binding lectin (MBL)  119 • Transforming growth factor  127
• Dendritic cell  131 • Margination (pavementing)  131 • Transforming growth factor-beta
• Diapedesis  131 • Mast cell  127 (TGF-β)  127
• Endogenous pyrogen  132 • Matrix metalloproteinase (MMP)  135 • Tumor necrosis factor-alpha
• Endothelial cell  129 • Monocyte  129 (TNF-α)  126
• Eosinophil  131 • Myofibroblast  136 • Wound contraction  136
• Eosinophil chemotactic factor of • Neutrophil (polymorphonuclear
­anaphylaxis (ECF-A)  127 ­neutrophil [PMN])  129

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CHAPTER

6
Adaptive Immunity
Neal S. Rote

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

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• Review Questions and Answers • Critical Thinking Questions with Answers
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CHAPTER OUTLINE
Third Line of Defense: Adaptive Immunity, 142 Immune Response: Collaboration of B Cells and T Cells, 152
Humoral and Cellular Immunity, 143 Generation of Clonal Diversity, 152
Active and Passive Immunity, 143 Clonal Selection, 153
Antigens and Immunogens, 144 T Lymphocyte Functions, 160
Humoral Immune Response, 146 PEDIATRIC CONSIDERATIONS: Age-Related Factors Affecting
Antibodies, 146 Mechanisms of Self-Defense in the Newborn Child, 162
Cell-Mediated Immunity, 152 GERIATRIC CONSIDERATIONS: Age-Related Factors Affecting
T Lymphocytes, 152 Mechanisms of Self-Defense in the Elderly, 162

The third line of defense in the human body is adaptive (acquired) specific (among many pathogens a unique pathogen is identified
immunity, often called the immune response or immunity. Once and eliminated) and has memory, conferring a permanent or long-
external barriers have been compromised and inflammation (innate term protection against specific microorganisms. Many compo-
immunity, see Chapter 5) has been activated, the adaptive immune nents of innate resistance are necessary for the development of the
response is called into action. adaptive immune response. Conversely, products of the adaptive
It develops more slowly than the inflammatory response and is spe- immune response activate components of innate resistance. Thus,
cific (compared to inflammation that is nonspecific) and has memory. both systems are essential for complete protection against infec-
Adaptive immunity serves two purposes: destroying infectious micro- tious disease.
organisms that are resistant to inflammation and providing long- The immune system is capable of identifying substances that are
term highly effective protection against future exposure to the same foreign, or nonself. In general, substances that react with molecules
microorganism. of the immune system (antibodies, receptors on B and T cells) are
Genetic or acquired deficiencies in components of the innate or called antigens. Antigens are on infectious agents (e.g., viruses, bac-
adaptive immune systems may prevent an effective protective response. teria, fungi, or parasites), on noninfectious substances from the envi-
Many of these defects are discussed in Chapter 7. ronment (e.g., pollens, foods, or bee venoms), or on drugs, vaccines,
transfusions, and transplanted tissues (Table 6-1).
The products of the adaptive immune response include a type of
THIRD LINE OF DEFENSE: ADAPTIVE IMMUNITY serum protein—immunoglobulins (Ig) or antibodies—and a type
The third line of defense is adaptive (acquired) immunity, often of blood cell—lymphocytes (Figure 6-1). Before birth, humans pro-
called the immune response.1 It is inducible (must recognize the duce a large population of T lymphocytes (T cells, T indicates thy-
pathogen as foreign or “nonself”) and thus develops more slowly mus) and B lymphocytes (B cells, B indicates bone marrow derived)
than the inflammatory response. The immune response is also that have the capacity to recognize almost any foreign antigen found

142
 CHAPTER 6  Adaptive Immunity 143

TABLE 6-1 CLINICAL USE OF ANTIGEN OR ANTIBODY

USE OF ANTIGEN OR ANTIBODY
ANTIGEN PROTECTION: COMBAT PROTECTION:
SOURCE ACTIVE DISEASE VACCINATION DIAGNOSIS THERAPY
Infectious Neutralize or destroy pathogenic Induce safe and protective Measure circulating antigen from Passive treatment with antibody to
agents microorganisms (e.g., antibody immune response (e.g., infectious agent or antibody (e.g., treat or prevent infection (e.g.,
response against viral infections) recommended childhood diagnosis of hepatitis B infection) administration of antibody against
vaccines) hepatitis A)
Cancers Prevent tumor growth or spread Prevent cancer growth or Measure circulating antigen (e.g., Immunotherapy (e.g., treatment of
(e.g., immune surveillance to spread (e.g., vaccination circulating PSA for diagnosis of cancer with antibodies against
prevent early cancers) with cancer antigens) prostate cancer) cancer antigens)
Environmental Prevent entrance into body (e.g., No clear example Measure circulating antigen or Immunotherapy (e.g., administration
substances secretory IgA limits systemic antibody (e.g., diagnosis of allergy of antigen for desensitization of
exposure to potential allergens) by measuring circulating IgE) individuals with severe allergies)
Self-antigens Immune system tolerance to self- Some cases of vaccination Measure circulating antibody Oral administration of self-antigens
antigens, which may be altered alter tolerance to self-anti- against self-antigen for diagnosis to diminish production of autoim-
by an infectious agent leading gens, leading to autoimmune of autoimmune disease (see mune disease associated autoan-
to autoimmune disease (see disease Chapter 7) tibodies
Chapter 7)

PSA, Prostate-specific antigen.

Humoral and Cellular Immunity

Adaptive immunity or the immune response has two components:
antibodies and T cells, both of which protect against infection (Figure
6-3).2 Antibodies are proteins that are produced by B cells, circulate in
the blood, and bind to antigens on infectious agents. This interaction
can result in direct inactivation of the microorganism or activation of
a variety of inflammatory mediators that will destroy the pathogen.
Antibodies are primarily responsible for protection against many bac-
teria and viruses. This arm of the immune response is termed humoral
immunity.
T cells are a subset of lymphocytes that undergo differentiation
during an immune response and develop into several subpopulations
of effector T cells that have an effect on many other cells. Some develop
into T-cytotoxic (Tc) cells that attack and kill targets directly. Targets
for Tc cells include cells infected by viruses, as well as cells that have
become cancerous. Others may develop into T cells that can stimu-
late the activities of other leukocytes through cell-to-cell contact or
FIGURE 6-1  Lymphocytes. A scanning electron micrograph show-
ing lymphocytes (yellow, like cotton candy), red blood cells, and through the secretion of cytokines. This arm of the immune response
platelets. (Copyright Dennis Kunkel Microscopy, Inc.) is termed cellular, or cell-mediated, immunity.
The success of an acquired immune response depends on the func-
tions of both the humoral and cellular responses, as well as the appro-
in the environment. Each individual T or B cell, however, specifically priate interactions between them. The collaboration between B cells
recognizes only one particular antigen, but the sum of the population and a subset of T cells (T-helper cells, Th cells) is essential for almost all
of lymphocyte specificities may represent millions of foreign antigens. antibody responses to antigens. Additionally, both arms produce spe-
This process is called the generation of clonal diversity and occurs in cialized subpopulations of memory cells, which are capable of remem-
specialized (primary) lymphoid organs (see Figure 6-3). While passing bering the specific antigen and responding more rapidly and efficiently
through these organs, the lymphocytes mature and undergo changes against future infections.
that commit them to either B or T cells. Lymphocytes are released from
these organs into the circulation as immature cells that react with anti- Active and Passive Immunity
gens (immunocompetent). These cells migrate to other (secondary) Adaptive immunity can be either active or passive, depending on
lymphoid organs in the body in preparation for exposure to antigens whether the antibodies or T cells are produced by the individual in
(Figure 6-2). response to antigens or are administered directly to the individual.
The lymphocytes remain dormant until antigen initiates the second Active acquired immunity (active immunity) is produced by an indi-
phase of the immune response, clonal selection (see Figure 6-3). This vidual either after natural exposure to antigens or after immuniza-
process involves a complex interaction among cells, discussed further tion, whereas passive acquired immunity (passive immunity) does
in the section titled Immune Response: Collaboration of B Cells and not involve the host’s immune response at all. Rather, passive immu-
T Cells. nity occurs when preformed antibodies or T cells are transferred from
144 CHAPTER 6  Adaptive Immunity

Adenoid
Tonsils Peripheral
Lymph nodes

Central Thymus Lymphatic vessels

Lymph nodes

Spleen Peripheral

Lymph nodes
Peyer patches in jejunum
Peripheral
(ileum only)
Lymph nodes

Bone
Central
marrow

FIGURE 6-2  Lymphoid Tissues: Sites of B Cell and T Cell Differentiation. Immature lymphocytes
migrate through central (primary) lymphoid tissues: the bone marrow (central lymphoid tissue for B
lymphocytes) and the thymus (central lymphoid tissue for T lymphocytes). Mature lymphocytes later
reside in the T and B lymphocyte–rich areas of the peripheral (secondary) lymphoid tissues.

a donor to the recipient. This can occur naturally, as during preg- Certain criteria influence the degree to which an antigen is immu-
nancy when maternal antibodies cross the placenta to the fetus, or nogenic. These include (1) foreignness to the host, (2) adequate
artificially, as when antibodies are injected to fight against a specific size, and (3) being present in a sufficient quantity. These criteria are
disease.3,4 For instance, unvaccinated individuals who are exposed important for development of vaccines, which must be highly immu-
to particular infectious agents (e.g., hepatitis A virus, rabies virus) nogenic to produce protective immune responses against pathogenic
often will be given immune globulins, which are prepared from indi- microorganisms.
viduals who already have antibodies against that particular pathogen. Foremost among the criteria for immunogenicity is the antigen’s
Whereas active acquired immunity is long lived, passive immunity is foreignness. A self-antigen that fulfills all the criteria listed previously
only temporary because the donor’s antibodies or T cells are eventu- except foreignness does not normally elicit an immune response. Thus,
ally destroyed. most individuals are tolerant to their own antigens. Some pathogens are
successful because they develop the capacity to mimic self-antigens and
avoid inducing an immune response. In Chapter 7 we discuss specific
ANTIGENS AND IMMUNOGENS diseases resulting from a breakdown of tolerance that leads to an individ-
Although the terms antigen and immunogen are commonly used as ual’s immune system attacking its own antigens (autoimmune diseases).
synonyms, there are important differences between the two. Whereas Molecular size also contributes to an antigen’s immunogenicity. In
an antigen, a molecule or molecular fragment (i.e., proteins or carbo- general, large molecules (those bigger than 10,000 daltons), such as
hydrates), can bind with antibodies or antigen receptors on B and T proteins, polysaccharides, and nucleic acids, are most immunogenic.
cells, a molecule that will induce an immune response is an immuno- Many low-molecular-weight molecules can function as haptens, anti-
gen. Thus all immunogens are antigens but not all antigens are immu- gens that are too small to be immunogens by themselves but become
nogens and some clinically important conditions arise when particular immunogenic after combining with larger molecules that function as
antigens are not immunogenic. For example, urushiol is a toxin found carriers for the hapten. For example, the antigens of poison ivy are
in poison ivy and is a very small antigen (called a hapten) but not haptens, but they initiate allergic responses in individuals after binding
immunogenic. Several of these types of conditions will be discussed to large-molecular-weight proteins in the skin. Antigens that induce an
in Chapter 7. allergic response are also called allergens.
 CHAPTER 6  Adaptive Immunity 145

GENERATION OF CLONAL SELECTION

CLONAL DIVERSITY
Selection, proliferation, and differentiation of individual
Production of T and B cells T and B cells with receptors for a specific antigen
with all possible receptors for antigen

CELLULAR
IMMUNITY
Immunocompetent
T cell Antigen T regulatory
cell
APC Cytotoxic
T cell
Thymus
Memory
T cell

Lymphoid Immunocompetent
stem cell B cell Th cell Memory
B cell
Bone
marrow
Secondary Plasma
Bone lymphoid organs cell
marrow
HUMORAL
Central lymphoid
IMMUNITY
organs
Antibody
FIGURE 6-3  Overview of the Immune Response. The immune response can be separated into two
phases: the generation of clonal diversity and clonal selection. During the generation of clonal diver-
sity, lymphoid stem cells from the bone marrow migrate to the central lymphoid organs (the thymus
or regions of the bone marrow), where they undergo a series of cellular division and differentiation
stages resulting in either immunocompetent T cells from the thymus or immunocompetent B cells
from the bone marrow. These cells are still naïve in that they have never encountered foreign anti-
gen. The immunocompetent cells enter the circulation and migrate to the secondary lymphoid organs
(e.g., spleen and lymph nodes), where they establish residence in B and T cell–rich areas. The clonal
selection phase is initiated by exposure to foreign antigen. The antigen is usually processed by antigen-
presenting cells (APCs) for presentation to T-helper cells (Th cells). The intercellular cooperation among
APCs, Th cells, and immunocompetent T and B cells results in a second stage of cellular proliferation
and differentiation. Because antigen has “selected” those T and B cells with compatible antigen recep-
tors, only a small population of T and B cells undergo this process at one time. The result is an active
cellular immunity or humoral immunity, or both. Cellular immunity is mediated by a population of effec-
tor T cells that can kill targets (T-cytotoxic cells) or regulate the immune response (T-regulatory cells),
as well as a population of memory cells (T-memory cells) that can respond more quickly to a second
challenge with the same antigen. Humoral immunity is mediated by a population of soluble proteins
(antibodies) produced by plasma cells and by a population of memory B cells that can produce more
antibody rapidly to a second challenge with the same antigen.

Finally, antigens that are present in extremely small or large quanti- by one route, but may be less protected if administered through a dif-
ties may be unable to elicit an immune response. In many cases, high ferent route (e.g., oral versus injected polio vaccines, discussed later in
or low extremes of antigen quantities may induce a state of tolerance this chapter under Secretory Immune System). Immunogenicity of an
rather than immunity. antigen also may be altered by being delivered along with substances
Even if an antigen fulfills all these criteria, the quality and intensity that stimulate the immune response; these substances are known as
of the immune response may still be affected by a variety of additional adjuvants. Finally, the genetic makeup of the individual can play a crit-
factors. For example, the route of antigen entry or administration is ical role in the immune system’s ability to respond to many antigens.
critical to the immunogenicity of some antigens. This has important Some individuals appear to be unable to respond to immunization
clinical implications. The most common routes for clinical adminis- with a particular antigen, whereas they respond well to other antigens.
tration of antigens are intravenous, intraperitoneal, subcutaneous, For instance, a small percentage of the population may fail to produce
intranasal, and oral. Each route preferentially stimulates a different set a measurable immune response to a common vaccine, despite multiple
of lymphocyte-containing (lymphoid) tissues and therefore results in injections. An individual’s immune response can also be affected by
the induction of different types of cell-mediated or humoral immune age, nutritional status, genetic background, and reproductive status, as
responses. For some vaccines, the route may affect the protectiveness of well as exposure to traumatic injury, concurrent disease, or the use of
the immune response so that the individual is protected if immunized immunosuppressive medications.
146 CHAPTER 6  Adaptive Immunity

4 QUICK CHECK 6-1

and function (Table 6-2 and Figure 6-4). Within two of the immuno-
globulin classes are several distinct subclasses: four subclasses of IgG
1. Define acquired immunity.
and two subclasses of IgA.
2. Distinguish between innate and acquired immunity.
3. Distinguish between humoral and cell-mediated immunity. Classes of Immunoglobulins
4. What are the differences among antigens, immunogens, and haptens?
IgG is the most abundant class of immunoglobulins, constituting 80%
to 85% of the immunoglobulins in the blood and accounting for most
of the protective activity against infections. As a result of selective
HUMORAL IMMUNE RESPONSE transport across the placenta, maternal IgG is the major class of anti-
body found in blood of the fetus and newborn. Four subclasses of IgG
Antibodies have been described: IgG1, IgG2, IgG3, and IgG4.
An antibody, or immunoglobulin (Ig), is a serum glycoprotein pro- IgA has two subclasses: IgA1 and IgA2. IgA1 is found predomi-
duced by plasma cells that mature from lymphocytes, called B lym- nantly in the blood, whereas IgA2 is the predominant class found in
phocytes (B cells), in response to an antigen.5 Although B cells develop body secretions (secretory IgA). Secretory IgA is a dimer (a molecule
in the bone marrow of humans, a discrete organ (bursa of Fabricius) consisting of two identical smaller molecules) of two IgA molecules
for B cell maturation was originally discovered in chickens, resulting in held together through a J chain and secretory piece. The secretory piece
the term B cell. The term immunoglobulin (Ig) is generally used for is attached to IgA inside mucosal epithelial cells to protect these immu-
all antibodies, whereas the term antibody is mostly used to denote one noglobulins against degradation by enzymes also found in secretions.
particular set of immunoglobulins known to have specificity for a par- IgM is the largest immunoglobulin and usually exists as a pentamer
ticular antigen. There are five classes of immunoglobulins (IgG, IgA, (a molecule consisting of five identical smaller molecules) that is stabi-
IgM, IgE, and IgD), which are characterized by differences in structure lized by a J chain. It is the first antibody produced during the initial, or

TABLE 6-2 PROPERTIES OF IMMUNOGLOBULINS

ADULT SERUM PRESENT IN COMPLEMENT MAST CELL PLACENTAL
CLASS SUBCLASS LEVELS (mg/dl) SECRETIONS ACTIVATION OPSONIN AGGLUTININ ACTIVATION TRANSFER
IgG IgG1 800–900 + ++ ++ + − +++
IgG2 280–300 + + − + − +
IgG3 90–100 + +++ ++ + − +++
IgG4 50 − − − + + ++
IgM 120–150 + ++++ − ++++ − −
IgA IgA1 280–300 + − − + − −
IgA2 50 + − − + − −
sIgA 5 ++++ − − + − −
IgD 3 − − − − − −
IgE 0.03 + − − − +++ −

sIgA, Secretory immunoglobulin A; − indicates lack of activity; + to ++++ indicate relative activity or concentration.

J chain

Secretory IgD
piece (monomer)
Secretory IgA
(dimer with secretory piece)

J chain

IgE IgG IgM

(monomer) (monomer) (pentamer)
FIGURE 6-4  Structure of Different Immunoglobulins. Secretory IgA, IgD, IgE, IgG, and IgM. The
black circles attached to each molecule represent carbohydrate residues.
 CHAPTER 6  Adaptive Immunity 147

Sites of
FRs papain
digestion
VH
CDR1 CH1
CDR2 CH1 Fab
VL
CDR3 Hi
CL CL
CH2 CH2
Fc

Antigen- CH3
CH3
binding site
CDRs

A B
Fab Light chains

6
CDRs

Antigen-
Antigen-
binding
Heavy binding
site Carbohydrate
chains site
chain

V V
C C
BCR complex
TCR complex

  
 
TM TM
Ig Ig
ZAP70 CD3

D E
FIGURE 6-5  Molecular Structure of an Antibody and Other Antigen-Binding Molecules. Antigen-
binding molecules include antibody and cell-surface receptors. A, The typical antibody molecule con-
sists of two identical heavy chains and two identical light chains connected by interchain disulfide
bonds (— between chains in the figure). Each heavy chain is divided into three regions with relatively
constant amino acid sequences (CH1, CH2, and CH3) and a region with a variable amino acid sequence
(VH). Each light chain is divided into a constant region (CL) and a variable region (VL). The hinge region
(Hi) provides flexibility in some classes of antibody. Within each variable region are three highly variable
complementary-determining regions (CDR1, CDR2, CDR3) separated by relatively constant framework
regions (FRs). B, Fragmentation of the antibody molecule by limited digestion with the enzyme papain
has identified three important portions of the molecule: an Fc fragment (crystalline fragment that binds
complement and Fc receptors) and two identical Fab fragments (antigen-binding fragments). C, A
molecular model of a typical antibody molecule; the light chains are the strands of red spheres (each
represents an individual amino acid). As the antibody folds, the CDRs are placed in proximity to form
the antigen-binding site. D, The antigen receptor on the surface of B cells (BCR complex) is a mono-
meric antibody with a structure similar to that of circulating antibody, with an additional transmembrane
region (TM) that anchors the molecule to the cell surface. The active BCR complex contains molecules
(Igα and Igβ) that are responsible for intracellular signaling after the receptor has bound antigen. E, The
T cell receptor (TCR) consists of an α and a β chain joined by a disulfide bond. Each chain consists of
a constant region (Cα and Cβ) and a variable region (Vα and Vβ). Each variable region contains CDRs
and FRs in a structure similar to that of antibody. The active TCR is associated with several molecules
that are responsible for intracellular signaling. These include CD3, which is a complex of γ (gamma),
ε (epsilon), and δ (delta) subunits and a complex of two ζ (zeta) molecules. The ζ molecules are attached
to a cytoplasmic protein kinase (ZAP70) that is critical to intracellular signaling.
148 CHAPTER 6  Adaptive Immunity

primary, response to antigens. IgM is synthesized early in neonatal life,

and its synthesis may be increased as a response to infection in utero.
IgD is found in low concentrations in the blood. Its primary func-
tion is as an antigen receptor on the surface of early B cells.
IgE is normally at low concentrations in the circulation. It has very Epitope 1 Epitope 2
specialized functions as a mediator of many common allergic responses
(see Chapter 7) and in the defense against parasitic infections.

Molecular Structure
The parts of an antibody molecule were named based on studies A
using the enzyme papain to digest IgG. Three fragments resulted,
two of which were identical (Figure 6-5). The two identical fragments
retained the ability to bind antigen and were termed antigen-binding
fragments (Fab).5 The third fragment crystallized and was termed Epitope Side chains
the crystalline fragment (Fc). The Fab portions contain the recogni-
tion sites (receptors) for antigens and confer the molecule’s specificity
toward a particular antigen. The Fc portion is responsible for most of
the biologic functions of antibodies. Backbone
B
An immunoglobulin molecule consists of four polypeptide chains:
two identical light (L) chains and two identical heavy (H) chains. The
class of antibody is determined by which heavy chain is used: gamma
(γ, IgG), mu (μ, IgM), alpha (α, IgA), epsilon (ε, IgE), or delta (δ, IgD).
The light chains of an antibody molecule are of either the kappa (κ) or
the lambda (λ) type. The light and heavy chains are held together by
noncovalent bonds and covalent disulfide linkages. A set of disulfide
linkages between the heavy chains occurs in the hinge region and, in
some instances, lends a degree of flexibility at that site. An individ-
ual plasma cell produces only one type of H chain and one type of L Antigen
chain at a time; for instance, one plasma cell may produce only IgGκ,
whereas other plasma cells will be producing other classes of antibody Antibody
or the same class with the λ light chain. Antigen
Each L and H chain is further subdivided structurally into constant
(C) and variable (V) regions. The constant regions have relatively sta-
ble amino acid sequences within a particular immunoglobulin class or
subclass. Thus, the amino acid sequence of the constant region of one C
IgG1 should be almost identical with the sequence of the same region FIGURE 6-6  Antigenic Determinants (Epitopes). Generic exam-
of another IgG1, even if they react with different antigens. Conversely, ples of epitopes on protein (A) and polysaccharide (B) molecules
among different antibodies, the sequences of the variable regions are are shown. In A, an antigenic protein may have multiple different
characterized by a large number of amino acid differences. Therefore, epitopes (epitopes 1 and 2) that react with different antibodies.
two IgG1 molecules against different antigens will have many differ- Each sphere represents an amino acid with the red spheres rep-
ences in the amino acid sequence of their variable regions. The amino resenting epitope 1 and the yellow spheres representing epitope
acid differences are clustered into three areas in the variable region. 2. Individual epitopes may consist of eight or nine amino acids. In
These three areas were once called hypervariable regions but are now B, a polysaccharide is constructed of a backbone with branched
side chains. Each sphere represents an individual carbohydrate with
called complementary-determining regions (CDRs) (see Figure 6-5,
the red spheres representing the carbohydrates that form the epi­
A). The four regions surrounding the CDRs have relatively stable tope. In this example, two identical epitopes are shown that would
amino acid sequences and are called framework regions (FRs). bind two identical antibodies. In C, this ribbon model of an antibody
shows the heavy chains in blue and the light chains in red. Green
Antigen-Antibody Binding represents antigen molecules bound to each antigen-binding site.
Because antigens are relative small, a large molecule (e.g., protein, (C from Patton KT, Thibodeau GA: Anatomy & physiology, ed 7,
polysaccharide, nucleic acid) usually contains multiple and diverse St Louis, 2010, Mosby.)
antigens. The precise area of the molecule that is recognized by an
antibody is called its antigenic determinant, or epitope (Figure 6-6).
The matching portion on the antibody is sometimes referred to as the chemical nature of the particular amino acids in the CDRs and the
antigen-binding site, or paratope. The size of an antigenic determi- shape of the binding site (see Figure 6-5, A). The antigen that will bind
nant is generally only a few amino acids or sugar residues. most strongly must have complementary chemistry and topography
The antigen-binding site is formed by folding of an antibody mol- with the binding site formed by the antibody. The antigen fits into this
ecule so that the CDRs of the variable regions of both the heavy (VH) binding site with the specificity of a key into a lock and is held there by
and the light (VL) chains are moved into close proximity, resulting in noncovalent chemical interactions.
an antigen-binding site that is lined by the three CDRs of the heavy Because the heavy and light chains are identical within the same
chain and the three CDRs of the light chain (see Figure 6-5, C).5 The antibody molecule, the two binding sites are also identical and have
antibody’s specificity toward a particular antigen is determined by the specificity for the same antigen. The number of functional binding
 CHAPTER 6  Adaptive Immunity 149

Virus neutralization Toxin neutralization

Virus Bacterium

Bacterial
Virus toxin
DIRECT receptor

Phagocytosis
Complement-mediated
killing
Bacterium
MAC
INDIRECT C3b
Bacterium FcR
C3bR

Classic
C1 pathway

Macrophage

FIGURE 6-7  Direct and Indirect Functions of Antibody. Protective activities of antibodies can be
direct (through the action of antibody alone) or indirect (requiring activation of other components of
the innate immune response, usually through the Fc region). Direct means include neutralization of
viruses or bacterial toxins before they bind to receptors on the surface of the host’s cells. Indirect
means include activation of the classical complement pathway through C1, resulting in formation of the
membrane-attack complex (MAC), or increased phagocytosis of bacteria opsonized with antibody and
complement components bound to appropriate surface receptors (FcR and C3bR).

sites on a molecule is called its valence. Most antibody classes (i.e., IgG,
BOX 6-1 MONOCLONAL ANTIBODIES
IgE, IgD, and circulating IgA) have a valence of 2, but secretory IgA has
a valence of 4. IgM, being a pentamer, has a theoretic valence of 10, but Most humoral immune responses are polyclonal—that is, a mixture of anti-
it can simultaneously use only about five binding sites because antigen bodies produced from multiple B lymphocytes. Most antigenic molecules have
binding to one site blocks antigen binding to another site. multiple antigenic determinants, each of which induces a different group of
antibodies. Thus, a polyclonal response is a mixture of antibody classes, speci-
Function of Antibodies ficities, and function, some of which are more protective than others.
The chief function of antibodies is to protect against infection. The Monoclonal antibody is produced in the laboratory from one B cell that has
mechanism can be either direct or indirect (Figure 6-7). Directly, anti- been cloned; thus all the antibody is of the same class, specificity, and func-
bodies can affect infectious agents or their toxic products by neutral- tion. The advantages of monoclonal antibodies are that (1) a single antibody
ization (inactivating or blocking the binding of antigens to receptors), of known antigenic specificity is generated rather than a mixture of different
agglutination (clumping insoluble particles that are in suspension), antibodies; (2) monoclonal antibodies have a single, constant binding affinity;
or precipitation (making a soluble antigen into an insoluble precipi- (3) monoclonal antibodies can be diluted to a constant titer (concentration in
tate). Indirectly, antibodies activate components of innate resistance, fluid) because the actual antibody concentration is known; and (4) the antibody
including complement and phagocytes. Antibodies are generally a can be easily purified. Thus, a highly concentrated antibody with optimal func-
mixed population of classes, specificities, and capacity to provide the tion has been used to develop extremely specific and sensitive laboratory tests
functions previously listed. It is now a common procedure to clone the (e.g., home and laboratory pregnancy tests) and therapies (e.g., for certain
“best” antibodies (monoclonal antibodies) for use in diagnostic tests infectious diseases or several experimental therapies for cancer).
and for therapy (Box 6-1).
Direct effects. Many pathogens initiate infection by attaching to
specific receptors on cells. For instance, viruses that cause the common Some bacteria secrete toxins that harm individuals. For instance,
cold or the influenza virus must attach to specific receptors on respira- specific bacterial toxins cause the symptoms of tetanus or diphthe-
tory epithelial cells. Some bacteria, such as Neisseria gonorrhoeae that ria. Most toxins are proteins that bind to surface molecules on cells
causes gonorrhea, must attach to specific sites on urogenital epithelial and damage those cells. Protective antibodies can bind to the toxins,
cells. Antibodies may protect the host by covering sites on the microor- prevent their interaction with host cells, and neutralize their biologic
ganism that are needed for attachment, thereby preventing infection. effects. Detection of the presence of an antibody response against a
Many viral infections can be prevented by vaccination with inactivated specific toxin (antibodies referred to as antitoxins) can aid in the diag-
or attenuated (weakened) viruses to induce neutralizing antibody pro- nosis of diseases. For example, laboratory tests that detect antistrep-
duction at the site of the entrance of the virus into the body. tolysin O can be useful in diagnosing group A streptococcal infections.
150 CHAPTER 6  Adaptive Immunity

Mast cell degranulation

IgE

Antigen

Acute
Mast cell degranulation
inflammation

Antigen-antibody

C5a

other
Complement fragments
activation

Neutrophil chemotaxis
Antigen
T lymphocyte
Acute or
Lymphokines chronic
inflammation

Activation of
monocyte/macrophage
FIGURE 6-8  Immunologic Mechanisms That Activate the Inflammatory Response. Immunologic
factors may activate inflammation through three mechanisms: (1) IgE can bind to the surface of a mast
cell and, after binding antigen, induce the cell’s degranulation; (2) antigen and antibody can activate the
complement system, releasing anaphylatoxins and chemotactic factors, especially C5a, that result in
mast cell degranulation and neutrophil chemotaxis; and (3) antigen may also react with T lymphocytes,
resulting in the production of lymphokines that may contribute to the development of either acute or
chronic inflammation.

Indirect effects. Antibodies are protective by interacting with or

activating components of inflammation (Figure 6-8). The Fc portion is Eosinophil (diapedesis)
Endothelium
responsible for opsonic activity leading to enhanced phagocytosis and
activation of the complement system that may lead to destruction of
the pathogen or increased opsonic activity through deposition of C3b.
Eosinophil
IgE. IgE is a special class of antibody that protects the individual
from infection with large parasites. However, when IgE is produced 4
against relatively innocuous environmental antigens, it is also the pri- ECF-A
mary cause of common allergies (e.g., hay fever, dust allergies, bee 5 Mast cell

stings). The role of IgE in allergies is discussed in Chapter 7.

Large multicellular parasites usually invade mucosal tissues. Many
antigens from the parasites induce IgE, as well as other antibody 6
IgE
classes. IgG, IgM, and IgA bind to the surface of parasites, activate Parasite
3
complement, generate chemotactic factors for neutrophils and macro- Parasite
2
phages, and serve as opsonins for those phagocytic cells. This response, antigen
however, does not greatly damage parasites. The only inflammatory 1
cell that can adequately damage a parasite is the eosinophil because of
B Cell
the special contents of its granules, particularly major basic protein.6
Thus, IgE is designed to specifically initiate an inflammatory reaction FIGURE 6-9  IgE Function. (1) Soluble antigens from a parasitic
that preferentially attracts eosinophils to the site of parasitic infection infection cause production of IgE antibody by B cells. (2) Secreted
(Figure 6-9). IgE binds to IgE-specific receptors on the mast cell. (3) Additional
Mast cells in the tissues have Fc receptors that specifically and with soluble parasite antigen cross-links the IgE on the mast cell surface,
high affinity bind IgE. IgEs against antigens of the parasite are rapidly (4) leading to mast cell degranulation and release of many proin-
bound to the mast cell surface. Soluble parasite antigens with multiple flammatory products, including eosinophil chemotactic factor of
antigenic determinants diffuse to neighboring mast cells and simulta- anaphylaxis (ECF-A). (5) ECF-A attracts eosinophils from the circula-
neously bind to multiple IgE molecules. This reaction initiates mast tion. (6) The eosinophil attaches to the surface of the parasite and
cell degranulation and secretion of eosinophil chemotactic factor of releases potent lysosomal enzymes that damage microorganisms.
 CHAPTER 6  Adaptive Immunity 151

anaphylaxis (ECF-A). ECF-A is specifically chemotactic for eosino- Because of the extremely large size of typical parasites, engulfment is
phils, resulting in eosinophil migration from the circulation into the unsuccessful. The eosinophilic granules move to the cell membrane in
tissues as well as increased expression of surface receptors for IgG and contact with the parasite and undergo normal degranulation, releasing
complement component C3b.7 The eosinophil attaches to the surface major basic protein and other antimicrobial peptides onto the para-
of the parasite through these receptors and attempts phagocytosis. site’s surface. Being highly cationic, major basic protein acts almost

Lacrimal glands

Salivary glands

Bronchial-associated
lymphoid tissue Regional
Mucosal- lymph nodes
associated
Mammary-associated lymphoid tissue
lymphoid tissue

Gut-associated Blood
lymphoid tissue
(lymph nodes, Thoracic
Peyer patches) duct

Genital-associated
lymphoid tissue

Organized
Intraepithelial lymphoid tissues
Antibodies
Villus lymphocytes
(IgA) M cell

Intestinal
lumen Mucous
layer
Peyer Mucous
patch epithelium

Follicle

Afferent
Lymphatic lymphatic
Crypt
drainage
Lamina
propria

Mesenteric
lymph node
B
FIGURE 6-10  Secretory Immune System. A, Lymphocytes from the mucosal-associated lymphoid
tissues circulate throughout the body in a pattern separate from other lymphocytes. For example,
lymphocytes from the gut-associated lymphoid tissue circulate through the regional lymph nodes, the
thoracic duct, and the blood and return to other mucosal-associated lymphoid tissues rather than to
lymphoid tissue of the systemic immune system. B, Lymphoid tissue associated with mucous mem-
branes is called mucosal-associated lymphoid tissue (MALT).
152 CHAPTER 6  Adaptive Immunity

like sodium hydroxide and causes extensive damage to the parasite. CELL-MEDIATED IMMUNITY
The parasite will die if an adequate number of eosinophils are involved.
T Lymphocytes
Secretory Immune System Most lymphocytes are members of the acquired immune system. The
The entire body is protected by the systemic immune system. Another, B cells and plasma cells produce antibodies, whereas T lymphocytes
partially independent, immune system protects the external surfaces of (T cells) represent a large spectrum of cell types and functions. These
the body. This system is called the secretory (mucosal) immune sys- cell types include broadly T-cytotoxic (Tc) cells that attack antigens
tem (Figure 6-10).2 Antibodies in bodily secretions such as tears, sweat, directly and destroy cells that bear foreign antigens; regulatory cells,
saliva, mucus, and breast milk provide local protection against infec- primarily T-helper (Th) cells, that control both cell-mediated and
tious microorganisms. Pathogens can infect the body’s surfaces and humoral immune responses (including lymphokine-producing cells
possibly penetrate to cause systemic disease. Alternatively, the micro- that secrete cytokines that activate other cells, such as macrophages);
organisms may reside in the membranes without causing disease and and memory cells that remember an antigen that has been previously
be a source of infection for other individuals. Thus, an individual may seen by the immune system and induce a secondary immune response
become a carrier for a particular infectious organism. For instance, in that is much quicker than the initial (primary) immune response. T
the 1950s two vaccines were developed to prevent infection with polio cells are particularly important in protection against viruses, tumors,
virus, which enters through the gastrointestinal tract. The Sabin vac- and pathogens that are resistant to killing by normal neutrophils and
cine was administered orally as an attenuated (i.e., inactivated so as macrophages. They are also absolutely essential for the development of
to render relatively harmless) live virus. This route caused a transient, most humoral responses. Because both B cell and T cell functions pro-
limited infection and induced effective systemic and secretory immu- duce the effective immune response, the mechanisms governing these
nity that prevented both the disease and the establishment of a carrier functions will be discussed in the following section.
state. The Salk vaccine, on the other hand, consisted of killed viruses
administered by injection in the skin. It induced adequate systemic IMMUNE RESPONSE: COLLABORATION
protection but did not generally prevent an intestinal carrier state. OF B CELLS AND T CELLS
Thus, recipients of the Salk vaccine were protected from disease but
could still shed the virus and infect others. Generation of Clonal Diversity
IgA is the dominant secretory immunoglobulin, although IgM The immune response occurs in two phases: generation of clonal
and IgG also are present in secretions. The primary role of IgA is to diversity and clonal selection (Table 6-3 and see Figure 6-3). Before
prevent the attachment and invasion of pathogens through mucosal birth, humans produce a large population of T cells and B cells that
membranes, such as those of the gastrointestinal, pulmonary, and gen- have the capacity to recognize almost any foreign antigen found in the
itourinary tracts. Antibodies in secretions are produced by plasma cells environment (generation of clonal diversity). This process mostly
of the secretory (mucosal) immune system. occurs in specialized lymphoid organs (the primary [central] lym-
The B cells of the secretory immune system follow a different pat- phoid organs): the thymus for T cells and the bone marrow for B cells.
tern of migration through the body than cells of the systemic immune The result is the differentiation of lymphoid stem cells into B and T
system, residing in a different group of lymphoid tissues including the lymphocytes with the ability to react against almost any antigen that
lacrimal and salivary glands and the lymphoid tissues of the breasts, will be encountered throughout life. It is estimated that B and T cells
bronchi, intestines, and genitourinary tract. The lymphoid tissues of can collectively recognize more than 108 different antigenic determi-
the secretory immune system are connected; thus many foreign anti- nants. Lymphocytes are released from these organs into the circulation
gens in a mother’s gastrointestinal tract (e.g., polio virus) induce secre- as mature cells that have the capacity to react with antigens (immuno-
tion of specific IgAs, IgMs, and IgGs into the breast milk.8 Antibodies competent) and migrate to other (secondary) lymphoid organs in the
in the milk may protect the nursing newborn against these infectious body.
disease agents. Although colostral antibodies (i.e., found in colostrum
of breast milk) provide the newborn with passive immunity against Development of B Lymphocytes
gastrointestinal infections, they do not provide systemic immunity In birds, an organ called the bursa of Fabricius is responsible for the
because they do not cross the newborn’s gut into the bloodstream after maturation of B (bursal-derived) lymphocytes. Humans have no dis-
the first 24 hours of life. Maternal antibodies that pass across the pla- crete bursa, but the bone marrow makes up the human bursal equiva-
centa into the fetus before birth provide passive systemic immunity. lent and serves as the primary lymphoid organ for B cell development.

TABLE 6-3 GENERATION OF CLONAL DIVERSITY VS. CLONAL SELECTION

GENERATION OF CLONAL DIVERSITY CLONAL SELECTION
Purpose? To produce large numbers of T and B lymphocytes Select, expand, and differentiate clones of T and B cells against
with maximum diversity of antigen receptors specific antigen
When does it occur? Primarily in fetus Primarily after birth and throughout life
Where does it occur? Central lymphoid organs: thymus for T cells, bone Peripheral lymphoid organs, including lymph nodes, spleen, and
marrow for B cells other lymphoid tissues
Is foreign antigen involved? No Yes, antigen determines which clones of cells will be selected
What hormones or ­cytokines are involved? Thymic hormones, IL-7, others Many cytokines produced by Th cells and APCs
Final product? Immunocompetent T and B cells that can react Plasma cells that produce antibody, effector T cells that help
with antigen, but have not seen antigen, and (Th cells), kill targets (Tc cells), or regulate immune responses
migrate to secondary lymphoid organs (Treg cells); memory B and T cells

APCs, Antigen-presenting cells; Tc cells, T-cytotoxic cells; Th cells, T-helper cells; Treg cells, T-regulatory cells.
 CHAPTER 6  Adaptive Immunity 153

Lymphocytes destined to become B cells circulate through the bursal

equivalent, where they are exposed to hormones that, without the
4 QUICK CHECK 6-2
1. What are the major functions of antibodies?
presence of antigens, induce proliferation and differentiation into B
2. What is the difference between the secretory and systemic immune
cells. Each B cell, however, responds to only one specific antigen. They
systems?
exit the bone marrow and establish residence in other lymphoid organs
3. What are the different types of T cells, and what function does each have?
(secondary lymphoid organs) as immunocompetent B cells.

Development of T Lymphocytes
The process of T cell proliferation and differentiation is similar to Clonal Selection
that for B cells. The primary lymphoid organ for T cell development Antigens initiate the second phase of the immune response, clonal
is the thymus. Lymphoid stem cells journey through the thymus, selection. This process involves a complex interaction among cells in
where, under the pressure and guidance of thymic hormones (thy- the secondary lymphoid organs (see Figure 6-3). To initiate an effec-
mosin, thymopoietin, thymostimulin, and several other hormones tive immune response, most antigens must be processed: because they
produced by the epithelium), the cytokine IL-7, and without the cannot react directly with cells of the immune system the antigens
presence of antigens, they are driven to undergo cell division and must be shown or presented to the immune cells in a specific manner.
simultaneously produce receptors (T cell receptors [TCRs]) against This is the job of antigen-processing (antigen-presenting) cells (usu-
the diversity of antigens the individual will encounter throughout ally dendritic cells, macrophages, or similar cells), generally referred
life.9 They exit the thymus through the blood vessels and lymphatics to as APCs. The interaction among APCs, subpopulations of T cells
as mature (immunocompetent) T cells with antigen-specific recep- that facilitate immune responses (T-helper [Th] cells), and immuno-
tors on the cell surface and establish residence in secondary lymphoid competent B or T cells results in differentiation of B cells into active
organs. antibody-producing cells (plasma cells) and T cells into effector cells,

Invader

Engulfed by

Antigen-presenting
Primes by cell (APC)
presenting antigen

Presents antigen
Secretes IL-1
Antigen
Helper T cell primes

Cell division Cell division

Effector Memory
helper T cell helper T cell

Naïve cytotoxic T cell Naïve B cell

IL-2 IL-2

Cell division Cell division

Cell division Cell division

Plasma cells Memory B cells

Memory Effector
cytotoxic T cells cytotoxic T cells

Secrete
Antibodies

Carry out
Carry out
Cell-mediated
response Antibody-mediated
response

FIGURE 6-11  Summary of Adaptive Immunity This simplified flowchart summarizes an example of
adaptive immune responses when exposed to a microbial antigen. (From Patton KT, Thibodeau GA:
Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)
154 CHAPTER 6  Adaptive Immunity

Log of
Primary response Secondary response
antibody
titer

IgM
IgG

First Subsequent
exposure exposure
to antigen to same antigen

Relative time after exposure

FIGURE 6-12  Primary and Secondary Immune Responses. The initial administration of antigen
induces a primary response during which IgM is initially produced, followed by IgG. Another adminis-
tration of the antigen induces the secondary response in which IgM is transiently produced and larger
amounts of IgG are produced over a longer period of time.

such as T-cytotoxic cells. Both lines also develop into memory cells Cellular Interactions in the Immune Response
that respond even faster when that antigen enters the body again. Thus, Clonal selection generally occurs in lymphoid organs called the sec-
activation of the immune system produces a specific and long-lasting ondary (peripheral) lymphoid organs, in which antigens selectively
protection against specific antigens (Figure 6-11). Defects in any aspect react with B or T cells. The secondary lymphoid organs include the
of cellular collaboration will lead to defects in cell-mediated immunity, spleen, lymph nodes, adenoids, tonsils, Peyer patches (intestines),
humoral immunity, or both and, depending on the particular defect, and the appendix. Under the control of a variety of cytokines and
the individual’s death (Chapter 7). complex cellular interactions, the selected B or T cells further pro-
liferate and differentiate into plasma cells that produce antibodies,
Primary and Secondary Immune Responses T cells that can attack cellular targets, or B or T memory cells that
The immune response to antigens has classically been divided into two will respond more quickly to a second exposure to the same antigen.
phases—the primary and secondary responses—that are most easily B cell receptor for antigen. During differentiation into effector
demonstrated by measuring concentrations of circulating antibodies cells both T cells and B cells must react directly with antigens through
over time (Figure 6-12). After a single initial exposure to most antigens, antigen-specific receptors on the cell surface. The B cell receptor (BCR)
there is a latent period, or lag phase, during which antigen processing is a complex of antibody bound to the cell surface and other molecules
and B cell differentiation and proliferation occur. After approximately involved in intracellular signaling (see Figure 6-5, D). Its role is to recog-
5 to 7 days, IgM antibody is detected in the circulation. The lag phase nize an antigen and communicate that information to the cell’s nucleus.
is the time necessary for the process of clonal selection. This is the pri-
mary immune response, characterized typically by initial production
of IgM followed by production of IgG against the same antigen. The Repetitive
quantity of IgG may be about equal to or less than the amount of IgM. antigen
The amount of antibody in a serum sample is frequently referred to as
the titer; a higher titer indicates more antibodies. If no further expo- BCR
sure to the antigen occurs, the circulating antibody is catabolized (bro-
ken down) and measurable quantities fall. The individual’s immune
system, however, has been primed.
A second challenge by the same antigen results in the secondary IgM
immune response, which is characterized by the more rapid produc-
tion of a larger amount of antibody than the primary response. The
rapidity of the secondary immune response is the result of memory B cell Plasma cell
cells that do not require further differentiation. IgM may be tran-
FIGURE 6-13  Activation of a B Cell by a T Cell–Independent
siently produced in the secondary response, but IgG production is Antigen. Molecules containing repeating identical antigenic deter-
increased considerably, making it the predominant antibody class. minants may interact simultaneously with several receptors on the
If the antigenic challenge is in the form of a vaccine (e.g., polio) or surface of the B cell and induce the proliferation and production
occurs through natural infection (e.g., rubella), the level of protective of immunoglobulins. Because Th2 cells do not participate, class
IgG may remain elevated for decades. switch does not occur and the resultant antibody response is IgM.
 CHAPTER 6  Adaptive Immunity 155

The BCRs in immunocompetent cells are membrane-associated IgM directly stimulate B cell maturation and proliferation. These are called
and IgD immunoglobulins that have identical specificities. The IgM is a T cell–independent antigens (Figure 6-13). They are mostly bacterial
monomer rather than the pentamer primarily found in the blood. After products that are large and are likely to have repeating identical anti-
having reacted with antigens and undergoing differentiation, the BCR genic determinants that bind and cross-link several B cell receptors.
on the developing plasma cell may change to other classes of antibody. The accumulated intracellular signal is adequate to induce differentia-
Although most antigens require B cells to interact with Th cells, tion into a plasma cell but is not adequate to induce a change in the
a few antigens can bypass the need for cellular interactions and can class of antibody that will be produced. Therefore, T cell–independent

Chromosome 6 Chromosome 1
DP DQ DR C’ Cyto B C A D A C B E

         

Class II MHC Class I MHC CD1

Structure Two transmembrane Single transmembrane Single transmembrane

chains (α and β) chain (α) and β2- chain (α) and β2-
microglobulin microglobulin

Distribution B cells, APCs, and some All nucleated cells and APCs
epithelial cells platelets

Presents “Exogenous” antigens “Endogenous” antigens “Exogenous” lipid

derived from extracellular (8-10 amino acids) antigens derived from
organisms derived from intracellular extracellular organisms
proteins

Reacts with CD4 on Th cells CD8 on Tc cells Unknown

Antigenic Antigenic
Antigenic peptide lipid
peptide
1 1 2
domain domain S
1 domain S 2
1
domain S S domain
S domain
S S
S
2 2 3 S 3
domain domain S domain S S domain
2M S S
S S S 2M S
S S

FIGURE 6-14  Antigen-Presenting Molecules. Two sets of molecules are primarily responsible for
antigen presentation: MHC class I and MHC class II. The MHC molecules are encoded from the major
histocompatibility complex on chromosome 6. This region contains information for the α chains of three
principal class I molecules, called HLA-A, HLA-B, and HLA-C. These will be discussed in more detail in
Chapter 7. Each of the MHC class I α chains forms a complex with β2-microglobulin, which is encoded
by a gene on chromosome 15. The MHC class I molecules present small peptide antigens (eight or nine
amino acids in length) in a pocket formed by the α1 and α2 domains of the α chain. The conformation of
the molecule is stabilized by β2-microglobulin as well as by intrachain disulfide bonds. The α and β chains
of class II molecules are also encoded in the MHC region. The principal class II molecules are HLA-DR,
HLA-DP, and HLA-DQ. The MHC class II molecules present peptide antigens in a pocket formed by the
α1 domain of the α chain and the β1 domain of the β chain. Both MHC class I and class II molecules are
anchored to the plasma membrane by hydrophobic regions on the ends of the α and β chains.
156 CHAPTER 6  Adaptive Immunity

antigens usually induce relatively pure IgM primary and secondary MHC class I molecules present antigens that are endogenous—
immune responses. All other antigens must be processed and pre- antigens originating within the cell. Examples of endogenous anti-
sented to Th cells before an antibody response can occur. gens include antigens from viruses that infect cells and use the normal
Antigen processing and presentation. In most cases several steps cellular protein-synthesizing machinery to produce viral proteins
involving cellular interactions must occur to produce a protective and antigens that are uniquely produced by cancerous cells. Anti-
humoral or cellular immune response. Antigens that enter the blood- gens presented by MHC class I molecules are primarily recognized
stream or lymphatics encounter a variety of phagocytic cells, including by T-cytotoxic cells. Because MHC class I molecules are expressed
dendritic cells and macrophages, that phagocytose, break up (process), on all cells, except red blood cells, any change in that cell caused by
and present antigenic fragments.10 Although these cells are the principal viral infection or malignancy may result in foreign antigens being
APCs, almost every cell can present antigens to some degree. presented.
Antigen-presenting molecules. Processed antigens must be pre- MHC class II molecules present exogenous antigens—antigens
sented on the APC surface by specialized molecules, molecules of the that originate from outside the body (Figure 6-15). These antigens
major histocompatibility complex (MHC) (Figure 6-14). MHC mole- are found primarily on infectious microorganisms that must initially
cules are discussed in more detail in Chapter 7. Major histocompatibil- undergo phagocytosis. MHC class II molecules are co-expressed with
ity complex (MHC) molecules are glycoproteins found on the surface MHC class I on a limited number of cells that have APC function,
of all human cells except red blood cells. They are divided into two gen- including macrophages, dendritic cells, and B lymphocytes. A den-
eral classes, class I and class II, based on their molecular structure, dis- dritic cell is an antigen-presenting leukocyte that is found in the skin,
tribution among cell populations, and function in antigen presentation. mucosa, and lymphoid tissues and that initiates a primary immune
MHC class I molecules are composed of a large alpha (α) chain along response (Figure 6-16). Antigen presented by MHC class II molecules
with a smaller chain called β2-microglobulin. MHC class II molecules is preferentially recognized by T-helper cells.
are composed of α and β chains that differ from the ones used for MHC Thus, the term antigen processing relates to the process by which
class I. The α and β chains of the MHC molecules are encoded from dif- large exogenous and endogenous antigens are cut up by enzymes into
ferent genetic loci located as a large complex of genes on human chro- small antigenic fragments that are linked with the appropriate MHC
mosome 6 (β2-microglobulin is found on a different chromosome). molecules.

Antigenic peptides Invariant Class II MHC

from cytoplasm chain
Endogenous
antigen 1
processing Endoplasmic 5
reticulum 4
Phagolysosome
Class I
MHC 2

Exogenous
antigen
processing
7

6
Antigenic
fragments
3
8
Phagosome Bacterium

Cell
membrane
Phagocytosis
Class I Class II
MHC MHC
Bacterium
FIGURE 6-15  Antigen Processing. Antigen processing and presentation are required for initiation of
most immune responses. Foreign antigen may be either endogenous (cytoplasmic protein) or exoge-
nous (e.g., bacterium). Endogenous antigenic peptides are transported into the endoplasmic reticulum
(ER) (1), where the MHC molecules are being assembled. In the ER, antigenic peptides bind to the α
chains of the MHC class I molecule (2),  and the complex is transported to the cell surface (3).  The α
and β chains of the MHC class II molecules are also being assembled in the endoplasmic reticulum (4), 
but the antigen-binding site is blocked by a small molecule (invariant chain) to prevent interactions with
endogenous antigenic peptides. The MHC class II–invariant chain complex is transported to phagolyso-
somes (5)  where exogenous antigenic fragments have been produced as a result of phagocytosis (6). 
In the phagolysosomes, the invariant chain is digested and replaced by exogenous antigenic peptides
(7),  after which the MHC class II–antigen complex is inserted into the cell membrane (8). 
 CHAPTER 6  Adaptive Immunity 157

A B

Antigen Antigen capture Inflammatory Loss of DC

capture by dendritic cells (DC) cytokines adhesiveness

Immature DC
in epidermis
(Langerhans cell)

Migration
of DC

Maturation of
migrating DC

Afferent lymphatic vessel

Antigen Lymph
presentation node

Mature
dendritic cell
presenting
antigen to
T cells naive T cell

C
FIGURE 6-16  Dendritic Cells and Cell-Mediated Immunity. A, Dendritic cells are phagocytic antigen-
presenting cells (APCs) found in the skin, mucosa, and lymphoid tissues. B, Dendritic cells (Langerhans
cells) are marked by the blue stain in the epidermis. C, Dendritic cells capturing microbial antigens from
epithelia and transporting them to regional lymph nodes. The T cells are then activated to proliferate
and to differentiate into effector and memory cells, which migrate to sites of infection and promote
various functions in cell-mediated immunity. (A and B from Patton KT, Thibodeau GA: Anatomy & physi-
ology, ed 7, St Louis, 2010, Mosby; C from Kumar V, Abbas A, Fausto N: Robbins and Cotran pathologic
basis of disease, ed 7, Philadelphia, 2005, Saunders.)
158 CHAPTER 6  Adaptive Immunity

T cell receptor for antigen. T lymphocytes recognize processed CD molecules is constantly increasing (currently in excess of 250). We
antigens using a receptor that is similar to the B cell receptor. The T will focus on a small number of highly important examples to illustrate
cell receptor (TCR) complex is composed of an antibody-like pro- the immensely complicated, but highly effective, interactions that take
tein (TCR) and a group of accessory proteins that are involved in place to produce a protective immune response.
signaling to the nucleus (see Figure 6-5, E). Although the compo- T-helper lymphocytes. Regardless of whether an antigen primarily
nents of the TCR resemble antibody, they are encoded by different induces a cellular or humoral immune response, APCs usually must
genes. All of the TCRs on a single T cell are identical in structure and present antigens to T-helper cells (Th cells). This extremely important
specificity. role involves three distinct steps: (1) the Th cell directly interacts with
CD molecules. Cellular cooperation to produce an immune the APC through a variety of antigen-specific and antigen-indepen-
response requires a large array of accessory molecules. Many accessory dent mechanisms; (2) the Th cell undergoes a differentiation process
molecules are part of a nomenclature that uses the prefix CD (cluster during which a variety of cytokine genes are activated; and (3) depend-
of differentiation) followed by a number (e.g., CD1 or CD2). The list of ing on the pattern of cytokines expressed, the mature Th cell interacts

1 TNF-β Cellular
IL-12 IL-2 immunity
IFN-γ IFN-γ
APC Th1 cell

2
IL-4
IL-5 Humoral
Th2 cell IL-6 immunity
IL-4
MHC
Class II
Thp-cell
TCR CD4
IL-1 IL-17
IL-21 Inflammation
IL-6
TGF-β Th17 cell IL-22
IL-2

Suppress
TGF-β immune
IL-2 response
IL-2
Treg cell
TGF-β

FIGURE 6-17  Development of T Cell Subsets. The most important step in clonal selection is the
production of populations of T-helper (Th) cells (Th1, Th2, and Th17) and T-regulatory (Treg) cells that
are necessary for the development of cellular and humoral immune responses. In this model, APCs (1)
(probably multiple populations) may influence whether a precursor Th cell (Thp cell) (2) will differenti-
ate into a Th1, Th2, Th17, or Treg cell (3). Differentiation of the Thp cell is initiated by three signaling
events. The antigen signal is produced by the interaction of the T cell receptor (TCR) and CD4 with anti-
gen presented by MHC class II molecules. A set of co-stimulatory signals is produced from interactions
between adhesion molecules (not shown). A third signal is produced by the interactions of cytokines
(particularly interleukin-1 [IL-1]) with appropriate cytokine receptors (IL-1R) on the Thp cell. The Thp
cell up-regulates IL-2 production and expression of the IL-2 receptor (IL-2R), which acts in an autocrine
fashion to accelerate Thp cell differentiation and proliferation. Commitment to a particular phenotype
results from the relative concentrations of other cytokines. IL-12 and IFN-γ produced by some popula-
tions of APCs favor differentiation into the Th1 cell phenotype; IL-4, which is produced by a variety of
cells, favors differentiation into the Th2 cell phenotype; IL-6 and TGF-β (T cell growth factor) facilitate
differentiation into Th17 cells; IL-2 and TGF-β induce differentiation into Treg cells. The Th1 cell is char-
acterized by the production of cytokines that assist in the differentiation of T-cytotoxic (Tc) cells, lead-
ing to cellular immunity, whereas the Th2 cell produces cytokines that favor B cell differentiation and
humoral immunity. Th1 and Th2 cells affect each other through the production of inhibitory cytokines:
IFN-γ will inhibit development of Th2 cells, and IL-4 will inhibit the development of Th1 cells. Th17 cells
produce cytokines that affect phagocytes and increase inflammation. Treg cells produce immunosup-
pressive cytokines that prevent the immune response from being excessive. APC, Antigen-presenting
cell; IFN, interferon; MHC, major histocompatibility complex; TGF, transforming growth factor.
 CHAPTER 6  Adaptive Immunity 159

with either immunocompetent B or T cells to cause their differentia-

tion into either plasma cells or effector T cells, respectively. “Abnormal”
When T cells develop in the thymus, two different populations are cell
produced. T cells that are destined to become Th cells emerge from MHC
the thymus with a characteristic cell-surface protein, called CD4 (CD4- Class I
CD8 Effector
positive cells). Cells destined to become Tc cells have a different cell- ANTIGEN Antigen
Tc-cell
surface protein, called CD8 (CD8-positive cells). The role of CD4 and SIGNAL
TCR
CD8 is to help the interaction between T cells and APCs by reacting
1
with antigen-presenting molecules. Interaction is restricted because 3
CD4 can only interact with MHC class II molecules, whereas CD8 Immunocompetent
reacts only with MHC class I molecules. Thus CD4-positive Th cells Tc cell
are restricted to interactions with cells presenting antigens by MHC
class II molecules. 2
Other intercellular signals are required for maturation of Th cells: CYTOKINE
interaction of cell-surface adhesion molecules (not discussed further IL-2
SIGNAL
here) and exposure to specific cytokines.11 At this early stage of cell
differentiation, the Th cell needs IL-1 secreted by the APC (Figure
6-17).12 Afterwards the Th cell produces IL-2, which is secreted and Th1 cell
acts in an autocrine (self-stimulating) fashion to induce further matu-
ration and proliferation of the Th cell. Without IL-2 production, the FIGURE 6-18  Tc Cell Clonal Selection. The immunocompetent Tc
Th cell cannot efficiently mature into a functional helper cell. cell can react with antigen but cannot yet kill target cells. During
At this point, Th cells undergo differentiation into either Th1, clonal selection, this cell reacts with antigen presented by MHC
Th2, or Th17 cells.13 These subsets have different functions: Th1 cells class I molecules on the surface of a virally infected or cancerous
appear to provide more help in developing cell-mediated immunity, abnormal cell. (1) The antigen–MHC class I complex is recognized
Th2 cells provide more help for humoral immunity, and Th17 cells simultaneously by the T cell receptor (TCR), which binds to antigen,
activate macrophages.14 The Th subsets differ considerably in the spec- and CD8, which binds to the MHC class I molecule. (2) A separate
trum of cytokines they produce. Additionally, Th1 and Th2 cells may signal is provided by cytokines, particularly IL-2 from Th1 cells. (3)
In response to these signals, the Tc cell develops into an effector
suppress each other so that the immune response may favor either
Tc cell with the ability to kill abnormal cells.
antibody formation, with suppression of a cell-mediated response,
or the opposite. For example, antigens derived from viral or bacterial
pathogens and those derived from cancer cells seem to induce a greater
number of Th1 cells relative to Th2 cells, whereas antigens derived toxins produced by Staphylococcus aureus and Streptococcus pyogenes
from multicellular parasites and allergens may result in production of (SAGs that cause toxic shock syndrome and food poisoning).
more Th2 cells. Many antigens (e.g., tetanus vaccine), however, will B cell clonal selection: the humoral immune response. A further
produce excellent humoral and cell-mediated responses simultane- sequence of cellular interactions is required to produce an effective
ously. Th cells are necessary for development of most humoral and antibody response. The immunocompetent B cell is also an APC and
cellular immune responses; therefore the virus that causes acquired expresses surface IgM and IgD B cell receptors (BCRs) (Figure 6-20).
immune deficiency syndrome (AIDS) results in life-threatening infec- Unlike the T cell receptor that can only see processed and presented
tions because it specifically infects and destroys Th cells. antigens, the BCR can react with soluble antigens that have not been
T cell clonal selection: the cellular immune response. For T cells processed. Antigen binding to the BCR activates the B cell, resulting
to mature, another set of cellular interactions is required. Because in internalization and processing of the antigen and presentation of
T-cytotoxic (Tc) cells express CD8, rather than CD4, they must react antigen fragments by MHC class II molecules. The antigen presented
with antigens presented by MHC class I molecules on the surface of on the B cell surface is recognized by a Th2 cell through the TCR and
antigen-presenting cells or other target cells (Figure 6-18).15 Differen- CD4.16 The intercellular bridges created through antigen and other
tiation of Tc cells also requires IL-2 produced by Th1 cells. intercellular adhesion molecules induce the Th2 cell to secrete cyto-
Superantigens. Certain diseases are produced by a group of mol- kines (particularly IL-4) that cause B cell proliferation and maturation
ecules called superantigens (SAGs). SAGs bind to the portion of the into plasma cells.
TCR outside of its normal antigen-specific binding site, as well as to A major component of B cell maturation is class switch, the pro-
MHC class II molecules outside of their antigen-presentation sites cess that results in the change in antibody production from one class
(Figure 6-19). Thus, SAGs are not digested and processed by an APC to another (e.g., IgM to IgG during the primary immune response).
to be presented to an immune cell. This binding, which is independent Before exposure to antigens and Th2 cells, the B cell produces IgM
of antigen recognition, provides a signal for Th cell activation, prolif- and IgD, which are used as cell membrane receptors. During the clonal
eration, and cytokine production. The normal antigen-specific recog- selection process, a B cell proliferates and develops into antibody-
nition between Th cells and APCs results in activation of relatively few secreting plasma cells, and each B cell has the option of becoming a
cells—only those cells with specific TCRs against that antigen. SAGs secretor of IgM or changing the class of antibody to a secreted form of
activate a large population of Th cells, regardless of antigen specificity, IgG, IgA, or IgE. Class switch occurs at the genetic level with the vari-
and induce excessive production of cytokines, including IL-2, inter- able region of the antibody heavy chain being combined with a differ-
feron gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α). The ent constant region of the heavy chain. Because the variable region is
overproduction of inflammatory cytokines results in symptoms of a conserved and the light chain remains unchanged the antigenic speci-
systemic inflammatory reaction, including fever, low blood pressure, ficity of the antibody also remains unchanged. The particular constant
and, potentially, fatal shock. Some examples of SAGs are the bacterial region chosen by each cell during class switch appears to be, at least
160 CHAPTER 6  Adaptive Immunity

partially, under the control of specific Th2 cytokines. For instance,

Antigen Superantigen
IL-4 and IL-13 appear to preferentially stimulate switch to IgE secre-
TCR TCR tion, and transforming growth factor-beta (TGF-β) and IL-5 appear to
play major roles in class switch to IgA secretion. Thus, during clonal
V V V V selection, a B cell may produce a population of plasma cells that are
capable of producing many different classes of antibodies against the
same antigen.
Memory cells. During the clonal selection process, both B cells and
T cells differentiate into sets of long-lived memory cells.17 Memory
cells remain inactive until subsequent exposure to the same antigen.
Upon reexposure, these memory cells do not require much further
differentiation and will therefore rapidly become new plasma cells or
effector T cells without the cellular interactions described previously.18

T Lymphocyte Functions
T-Cytotoxic Lymphocytes
MHC class II MHC class II T-cytotoxic (Tc) cells are responsible for the cell-mediated destruction
of tumor cells or cells infected with viruses. The Tc cell must directly
Recognition of antigenic Recognition of V alone
adhere to the target cell through antigen presented by MHC class I
peptide in MHC groove
molecules and CD8 (Figure 6-21). Because of the broad cellular dis-
Low frequency of antigen- High frequency of antigen- tribution of MHC class I molecules, Tc cells can recognize antigens on
specific cells (0.01%) specific cells (10%) the surface of almost any type of cell that has been infected by a virus
or has become cancerous.19 After attachment to a target cell, killing
FIGURE 6-19  Superantigens. The T cell receptor (TCR) and major occurs by induction of apoptosis.20
histocompatibility complex (MHC) class II molecule are normally Various other cells kill targets in a fashion similar to Tc lympho-
held together by processed antigen. Superantigens, such as some cytes. Prominent among these cells are natural killer cells.21 Natural
bacterial exotoxins, bind directly to the variable region of the TCR β killer (NK) cells are a special group of lymphoid cells that are similar
chain and the MHC class II molecule. Each superantigen activates to T cells but lack antigen-specific receptors. Instead, they express a
sets of Vβ chains independently of the antigen specificity of the variety of cell-surface receptors that identify protein changes on the
TCR. surface of cells infected with viruses or that have become cancerous.
After attachment, the NK cell kills its target in a manner similar to that

Immunocompetent
Antigen
B cell

BCR 1

ANTIGEN
SIGNAL

5
2
Antigen
processing 4

MHC Class II
Plasma
Antigen IL-4 cell
CD4 6
3
CYTOKINE
TCR SIGNAL

Th2-cell
Antibody

FIGURE 6-20  Bc Cell Clonal Selection. Immunocompetent B cells undergo proliferation and differ-
entiation into antibody-secreting plasma cells. Multiple signals are necessary (1). The B cell itself can
directly bind soluble antigen through the B cell receptor (BCR) and act as an antigen processing cell.
Antigen is internalized, processed (2), and presented (3)  to the TCR on a Th2 cell by MHC class II mol-
ecules (4).  A cytokine signal is provided by the Th2 cell cytokines (e.g., IL-4) that react with the B cell
(5). The B cell differentiates into plasma cells that secrete antibody (6).
 CHAPTER 6  Adaptive Immunity 161

Tu

L
L L

TCR
MHC I
1. Killing Antigen
by Tc recognition Activation
CD8
Abnormal receptor
surface
change

APOPTOSIS Ag
2. Killing
APOPTOSIS by NK cell
Target cell
with MHC FcR IgG
class I

Target cell
without
MHC class I
3. Killing
by ADCC

FIGURE 6-21  Cellular Killing Mechanisms. Several cells have the capacity to kill abnormal (e.g.,
virally infected, cancerous) target cells. (1) T-cytotoxic (Tc) cells recognized endogenous antigen pre-
sented by MHC class I molecules. The Tc cell mobilizes multiple killing mechanisms that induce apop-
tosis of the target cell. (2)  Natural killer (NK) cells identify and kill target cells through receptors that
recognize abnormal surface changes. NK cells specifically kill targets that do not express surface MHC
class I molecules. (3)  Several cells, including macrophages and NK cells, can kill by antibody-dependent
cellular cytotoxicity (ADCC). IgG antibodies bind to foreign antigen on the target cell, and cells involved
in ADCC bind IgG through Fc receptors (FcR) and initiate killing. The insert is a scanning electron micro-
scopic view of Tc cells (L)  attacking a much larger tumor cell (Tu). (Insert from Thibodeau GA, Patton KT:
Anatomy & physiology, ed 6, St Louis, 2007, Mosby.)

of Tc cells. NK cells also have receptors for MHC class I. However, NK T-Regulatory Lymphocytes
cells lack CD8; therefore binding to MHC class I molecules results in T-regulatory (Treg) cells are a group of T cells that control the
inactivation of the NK cell. Thus, NK cells primarily kill target cells that immune response, usually suppressing the response.23 This population
have suppressed the expression of MHC class I, as do some tumors. of Treg cells express CD4, as do Th cells, and bind to antigens pre-
NK cells, as well as some macrophages, can specifically kill targets sented by MHC class I molecules. Unlike Th cells, however, Treg cells
through use of antibodies.22 These cells also express Fc receptors for express CD17. However, their differentiation is controlled by a differ-
IgG. If antigens on a pathogen or abnormal cell bind IgG, the NK cell ent group of cytokines, primarily TGF-β and IL-2. Treg cells produce
can attach through Fc receptors and activate its normal killing mecha- very high levels of TGF-β and IL-10, an immunosuppressive cytokine,
nisms. This is referred to as antibody-dependent cellular cytotoxicity which generally decrease Th1 and Th2 activity by suppressing antigen
(ADCC). recognition and Th cell proliferation.24

T Cells That Activate Macrophages

During inflammation Th17 cells may produce cytokines that activate
4 QUICK CHECK 6-3
1. What are antigen-presenting cells?
macrophages. The cytokines (particularly IFN-γ) stimulate the mac- 2. Define BCR and TCR.
rophage to become a more efficient phagocyte and increase produc- 3. What is the role of T-helper cells?
tion of proteolytic enzymes and other antimicrobial substances (see 4. Why are cytokines important to the immune response?
Chapter 5).
162 CHAPTER 6  Adaptive Immunity

PEDIATRIC CONSIDERATIONS
Age-Related Factors Affecting Mechanisms of Self-Defense in the Newborn Child
• Normal human newborns are immunologically immature; they have deficient
Adult levels
antibody production, phagocytic activity, and complement activity, especially
of IgG
components of alternative pathways (e.g., factor B).
• The newborn cannot produce all classes of antibody; IgM is produced by the Maternal
newborn (develops in the last trimester) to in utero infections (e.g., cytomega- IgG
lovirus, rubella virus, and Toxoplasma gondii); only limited amounts of IgA are Relative
produced in the newborn; IgG production begins after birth and rises steadily concentration
throughout the first year of life. of IgG
• Maternal antibodies provide protection within the newborn’s circulation (see
Child’s
figure below).
IgG
• Deficits in specific maternal transplacental antibody may lead to a tendency
to develop severe, overwhelming sepsis and meningitis in the newborn.

Maternal circulation 3 6 9 2 4 6 8 10 12
IgG
Months Birth Months after delivery
gestation
Antibody Levels in Umbilical Cord Blood and in Neonatal
­Circulation. Early in gestation, maternal IgG begins active transport across
Placental syncytiotrophoblast the placenta and enters the fetal circulation. At birth, the fetal circulation may
contain nearly adult levels of IgG, which is almost exclusively from the maternal
source. The fetal immune system has the capacity to produce IgM and small
FcR amounts of IgA before birth (not shown). After delivery, maternal IgG is rapidly
destroyed and neonatal IgG production increases.
To fetal circulation

GERIATRIC CONSIDERATIONS
Age-Related Factors Affecting Mechanisms of Self-Defense in the Elderly
• Immune function decreases with age; diminished T cell function and reduced • With age there is a decrease in thymic hormone production and the organ’s
antibody responses to antigenic challenge occur with age. ability to mediate T cell differentiation.
• The thymus reaches maximum size at sexual maturity and then undergoes
involution until it is a vestigial remnant by middle age; by 45 to 50 years of
age, the thymus is only 15% of its maximum size.

DID YOU UNDERSTAND?

Third Line of Defense: Adaptive Immunity Antigens and Immunogens
1. Adaptive immunity is a state of protection, primarily against infectious 1. Antigens are molecules that bind and react with components of the immune
agents, that differs from inflammation by being slower to develop, being response, such as antibodies and receptors on B and T cells. Most antigens
more specific, and having memory that makes it much longer lived. can induce an immune response, and these antigens are called immunogens.
2. The adaptive immune response is most often initiated by cells of the innate 2. All immunogens are antigens but not all antigens are immunogens.
system. These cells process and present portions of invading pathogens (i.e., 3. Some pathogens are successful because they mimic self-antigens but avoid
antigens) to lymphocytes in peripheral lymphoid tissue. inducing an immune response.
3. The adaptive immune response is mediated by two different types of lym- 4. Large molecules, such as proteins, polysaccharides, and nucleic acids, are
phocytes—B lymphocytes and T lymphocytes. Each has distinct functions. most immunogenic. Thus molecular size is an important factor for antigen
B cells are responsible for humoral immunity that is mediated by circulating immunogenicity.
antibodies (immunoglobulins), whereas T cells are responsible for cell-medi- 5. Haptens are antigens too small to be immunogens by themselves but become
ated immunity, in which they kill targets directly or stimulate the activity of immunogenic after combining with larger molecules.
other leukocytes. 6. The antigenic determinant, or epitope, is the precise chemical structure with
4. Adaptive immunity can be either active or passive depending on whether which an antibody or B cell/T cell receptor reacts.
immune response components originated in the host or came from a donor.
 CHAPTER 6  Adaptive Immunity 163

DID YOU UNDERSTAND?—cont’d

7. Self-antigens are antigens on an individual’s own cells. The individual’s 2. Immunocompetent T and B cells migrate from the primary lymphoid organs
immune system does not normally recognize self-antigens as immunogenic, into the circulation and secondary lymphoid organs to await antigen.
a condition known as tolerance. 3. Induction of an immune response, or clonal selection, begins when antigen
8. The response to antigen can be divided into two phases: the primary and sec- enters the individual’s body.
ondary responses. The primary response of humoral immunity is usually domi- 4. Most antigens must first interact with antigen-presenting cells (APCs) (e.g.,
nated by IgM, with lesser amounts of IgG. The secondary immune response has macrophages). Dendritic cells present in the skin, mucosa, and lymphoid tis-
a more rapid production of a larger amount of antibodies, predominantly IgG. sues also present antigen.
5. Antigen is processed in the APCs and presented on the cell surface by mol-
Humoral Immune Response ecules of the MHC. The particular MHC molecule (class I or class II) that
1. The humoral immune response consists of molecules (antibodies) produced presents antigen determines which cell will respond to that antigen. Th
by B cells. B cells are lymphocytes. cells require that the antigen be presented in a complex with MHC class
2. Antibodies are plasma glycoproteins that can be classified by chemical struc- II molecules. Tc cells require that the antigen be presented by MHC class I
ture and biologic activity as IgG, IgM, IgA, IgE, or IgD. molecules.
3. A typical antibody molecule is constructed of two identical heavy chains and 6. The T cell sees the presented antigen through the T cell receptor (TCR) and
two identical light chains (either κ or λ) and has two Fab portions that bind accessory molecules: CD4 or CD8. CD4 is found on Th cells and reacts specifi-
antigen and an Fc portion that interacts with complement or receptors on cells. cally with MHC class II. CD8 is found on Tc cells and reacts specifically with
4. The protective effects of antibodies may be direct or indirect. MHC class I.
5. Direct effects result from the binding of antibodies directly to a harmful 7. Th cells consist of Th1 cells, which help Tc cells respond to antigen; Th2
antigen or infectious agent. These include inhibition of processes that are cells, which help B cells develop into plasma cells; and Th17 cells, which help
necessary for infection, such as the reaction of an infectious agent with a activate macrophages.
particular cell in the body or neutralization of harmful bacterial toxins. 8. Tc cells bind to and kill cellular targets such as cells infected with viruses or
6. Indirect effects result from activation of inflammation by antibodies through cancer cells.
the Fc portion of the molecule. These include opsonization to increase phago- 9. The natural killer (NK) cell has some characteristics of the Tc cells and
cytosis, destruction of the infectious agent through activation of comple- is important for killing target cells in which viral infection or malignancy has
ment, and widespread activation of inflammation through the production of resulted in the loss of cellular MHC molecules.
biologically active complement components, such as C5a.
7. IgE is a special class of antibody that helps defend against parasitic PEDIATRIC CONSIDERATIONS: Age-Related Factors
infections. Affecting Mechanisms of Self-Defense in the Newborn Child
8. Antibodies of the systemic immune system function internally, in the blood- 1. Neonates often have transiently depressed inflammatory function, particu-
stream and tissues. Antibodies of the secretory, or mucosal, immune system larly neutrophil chemotaxis and alternative complement pathway activity.
(primarily secretory IgA) function externally, in the secretions of mucous 2. The T cell–independent immune response is adequate in the fetus and neo-
membranes. nate, but the T cell–dependent immune response develops slowly during the
first 6 months of life.
Cell-Mediated Immunity 3. Maternal IgG antibodies are transported across the placenta into the fetal
1. T cells are responsible for the cell-mediated immune response. T cells are blood and protect the neonate for the first 6 months, after which they are
lymphocytes. replaced by the child’s own antibodies.
2. There are several types of mature T cells: T-cytotoxic cells (Tc), T-helper cells
(Th), T-regulatory cells (Treg), and memory cells. GERIATRIC CONSIDERATIONS: Age-Related Factors
Affecting Mechanisms of Self-Defense in the Elderly
Immune Response: B Cells and T Cells Together 1. Elderly persons are at risk for impaired wound healing, usually because of
1. The production of B and T lymphocytes with receptors against millions of chronic illnesses.
antigens that possibly will be encountered in an individual’s lifetime occurs 2. T cell function and antibody production are somewhat deficient in elderly
in the fetus in the primary lymphoid organs: the thymus for T cells and por- persons. Elderly individuals also tend to have increased levels of circulating
tions of the bone marrow for B cells. This diversity is called clonal diversity. autoantibodies (antibodies against self-antigens).
164 CHAPTER 6  Adaptive Immunity

 KEY TERMS
• A ctive acquired immunity (active • C omplementary-determining region •  recipitation  149
P
immunity)  143 (CDR)  148 • Primary immune response  154
• Adaptive (acquired) immunity  142 • Crystalline fragment (Fc)  148 • Primary (central) lymphoid organ  152
• Agglutination  149 • Dendritic cell  156 • Regulatory cell  152
• Allergen  144 • Generation of clonal diversity  152 • Secondary immune response  154
• Antibody  142 • Hapten  144 • Secondary (peripheral) lymphoid
• Antibody-dependent cellular cytotoxicity • Human bursal equivalent  152 organ  154
(ADCC)  161 • Humoral immunity  143 • Secretory (mucosal) immune
• Antigen  142 • Immune response  142 system  152
• Antigen-binding fragment (Fab)  148 • Immunity  142 • Secretory immunoglobulin  152
• Antigen-binding site (paratope)  148 • Immunocompetent  143 • Superantigen (SAG)  159
• Antigen processing  153 • Immunogen  144 • Systemic immune system  152
• Antigen processing (antigen-presenting) • Immunoglobulin (Ig)  142 • T cell receptor (TCR)  153
cell (APC)  153 • Lymphocyte  142 • T-cytotoxic (Tc) cell  143
• Antigenic determinant (epitope)  148 • Lymphoid stem cell  152 • T-helper (Th) cell  153
• B cell receptor (BCR)  154 • Major histocompatibility complex • T lymphocyte (T cell)  152
• B lymphocyte (B cell)  146 (MHC)  156 • T-regulatory (Treg) cell  161
• CD molecule  158 • Memory cell  143 • Th1 cell  159
• CD4  159 • Natural killer (NK) cell  160 • Th2 cell  159
• CD8  159 • Neutralization  149 • Th17 cell  159
• Cellular immunity  143 • Passive acquired immunity (passive • Titer  154
• Class switch  159 immunity)  143
• Clonal selection  153 • Plasma cell  146

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1. Bonilla FA, Oettgen HC: Adaptive immunity, J Allergy Clin Immunol 13. Damsker JM, Hansen AM, Caspi RR: Th1 and Th17 cells: adversaries and
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125(2):S3–S23, 2010. 20(1):4–12, 2010.
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inflammation, Nat Rev Immunol 10(5):301–316, 2010. apse, Curr Top Microbiol Immunol 340(1):229–249, 2010.
4. Beck A, et al: Strategies and challenges for the next generation of therapeu- 16. Paul WE, Zhu J: How are TH2-type immune responses initiated and
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 CHAPTER

7
Infection and Defects in
Mechanisms of Defense
Neal S. Rote

http://evolve.elsevier.com/Huether/ • C ritical Thinking Questions with Answers

• Review Questions and Answers • Algorithm Completion Exercises
• Animations • WebLinks
• Quick Check Answers
• Key Terms Exercises

CHAPTER OUTLINE
Infection, 165 Secondary (Acquired) Immune Deficiencies, 181
Microorganisms and Humans: A Dynamic Relationship, 166 Evaluation and Care of Those With Immune Deficiency, 181
Classes of Infectious Microorganisms, 167 Replacement Therapies for Immune Deficiencies, 182
Pathogenic Defense Mechanisms, 168 Acquired Immunodeficiency Syndrome (AIDS), 183
Infection and Injury, 168 Hypersensitivity: Allergy, Autoimmunity, and Alloimmunity, 188
Clinical Manifestations of Infection, 175 Mechanisms of Hypersensitivity, 190
Countermeasures Against Pathogenic Defenses, 175 Antigenic Targets of Hypersensitivity Reactions, 197
Deficiencies in Immunity, 178
Initial Clinical Presentation, 178
Primary (Congenital) Immune Deficiencies, 179
 

The defensive system protecting the body from infection is a finely medications make death from infectious disease most common only
tuned network. Sometimes infectious agents can inhibit or escape among those with debilitating diseases or immunosuppression. In the
defense mechanisms or the system may break down, leading to inad- United States, heart disease and malignancies greatly surpass infectious
equate or inappropriate activation of the defenses. An inadequate disease as major causes of death.1 However, many deaths related to
response (commonly called an immune deficiency) may range from cancer are the result of secondary infections because the immune sys-
relatively mild defects to life-threatening severity. Inappropriate tem can be severely depressed both by the cancer itself and by many of
responses (hypersensitivity reactions) may be (1) exaggerated against the treatments used to fight the cancer. Influenza/pneumonia (eighth
noninfectious environmental substances (allergy); (2) misdirected leading cause) and sepsis (eleventh leading cause) accounted for more
against the body’s own cells (autoimmunity); or (3) directed against than 89,000 deaths (3.6% of the total number of deaths).
beneficial foreign tissues, such as transfusions or transplants (alloim- Infectious disease remains a significant threat to life in many parts
munity). Several of these inappropriate responses can be serious or of the world, including India, Africa, and Southeast Asia, although
life-threatening. the advent of sanitary living conditions, clean water, uncontaminated
food, vaccinations, and antimicrobial medications has improved
the health of many. As a result of these initiatives smallpox has been
INFECTION eradicated from the globe (the last reported case was in 1975 in Soma-
Modern healthcare has shown great progress in preventing and treating lia); measles has nearly been eliminated in the Western Hemisphere;
infectious diseases. In developed countries, sanitary living conditions, and many diseases, such as measles (decreased by 78% since 2000)2
clean water, uncontaminated food, vaccinations, and antimicrobial and polio (declined by more than 99% since 1988),3 are decreasing

165
166 CHAPTER 7  Infection and Defects in Mechanisms of Defense

in prevalence worldwide. Although vaccines and antimicrobials have

BOX 7-1 THE MANY RELATIONSHIPS
altered the prevalence of some infectious diseases, mutant strains of
bacteria and viruses have emerged with resistance to protection pro-
BETWEEN HUMANS
vided by drug therapy. The emergence of new diseases—such as West AND MICROORGANISMS
Nile virus, severe acute respiratory syndrome (SARS), Lyme disease, Symbiosis: Benefits only the human; no harm to the microorganism
and Hantavirus—and the development of drug-resistant tuberculosis Mutualism: Benefits the human and the microorganism
are examples of the current intense challenges in the struggle to pre- Commensalism: Benefits only the microorganism; no harm to the human
vent and control infectious disease. Some tropical diseases are emerg- Pathogenicity: Benefits the microorganism; harms the human (Opportunism is
ing for the first time in the United States (see Health Alert: Increase in the situation that occurs when benign microorganisms become pathogenic
United States of “Tropical Diseases”). because of decreased human host resistance.)

HEALTH ALERT
Increase in United States of “Tropical Diseases”
TABLE 7-1 NORMAL INDIGENOUS FLORA
There was a time when vector-borne tropical diseases were contained, par- OF THE HUMAN BODY
ticularly by active insect control programs. Recently, diseases such as malaria,
dengue hemorrhagic fever, yellow fever, and African trypanosomiasis are LOCATION MICROORGANISMS
reemerging in areas of Africa and the Americas where they had been elimi- Skin Predominantly gram-positive cocci and rods
nated or unreported. Although in recent history the United States has been Staphylococcus epidermidis, corynebacteria, myco-
relatively free of most of these diseases, it should not be forgotten that in bacteria, and streptococci are primary inhabitants;
1793 a yellow fever outbreak in Philadelphia killed 2000 of the city’s 55,000 Staphylococcus aureus in some people; also yeasts
inhabitants and forced the U.S. government to abandon the city until the out- (Candida, Pityrosporum) in some areas of skin
break ceased. The conditions necessary for resurgence of outbreaks still exist; Numerous transient microorganisms may become
the necessary vectors are still available, the population density and socio- temporary residents
economic conditions are favorable, and the population generally does not In moist areas, gram-negative bacteria
have existing immunity to these disease-causing agents. The effects of global Around sebaceous glands, Propionibacteria
warming on the spread of these diseases can only be speculated. and Brevibacteria
In early 2010 the CDC reported the results of their study of 28 cases of Mite Demodex folliculorum lives in hair follicles
locally-acquired dengue hemorrhagic fever in Key West, Florida. The den- and sebaceous glands around face
gue virus is transmitted by mosquitoes and yearly causes 50 to 100 million Nose Predominantly gram-positive cocci and rods, especially
infections worldwide and 25,000 deaths. These were the first cases of locally S. epidermidis
acquired disease in the United States since 1945. A survey of mosquito breed- Some people are nasal carriers of pathogenic bacteria,
ing pools discovered the virus in at least two sites. The report surmised, while including S. aureus, β-hemolytic streptococci, and
acknowledging that other factors could play a role, the increased incidence of Corynebacterium diphtheriae
dengue fever resulted from increased travel to localities where the disease Mouth Complex of bacteria that includes several species of strep-
was endemic, return of infected travelers, and transmission of the virus to the tococci, Actinomyces, lactobacilli, and Haemophilus
vector pool. The development of dengue vaccines is in progress. Anaerobic bacteria and spirochetes colonize gingival
crevices
Data from Miller N: Recent progress in dengue vaccine research and
Pharynx Similar to flora in mouth plus staphylococci, Neisseria,
development, Curr Opin Mol Ther 12(1):31–38, 2010; Randolph SE,
and diphtheroids
Rogers DJ: The arrival, establishment and spread of exotic diseases:
patterns and predictions, Nat Rev Microbiol 8(5):361–371, 2010; Trout Some asymptomatic persons also harbor pathogens
A et al: Locally acquired dengue—Key West, Florida, 2009–2010, pneumococcus, Haemophilus influenzae, Neisseria
MMWR Morb Mortal Wkly Rep 59(19):577–581, 2010. meningitidis, and C. diphtheria
Distal intestine Enterobacteria, streptococci, lactobacilli, anaerobic
bacteria, and C. albicans
Microorganisms and Humans: A Dynamic Relationship Colon Bacteroides, lactobacilli, clostridia, Salmonella, Shigella,
Klebsiella, Proteus, Pseudomonas, enterococci, and
For many microorganisms, the human body is a very hospitable site to
other streptococci, bacilli, and Escherichia coli
grow and flourish. The microorganisms are provided with nutrients
Distal urethra Typical bacteria found on skin, especially S. epidermidis
and appropriate conditions of temperature and humidity. In many
and diphtheroids; also lactobacilli and nonpathogenic
cases a mutual relationship exists in which humans and the microor-
streptococci
ganisms benefit (Box 7-1). For instance, the human gut is colonized by
Vagina Birth to 1 month: similar to adult
a large variety of microorganisms that make up normal human flora.
1 month to puberty: S. epidermidis, diphtheroids, E. coli,
The normal flora of different body areas are summarized in Table 7-1.
and streptococci
Bacteria in the GI tract are provided with nutrients from ingested food,
Puberty to menopause: Lactobacillus acidophilus,
and in exchange they produce (1) enzymes that facilitate the digestion
diphtheroids, staphylococci, streptococci, and variety
and utilization of many molecules in the human diet, (2) antibacterial
of anaerobes
factors that prevent colonization by pathogenic microorganisms (see
Postmenopause: similar to prepubescence
Chapter 5), and (3) usable metabolites (e.g., vitamin K, B vitamins).
This relationship normally is maintained through the physical integ- From Grimes DE: Infectious diseases, Mosby’s Clinical Nursing Series,
rity of the skin and mucosal epithelium and other mechanisms that St Louis, 1991, Mosby.
 CHAPTER 7  Infection and Defects in Mechanisms of Defense 167

guarantee that the immune and inflammatory systems do not attack penetrating protective barriers, pathogens then spread through the
these symbiotes. If those systems are compromised, many microor- lymph and blood for invasion of tissues and organs, where they
ganisms will leave their normal sites and cause infection. Individuals multiply and cause disease. In humans the route of entrance of
with deficiencies in their immune system become easily infected with many pathogenic microorganisms also becomes the site of shedding
opportunistic microorganisms—those that normally would not cause of new infectious agents to other individuals, completing a cycle of
disease but seize the opportunity provided by the person’s decreased infection.
immune or inflammatory responses.
True pathogens have devised means to circumvent the normal con- Classes of Infectious Microorganisms
trols provided by the host’s main defensive barriers: the inflammatory Infectious disease can be caused by microorganisms that range in size
system and the immune system. Several factors influence the capacity from 20 nanometers (nm) (poliovirus) to 10 meters (m) (tapeworm).
of a pathogen to cause disease. Classes of pathogenic microorganisms and their characteristics are
• Communicability: Ability to spread from one individual to others and summarized in Table 7-2. Some mechanisms of tissue damage caused
cause disease—for example, measles and pertussis spread very easily; by microorganisms are summarized in Table 7-3.
human immunodeficiency virus (HIV) is of lower communicability
• Immunogenicity: Ability of pathogens to induce an immune
response
• Infectivity: Ability of the pathogen to invade and multiply in the host
TABLE 7-3 EXAMPLES OF
• Mechanism of action: Manner in which the microorganism damages MICROORGANISMS THAT
tissue CAUSE TISSUE DAMAGE
• Pathogenicity: Ability of an agent to produce disease—success PATHOGENS THAT DIRECTLY CAUSE TISSUE DAMAGE
depends on communicability, infectivity, extent of tissue damage,
Produce Exotoxin
and virulence
Streptococcus pyogenes Tonsillitis, scarlet fever
• Portal of entry: Route by which a pathogenic microorganism infects
Staphylococcus aureus Boils, toxic shock syndrome, food
the host: direct contact, inhalation, ingestion, or bites of an animal
poisoning
or insect Corynebacterium diphtheriae Diphtheria
• Toxigenicity: Ability to produce soluble toxins or endotoxins, fac- Clostridium tetani Tetanus
tors that greatly influence the pathogen’s degree of virulence Vibrio cholerae Cholera
• Virulence: Capacity of a pathogen to cause severe disease—for
example, measles virus is of low virulence; rabies virus is highly Produce Endotoxin
virulent Escherichia coli Gram-negative sepsis
Infectivity is facilitated by the ability of pathogens to attach Haemophilus influenzae Meningitis, pneumonia
to cell surfaces, release enzymes that dissolve protective barriers, Salmonella typhi Typhoid
escape the action of phagocytes, or resist the effect of low pH. After Shigella Bacillary dysentery
Pseudomonas aeruginosa Wound infection
TABLE 7-2 CLASSES OF ORGANISMS Yersinia pestis Plague
INFECTIOUS TO HUMANS Cause Direct Damage With Invasion
SITE OF Variola Smallpox
CLASS SIZE REPRODUCTION EXAMPLE Varicella-zoster Chickenpox, shingles
Virus 20-300 nm Intracellular Poliomyelitis Hepatitis B virus Hepatitis
Chlamydiae 200-1000 nm Intracellular Urethritis Poliovirus Poliomyelitis
Rickettsiae 300-1200 nm Intracellular Rocky Mountain Measles virus Measles, subacute sclerosing panen-
spotted fever cephalitis
Mycoplasma 125-350 nm Extracellular Atypical pneumonia Influenza virus Influenza
Bacteria 0.8-15 mcg Skin Staphylococcal Herpes simplex virus Cold sores
wound infection PATHOGENS THAT INDIRECTLY CAUSE TISSUE DAMAGE
Mucous membranes Cholera
Produce Immune Complexes
Extracellular Streptococcal
Hepatitis B virus Kidney disease
pneumonia
S. pyogenes Glomerulonephritis
Intracellular Tuberculosis
Treponema pallidum Kidney damage in secondary syphilis
Fungi 2-200 mcg Skin Tinea pedis
Most acute infections Transient renal deposits
(athlete’s foot)
Mucous membranes Candidiasis Cause Cell-Mediated Immunity
(e.g., thrush) Mycobacterium tuberculosis Tuberculosis
Extracellular Sporotrichosis Mycobacterium leprae Tuberculoid leprosy
Intracellular Histoplasmosis Lymphocytic choriomeningitis virus Aseptic meningitis
Protozoa 1-50 mm Mucosal Giardiasis Borrelia burgdorferi Lyme arthritis
Extracellular Sleeping sickness Herpes simplex virus Herpes stromal keratitis
Helminths 3 mm to 10 m Intracellular Trichinosis
Extracellular Filariasis Data modified from Janeway CA et al: Immunobiology: the system in
health and disease, ed 5, New York, 2001, Garland.
168 CHAPTER 7  Infection and Defects in Mechanisms of Defense

TABLE 7-4 EXAMPLES OF MECHANISMS USED BY PATHOGENS TO RESIST THE IMMUNE

SYSTEM
EXAMPLE OF SPECIFIC
MECHANISMS EFFECT ON IMMUNITY MICROORGANISMS
Destroy or Block Component of Immune System
Produce toxins Kills phagocyte or interferes with chemotaxis Staphylococcus
Prevents phagocytosis by inhibiting fusion between phagosome Streptococcus
and lysosomal granules Mycobacterium tuberculosis
Produce antioxidants (e.g., catalase, Prevents killing by O2-dependent mechanisms Mycobacterium sp.
­superoxide dismutase) Promotes bacterial attachment Salmonella typhi
Produce protease to digest IgA Neisseria gonorrhoeae (urinary tract
infection), Haemophilus influenzae, and
Streptococcus pneumoniae (pneumonia)
Produce surface molecules that mimic Prevents activation of complement system Staphylococcus
Fc receptors and bind antibody Prevents antibody functioning as opsonin Herpes simplex virus

Mimic Self-Antigens
Produce surface antigens (e.g., M protein, Pathogen resembles individual’s own tissue; in some individuals, Group A Streptococcus (M protein)
red blood cell antigens) that are similar ­antibodies can be formed against self-antigen, leading to hypersen- Mycoplasma pneumoniae (red cell
to self-antigens sitivity disease (e.g., antibody to M protein also reacts with cardiac antigens)
tissue, causing rheumatic heart disease; antibody to red blood cell
antigens can cause anemia)

Change Antigenic Profile

Undergo mutation of antigens or activate Immune response delayed because of failure to recognize new antigen Influenza
genes that change surface molecules HIV
Some parasites

Pathogenic Defense Mechanisms occurs.8 The influenza virus undergoes yearly antigenic drift result-
Our multiple layers of defense against infection were described in ing from mutations in key surface antigens, hemagglutinin (H anti-
Chapters 5 and 6. True pathogens have devised ways of circumventing gen) and neuraminidase (N antigen), allowing the emergence of new
these barriers.4 For example, some bacteria produce thick capsules of strains of influenza virus. Thus immunity against the previous year’s
carbohydrate or protein that are antiphagocytic, preventing efficient viruses is no longer completely protective, creating the need for new
phagocytosis.5 Others defend themselves by producing toxins that vaccines every year. Antigenic shifts are major changes in antigenicity
destroy neutrophils. Because the primary immune response may take that occur from recombination of genes for H and N among differ-
a week to develop adequately, some pathogens proliferate at rates that ent strains of viruses and can result in major worldwide pandemics.
surpass the development of a protective response. Table 7-4 contains Other pathogens, such as some parasitic microorganisms, use a similar
examples of microorganisms that defeat the immune system or cause approach and change surface antigens by gene switching. A parasite
it to attack the host. (i.e., African trypanosomes) may carry thousands of genes for different
Viral pathogens bypass many defense mechanisms by hiding within surface molecules that the parasite can either activate or deactivate at
cells and away from normal inflammatory or immune responses.6 frequent intervals. Consequently, the immune system is always trying
Because some viral agents must leave the infected cell in order to to catch up by generating new antibodies and T cells against the new
spread, the immune response blocks spread and eventually cures the antigens.
infection; therefore the disease is described as self-limiting. Other
viruses (e.g., measles, herpes) are inaccessible to antibodies after initial Infection and Injury
infection because they do not circulate in the bloodstream but instead Bacterial Disease
remain inside infected cells, spreading by direct cell-to-cell contact. Bacteria are prokaryocytes (lacking a discrete nucleus) and are relatively
Antibodies that block a virus from attaching to a target cell (neutral- small. They can be aerobic or anaerobic and motile or immotile. Spher-
izing antibodies) are most effective in preventing the initial infection. ical bacteria are called cocci, rodlike forms are called bacilli, and spiral
Other viruses, such as polio and influenza, are distributed through the forms are termed spirochetes. Gram stain and acid-fast stain are impor-
blood, are more susceptible to the effects of circulating antibodies, and tant for differentiating gram-positive or gram-negative types of bacte-
can be controlled by antibodies even after the initial infection. Most ria. Examples of human diseases caused by specific bacteria are listed in
antiviral drugs help control the virus rather than destroy it (i.e., by pre- Table 7-5. The general structure of bacteria is reviewed in Figure 7-1.
venting its replication). Because the virus replicates inside the host cell, Bacterial survival and growth depend on the effectiveness of the
it is difficult to kill a specific virus without also damaging the host cell. body’s defense mechanisms and on the bacterium’s ability to resist
Some viruses can elude the immune response by undergoing anti- these defenses. Many pathogens have devised ways of preventing
genic variation.7 The virus can change its appearance by altering sur- destruction by the inflammatory and immune systems. The thick
face antigens. Influenza infection provides an example of how this capsules of carbohydrate or protein on encapsulated bacteria are
 CHAPTER 7  Infection and Defects in Mechanisms of Defense 169

TABLE 7-5 EXAMPLES OF COMMON BACTERIAL INFECTIONS

INTRACELLULAR
MICROORGANISM GRAM STAIN RESPIRATORY PATHWAY OR EXTRACELLULAR

Respiratory Infections
Upper Respiratory Tract Infections
  Corynebacterium diphtheriae (diphtheria) Gram + Facultative anaerobic Extracellular
  Haemophilus influenzae Gram − Facultative anaerobic Extracellular
  Streptococcus pyogenes (group A) Gram + Facultative anaerobic Extracellular

Otitis Media
  Haemophilus influenzae Gram − Facultative anaerobic Extracellular
  Streptococcus pneumoniae Gram + Facultative anaerobic Extracellular

Lower Respiratory Tract Infections

  Bacillus anthracis (pulmonary anthrax) Gram + Facultative anaerobic Extracellular
  Bordetella pertussis (whooping cough) Gram − Aerobic Extracellular
  Chlamydia pneumoniae Not stainable Aerobic Obligate intracellular
  Escherichia coli Gram − Facultative anaerobic Extracellular
  Haemophilus influenzae Gram − Facultative anaerobic Extracellular
  Legionella pneumophila Gram − Aerobic Facultative intracellular
  Mycobacterium tuberculosis Gram + (weakly) Aerobic Extracellular
  Mycoplasma pneumoniae Not stainable Aerobic Extracellular
  Neisseria meningitidis (develops into meningitis) Gram − Aerobic Extracellular
  Pseudomonas aeruginosa Gram − Aerobic Extracellular
  Streptococcus agalactiae (group B; develops to meningitis) Gram + Facultative anaerobic Extracellular
  Streptococcus pneumoniae Gram + Facultative anaerobic Extracellular
  Yersinia pestis (plague) Gram − Facultative anaerobic Extracellular

Gastrointestinal Infections
Inflammatory Gastrointestinal Infections
  Bacillus anthracis (gastrointestinal anthrax) Gram + Facultative anaerobic Extracellular
  Clostridium difficile Gram + Anaerobic Extracellular
  Escherichia coli O157:H7 Gram − Facultative anaerobic Extracellular
  Vibrio cholerae Gram − Facultative anaerobic Extracellular

Invasive Gastrointestinal Infections

 Brucella abortus (brucellosis, undulant fever, leading to Gram − Aerobic Intracellular
sepsis, heart infection)
  Helicobacter pylori (gastritis and peptic ulcers) Gram − Microaerophilic Extracellular
  Listeria monocytogenes (leading to sepsis and meningitis) Gram + Aerobic Intracellular
  Salmonella typhi (typhoid fever) Gram − Anaerobic Extracellular
  Shigella sonnei Gram − Facultative anaerobic Extracellular

Food Poisoning
  Bacillus cereus Gram + Facultative anaerobic Extracellular
  Clostridium botulinum Gram + Anaerobic Extracellular
  Clostridium perfringens Gram + Anaerobic Extracellular
  Staphylococcus aureus Gram + Facultative anaerobic Extracellular

Sexually Transmitted Infections

  Chlamydia trachomatis (pelvic inflammatory disease) Not stainable Aerobic Intracellular
  Neisseria gonorrhoeae (urethritis) Gram − Aerobic Facultative intracellular
  Treponema pallidum (spirochete; syphilis) Gram − Aerobic Extracellular

Skin and Wound Infections

  Bacillus anthracis (cutaneous anthrax) Gram + Facultative anaerobic Extracellular
  Borrelia burgdorferi (Lyme disease; spirochete) Gram − Aerobic Extracellular
  Clostridium tetani (tetanus) Gram + Anaerobic Extracellular
  Clostridium perfringens (gas gangrene) Gram + Anaerobic Extracellular
  Mycobaterium leprae (leprosy) Gram + (weakly) Aerobic Extracellular
Continued
170 CHAPTER 7  Infection and Defects in Mechanisms of Defense

TABLE 7-5 EXAMPLES OF COMMON BACTERIAL INFECTIONS—cont’d

INTRACELLULAR
MICROORGANISM GRAM STAIN RESPIRATORY PATHWAY OR EXTRACELLULAR
  Pseudomonas aeruginosa Gram − Aerobic Extracellular
  Rickettsia prowazekii (rickettsia; typhus) Gram − Aerobic Obligate intracellular
  Staphylococcus aureus Gram + Facultative anaerobic Extracellular
  Streptococcus pyogenes (group A) Gram + Facultative anaerobic Extracellular

Eye Infections
  Chlamydia trachomatis (conjunctivitis) Not stainable Aerobic Obligate intracellular
  Haemophilus aegyptius (pink eye) Gram − Facultative anaerobic Extracellular

Zoonotic Infections
  Bacillus anthracis (anthrax) Gram + Facultative anaerobic Extracellular
  Brucella abortus (brucellosis, also called undulant fever) Gram − Aerobic Intracellular
  Borrelia burgdorferi (spirochete; Lyme disease) Gram − Aerobic Extracellular
  Listeria monocytogenes Gram + Aerobic Intracellular
  Rickettsia rickettsii (rickettsia; Rocky Mountain spotted fever) Gram − Aerobic Obligate intracellular
  Rickettsia prowazekii (rickettsia; typhus) Gram − Aerobic Obligate intracellular
  Yersinia pestis (plague) Gram − Facultative anaerobic Extracellular

Nosocomial Infections
  Enterococcus faecalis Gram + Facultative anaerobic Extracellular
  Enterococcus faecium Gram + Facultative anaerobic Extracellular
  Escherichia coli (cystitis) Gram − Facultative anaerobic Extracellular
  Pseudomonas aeruginosa Gram − Obligate anaerobic Extracellular
  Staphylococcus aureus Gram + Facultative anaerobic Extracellular
  Staphylococcus epidermidis Gram + Facultative anaerobic Extracellular

Division septum
Outer membrane
Peptidoglycan (Pili) (Capsule)
Mesosome
(Capsule) layer Cytoplasmic
Inclusion membrane
body Inclusion
body
Peptidoglycan
layer
Porin
Cytoplasmic proteins
Ribosome Periplasmic
membrane Ribosome
Surface proteins Chromosome space
FIGURE 7-1  General Structure of Bacteria. A, The structure of the (Flagellum)
bacterial cell wall determines its staining characteristics with gram stain. A (Flagellum)
GRAM POSITIVE GRAM NEGATIVE
A gram-positive bacterium has a thick layer of peptidoglycan (left). A
gram-negative bacterium has a thick peptidoglycan layer and an outer
membrane (right). B, Example of a gram-positive (darkly stained micro-
organisms, arrow) group A Streptococcus. This microorganism consists
of cocci that frequently form chains. C, Example of a gram-negative (pink
microorganisms, arrow) Neisseria meningitides in cerebrospinal fluid.
Neisseria form complexes of two cocci (diplococci). (From Murray PR
et al: Medical microbiology, ed 4, St Louis, 2002, Mosby.)

B C
 CHAPTER 7  Infection and Defects in Mechanisms of Defense 171

antiphagocytic, preventing efficient opsonization and phagocytosis. microorganisms consisting of nucleic acid (the viral genome) pro-
Such coatings include the polysaccharide covering of the pneumococ- tected from the environment by a layer or layers of proteins. They are
cus and the waxy capsule surrounding the tubercle bacillus. The long sensitive to many environmental factors and have a short life span
M protein on the cell wall of the streptococcus suppresses complement outside the cell.
activation. Viral replication. Virions (viral particles) do not possess any of the
Other bacteria survive and proliferate in the body by producing metabolic organelles found in prokaryotes (e.g., bacteria) or eukary-
exotoxins and endotoxins that injure cells and tissues. Exotoxins are otes (e.g., human cells). Thus viruses have no metabolism. Unlike
proteins released during bacterial growth. They are usually enzymes bacteria, viruses are incapable of independent reproduction. Their
and have highly specific effects on host cells; they include cytotoxins, replication depends totally on their ability to infect a permissive host
neurotoxins, pneumotoxins, enterotoxins, and hemolysins. Exotoxins cell—a cell that cannot resist viral invasion and replication. The rep-
can damage cell membranes, activate second messengers, and inhibit lication cycle of most viruses can be divided into six distinct phases:
protein synthesis. Exotoxins are immunogenic and elicit the produc- adsorption, penetration, uncoating, replication, assembly, and release.
tion of antibodies known as antitoxins. Consequently, vaccines are Infection with a virus begins with a virion binding to a specific recep-
available for many of the exotoxins (i.e., tetanus, diphtheria, and per- tor on the plasma membrane of a host cell (Figure 7-2). The specificity
tussis). Some strains of toxin-producing group A streptococci cause of this virus-receptor interaction dictates the range of host cells that a
destructive skin infections (e.g., flesh-eating bacteria syndrome, or particular virus will infect and therefore the clinical symptoms, which
necrotizing fasciitis) and pneumonia that may result in an individual’s reflect the alteration of the function of the infected cells. For example,
death within 2 days. the influenza virus binds to a receptor on respiratory epithelial cells,
Endotoxins (lipopolysaccharides [LPSs]) are contained in the cell causing symptoms of an upper respiratory tract infection. Once bound,
walls of gram-negative bacteria and are released during lysis, or destruc- the virion penetrates the plasma membrane by one of several means:
tion, of the bacteria. Endotoxin may be released also from the membrane by receptor-mediated endocytosis, by viral envelope fusion with the
of the bacteria during bacterial growth or during treatment with antibi- plasma membrane, or by directly crossing the plasma membrane.
otics, which therefore cannot prevent the toxic effects of the endotoxin. Viruses contain their genetic information in either deoxyribonucleic
Bacteria that produce endotoxins are called pyrogenic bacteria because acid (DNA) or ribonucleic acid (RNA). The viral genetic material is pro-
they activate the inflammatory process and produce fever. The inner- tected by a protein coat that must be removed in the cytoplasm of the
most part of the lipopolysaccharide, lipid A, consists of polysaccharide infected host cell (uncoating). The viral genetic material may be pro-
and fatty acids and is responsible for the substance’s toxic effects. cessed by one of several paths, depending on the particular virus. Gener-
Inflammation is the body’s initial response to the presence of the ally, all RNA viruses, except influenza and retroviruses, replicate their
bacteria. Vascular permeability is increased, allowing blood-borne genetic material in the cytoplasm of the infected cell, and all DNA viruses,
substances (i.e., the complement system) involved in bacterial destruc- except poxviruses, require the DNA to enter the nucleus and use the
tion to access the site of infection. Endotoxins increase capillary per- cell’s DNA polymerases to replicate. Poxviruses provide their own DNA
meability further by activating the anaphylatoxins (C5a and C3a) of polymerase and replicate their DNA in the cytoplasm of the infected cell.
the complement cascade.9 Capillary permeability may increase suffi- Retroviruses generally convert their RNA genetic information to DNA
ciently to permit the escape of large volumes of plasma, contributing using an enzyme contained in the virion—reverse transcriptase.
to hypotension and, in severe cases, cardiovascular shock (see Chapter After infection, viruses usually make multiple copies of their genetic
23). Endotoxin also can activate the coagulation cascade, leading to the material and produce the necessary viral proteins for replication. New
syndrome of disseminated (or diffuse) intravascular coagulation (see
Chapter 20). Release
Virion Receptors
Bacteremia is the presence of bacteria in the blood, whereas septi- of new
Binding Host cell
cemia is growth of bacteria in the blood and is caused by a failure of the 1 infective
body’s defense mechanisms. The usual cause is proliferation of gram- Enzyme release virions
negative bacteria, although a few gram-positive bacteria and fungi can (adsorption)
also proliferate. Symptoms of gram-negative septic shock are produced
by endotoxins. Once in the blood, endotoxins cause the release of vaso- 2
active peptides and cytokines that affect blood vessels by producing 3 5
vasodilation, which reduces blood pressure, causes decreased oxygen Penetration 4
delivery, and produces subsequent cardiovascular shock (see Chapter
23). Sepsis is diagnosed from evaluation of blood cultures.
Endotoxic shock is a complication of sepsis and can be fatal to the
individual. The cytokine tumor necrosis factor-alpha (TNF-α) plays Uncoating Budding
a pivotal role in the pathogenesis of endotoxic shock. TNF-α is pro-
duced by activated macrophages on exposure to endotoxin from gram-­ Nucleus
negative bacterial infections. It is sometimes called cachectin because Assembly
of its role in promoting cachexia in individuals with cancer. (Types of and maturation
Replication
shock are discussed in Chapter 23.)

Viral Disease FIGURE 7-2  Stages of Viral Infection of a Host Cell. The virion
(1) becomes attached to the cell’s plasma membrane by absorp-
Viral diseases are the most common afflictions of humans and tion; (2) releases enzymes that weaken the membrane and allow
include a variety of diseases ranging from the common cold and the it to penetrate the cell; (3) uncoats itself; (4) replicates; and
“cold sore” of herpes simplex to several types of cancers and acquired (5) matures and escapes from the cell by budding from the plasma
immune deficiency syndrome (AIDS). Viruses are very simple membrane. The infection then can spread to other host cells.
172 CHAPTER 7  Infection and Defects in Mechanisms of Defense

virions are assembled in the host cell’s cytoplasm and are released from Cellular effects of viruses. Besides assuming control of the host
the cell for transmission of the viral infection to other host cells. This cell’s metabolic machinery, viral infection can injure cells. In some
cycle is referred to as the productive or lytic cycle because a large num- viral infections, cellular destruction results from large quantities of
ber of progeny are produced, and the result is often the destruction of virus being released from the cell’s plasma membrane. Alteration of
the host cell. the plasma membrane by the expression of new antigens as a result
Some viruses will not be productive initially but instead initiate a of viral infection can incite an immune response against the individu-
latency phase, during which the host cell is transformed. During this al’s infected cells (e.g., hepatitis B virus). Once inside the cell, virions
phase, the viral DNA may be integrated into the DNA of the host cell have many harmful effects, including the following:
and become a permanent passenger in that cell and its progeny. In 1. Cessation of DNA, RNA, and protein synthesis (e.g., herpesvirus)
response to stimuli, such as stress, hormonal changes, or disease, the 2. Disruption of lysosomal membranes, resulting in release of diges-
virus may exit latency and enter a productive cycle. tive lysosomal enzymes that can kill the cell (e.g., herpesvirus)

TABLE 7-6 EXAMPLES OF HUMAN DISEASES CAUSED BY SPECIFIC VIRUSES

BALTIMORE MAIN ROUTE
CLASSIFICATION FAMILY VIRUS ENVELOPE OF TRANSMISSION DISEASE
dsDNA Adenoviruses Adenovirus No Droplet contact Acute febrile pharyngitis
Herpesviruses Herpes simplex type 1 Yes Direct contact with saliva or Lesions in mouth, pharynx,
(HSV-1) lesions conjunctivitis
Herpes simplex type 2 Yes Sexually, contact with lesions Sores on labia, meningitis
(HSV-2) during birth in children
Herpes simplex type 8 Yes Sexually?, body fluids Kaposi sarcoma
(HSV-8)
Epstein-Barr virus (EBV) Yes Saliva Mononucleosis, Burkitt
lymphoma
Cytomegalovirus (CMV) Yes Body fluids, mother’s milk, Mononucleosis, congenital
­transplacental infection
Varicella-zoster virus (VZV) Yes Droplet contact Chickenpox, shingles
ssDNA Papovaviruses Papillomavirus No Direct contact Warts, cervical carcinoma
dsRNA Reoviruses Rotavirus No Fecal-oral Severe diarrhea
ssRNA+ Picornaviruses Coxsackievirus No Fecal-oral, droplet contact Nonspecific febrile illness,
conjunctivitis, meningitis
Hepatitis A virus No Fecal-oral Acute hepatitis
Poliovirus No Fecal-oral Poliomyelitis
Rhinovirus No Droplet contact Common cold
Flaviviruses Hepatitis C virus Yes Blood, sexually Acute or chronic hepatitis,
hepatocellular carcinoma
Yellow fever virus Yes Mosquito vector Yellow fever
Dengue virus Yes Mosquito vector Dengue fever
West Nile virus Yes Mosquito vector Meningitis, encephalitis
Togaviruses Rubella virus Yes Droplet contact, transplacental Acute or congenital rubella
Coronaviruses SARS Yes Droplets in aerosol or direct contact Severe respiratory disease
Caliciviruses Norovirus No Fecal-oral Gastroenteritis
ssRNA− Orthomyxoviruses Influenza virus Yes Droplet contact Influenza
Paramyxoviruses Measles virus Yes Droplet contact Measles
Mumps virus Yes Droplet contact Mumps
Parainfluenza virus Yes Droplet contact Croup, pneumonia, com-
mon cold
Respiratory syncytial virus Yes Droplet contact, hand-to-mouth Pneumonia, influenza-like
(RSV) syndrome
Rhabdoviruses Rabies virus Yes Animal bite, droplet contact Rabies
Bunyaviruses Hantavirus Yes Aerosolized animal fecal material Viral hemorrhagic fever
Filoviruses Ebola virus Yes Direct contact with body fluids Viral hemorrhagic fever
Marburg virus Yes Direct contact with body fluids Viral hemorrhagic fever
Arenavirus Lassa virus Yes Aerosolized animal fecal material Viral hemorrhagic fever
ssRNA+ with RT Retroviruses HIV Yes Sexually, blood products AIDS
dsDNA with RT Hepadnaviruses Hepatitis B virus Yes All body fluids Acute or chronic hepatitis,
hepatocellular carcinoma

AIDS, Acquired immunodeficiency syndrome; DNA, deoxyribonucleic acid; ds, double-stranded; HIV, human immunodeficiency virus;
RNA, ribonucleic acid; RT, reverse transcriptase; SARS, severe acute respiratory syndrome; ss, single-stranded.
 CHAPTER 7  Infection and Defects in Mechanisms of Defense 173

3. F usion of host cells, producing multinucleated giant cells (e.g., cures the infection; therefore the disease is usually self-limiting in that it
respiratory syncytial virus) resolves without the need for medications. Some viruses will persist, and a
4. Alteration of the antigenic properties, or identity, of the infected state of unapparent infection may result. In persistent infections, cellular
cell, causing the individual’s immune system to attack the cell as if injury may be minimal, and the virus persists until it is activated to rep-
it were foreign (e.g., hepatitis B virus) licate (e.g., the cold sores of herpesvirus infection). Immunity may limit
5. Transformation of host cells into cancerous cells, resulting in unin- recurrent outbreaks and protect the individual from an acute exacerba-
hibited and unregulated growth (e.g., human papillomavirus) tion only or may be sufficiently strong to prevent disease.
6. Promotion of secondary bacterial infection in tissues damaged by
viruses Fungal Disease
Examples of human diseases caused by specific viruses are listed in Fungi are relatively large microorganisms with thick walls that have
Table 7-6. two basic structures: single-celled yeasts (spheres) or multicelled
Viral pathogens bypass many defense mechanisms by developing molds (filaments or hyphae) (Figure 7-3). Some fungi can exist in
­intracellularly, thus hiding within cells and away from normal inflamma- either form and are called dimorphic fungi. The cell walls of fungi are
tory or immune responses. In many cases, however, because viral agents rigid and multilayered. The wall is composed of polysaccharides dif-
must spread from cell to cell, the developing immune response eventually ferent from the peptidoglycans of bacteria. The lack of peptidoglycans

MOLDS
Filamentous fungi grow as
multinucleate, branching
hyphae, forming a mycelium
(i.e., ringworm)

B
YEASTS
Yeasts grow as ovoid or
spherical; single cells multiply
by budding and division (i.e.,
Histoplasma)
A

C D
FIGURE 7-3  Morphology of Fungi. (A) Fungi may be either mold or yeast forms, or dimorphic.
(B) Photograph showing Candida albicans with both the mycelial and the yeast forms. (C) Oral infec-
tion with C. albicans (candidiasis, i.e., thrush). (D) Gram stain of sputum showing that clinical isolates
of C. albicans present as chains of elongated budding yeasts (× 1000). (A from Mims CA et al: Medical
microbiology, ed 3, London, 2004, Mosby; B from Townsend C et al: Sabiston textbook of surgery, ed
18, Philadelphia, 2008, Saunders; C from Mandell G, Bennett J, Dolin R: Principles and practice of infec-
tious diseases, ed 6, Philadelphia, 2005, Churchill Livingstone; D from McPherson R, Pincus M: H ­ enry’s
clinical diagnosis and management by laboratory methods, ed 21, Philadelphia, 2006, Saunders.)
174 CHAPTER 7  Infection and Defects in Mechanisms of Defense

TABLE 7-7 COMMON PATHOGENIC FUNGI

PRIMARY SITE OF INFECTION FUNGUS DISEASE (PRIMARY) SYMPTOMS
Superficial (no tissue invasion, little Malassezia furfur Tinea versicolor, seborrheic Red rash on body
inflammation) dermatitis, dandruff
Cutaneous (no tissue invasion, Dermatophytes Tinea pedis (athlete’s foot) Scaling, fissures, pruritus
­inflammatory response) Trichophyton mentagrophytes Tinea cruris (jock itch) Rash, pruritus
Trichophyton rubrum Tinea corporis (ringworm) Lesion, raised border, scaling
Microsporum canis
Candida albicans Cutaneous candidiasis Lesions in most areas of skin, mucous
membranes, thrush, vaginal infection
Subcutaneous (tissue invasion) Sporothrix schenckii Sporotrichosis Ulcers or abscesses on skin and other
organ systems
Systemic (dimorphic; causes disease in Stachybotrys chartarum or “black mold” Black mold disease Rash, headaches, nausea, pain
healthy individuals) Coccidioides immitis Coccidioidomycosis Valley fever, flulike symptoms
Histoplasma capsulatum Histoplasmosis Lung, flulike symptoms, disseminates
to multiple organs, eye
Blastomyces dermatitidis Blastomycosis Flulike symptoms, chest pains
Systemic (opportunistic) Aspergillus fumigatus, Aspergillus flavus Aspergillosis Invasive to lungs and other organs
Pneumocystis jiroveci Pneumocystis pneumonia (PCP) Pneumonia
Cryptococcus neoformans Cryptococcosis Pneumonia-like illness, skin lesions,
disseminates to brain, meningitis
Candidia albicans Systemic candidiasis Sepsis, endocarditis, meningitis

allows fungi to resist the action of bacterial cell wall inhibitors such found in the mouth, gastrointestinal tract, and vagina of normal indi-
as penicillin and cephalosporin. In contrast to bacteria, the cytosols viduals. Changes in pH and use of antibiotics that destroy bacteria
of fungi contain organelles: mitochondria, ribosomes, Golgi appara- that normally inhibit Candida growth permit rapid proliferation and
tus, microtubules, microvesicles, endoplasmic reticulum, and nuclei. overgrowth, which can lead to superficial or deep infection. Common
Molds are aerobic, and yeasts are facultative anaerobes, which adapt pathologic fungi are summarized in Table 7-7.
to, but do not require, anaerobic conditions. They usually reproduce Fungi are diagnosed by microscopic observation of specimens
by simple division or budding. treated with potassium hydroxide and stained to enhance visualiza-
Pathologic fungi cause disease by adapting to the host environ- tion of spheres and filaments. Specimens also can be cultured. Skin
ment. Fungi that colonize the skin can digest keratin. Other fungi tests are available for species of Aspergillus. No vaccines are available to
can grow with wide temperature variations in lower oxygen environ- prevent fungal disease effectively and techniques to prevent infection
ments. Still other fungi have the capacity to suppress host immune are important.10 Many of the antifungal drugs (e.g., amphotericin B,
defenses. Phagocytes and T lymphocytes are important in control- ketoconazole, fluconazole) used to treat deep or systemic infections
ling fungi. Low white blood cell counts promote fungal infection and are toxic to the host because the fungal cell composition is similar to
infection control is particularly important for individuals who are the host cell.
immunosuppressed.
Diseases caused by fungi are called mycoses. Mycoses can be super- Parasitic Disease
ficial, deep, or opportunistic. Superficial mycoses occur on or near Parasitic microorganisms establish symbiosis with another species in
skin or mucous membranes and usually produce mild and superficial which the parasite benefits at the expense of the other species. Para-
disease. Fungi that invade the skin, hair, or nails are known as der- sites range from unicellular protozoan to large worms. Parasitic worms
matophytes. The diseases they produce are called tineas (ringworm), (helminths) include intestinal and tissue nematodes (e.g., hookworm,
for example, tinea capitis (scalp), tinea pedis (feet), and tinea cruris roundworm), flukes (e.g., liver fluke, lung fluke), and tapeworms. A
(groin). Superficial dermatophytes grow in a ringlike, erythematous protozoan is a eukaryotic, unicellular microorganism with a nucleus
patch with a raised border. Itching (pruritus) often is intense, and and cytoplasm. Pathogenic protozoa include malaria (Plasmodium),
cracking of tissue can occur and lead to secondary bacterial infec- amoebae (e.g., Entamoeba histolytica, which causes amoebic dysen-
tion. Infections of the scalp are accompanied by scaling and hair loss. tery), and flagellates (e.g., Giardia lamblia, which causes diarrhea; Try-
(Chapter 39 discusses the various skin disorders caused by fungi.) panosoma, which causes sleeping sickness). Although less common in
Deep infections involving internal organs can be life-threatening the United States, parasites and protozoa are common causes of infec-
and are most common in association with other diseases or as an tions worldwide, with a significant effect on the mortality and mor-
opportunistic infection in immunosuppressed individuals. Fungi bidity of individuals in developing countries. Important parasites of
causing deep infection enter the body through inhalation or through humans are listed in Table 7-8.
open wounds. Filamentous forms can multiply extracellularly, but Parasitic and protozoal infections are rarely transmitted from
the spherical yeasts multiply within cells, including white blood cells. human to human. The predominant means is through vectors in
Some fungi are a part of the normal body flora and become patho- which the microorganism spends part of its life cycle. Examples
logic only when immunity is compromised, allowing exaggerated include the transmission of malaria (Plasmodium spp.) by mosquitoes,
growth and translocation. For example, Candida albicans is normally trypanosomes (Trypanosoma cruzi, which causes Chagas disease in
 CHAPTER 7  Infection and Defects in Mechanisms of Defense 175

TABLE 7-8 EXAMPLES OF PARASITES THAT ARE IMPORTANT IN HUMANS

CATEGORY SUBGROUP SPECIES DISEASE ORGANS AFFECTED/SYMPTOMS
Protozoa Ameboid Entamoeba histolytica Amebiasis Dysentary, liver abscess
Flagellate Giardia lamblia Giardiasis* Diarrhea
Trichomonas vaginalis Trichomoniasis Inflammation of reproductive organs
Trypanosoma cruzi, T. brucei Chagas disease: African Generalized, blood and lymph nodes,
­sleeping sickness progressing to cardiac and CNS
Ciliate Balantidium coli Balantidiasis Small intestines, invasion of colon, diar-
rhea
Sporozoa (nonmotile) Cryptosporidium parvum, C. hominis Cryptosporidiosis* Intestine, diarrhea
Plasmodium spp. Malaria Blood, liver
Toxoplasma gondii Toxoplasmosis* Intestine, eyes, blood, heart, liver
Helminths Flukes (trematodes) Fasciola hepatica Fasciolosis Liver destruction
Schistosoma mansoni Schistosomiasis Blood, diarrhea, bladder, generalized
symptoms
Tapeworms (cestodes) Taenia solium Pork tapeworm Encysts in muscle, brain, liver
Roundworms (nematodes) Ascaris lumbricoides Ascariasis Intestinal obstruction, bile duct obstruction
Necator americanus (hookworm) Hookworm disease Intestinal parasite
Trichinella spiralis Trichinosis* Intestine, diarrhea, muscle, CNS, death
Wuchereria bancrofti Filariasis, elephantiasis Lymphatics
Enterobius vermicularis (pinworm) Pinworm infection Intestines
Onchocerca volvulus Onchocerciasis Blindness, dermatitis

*Most common in the United States.

South America; Trypanosoma brucei, which causes sleeping sickness in dysentery, dehydration, and death in infants and young children.
Africa) by the tsetse fly, and Leishmania spp. by sand fleas. Many of the T. cruzi secretes a neurotoxin that affects the anatomic nervous system,
protozoal infectious agents (e.g., E. histolytica, G. lamblia) are encoun- a small-molecular-weight toxin that causes fever, and proteases and
tered in contaminated water or food and transmission is by ingestion. phospholipases, leading to tissue destruction.
The initial attachment depends on whether the microorganism The infected individual’s immune and inflammatory responses
is injected into the bloodstream by a vector or whether entrance is result in considerable pathology. Schistosomiasis results in the deposi-
through the gastrointestinal tract. Microorganisms in the bloodstream tion of eggs in organs (e.g., liver), which leads to formation of granu-
frequently have surface lectins that react with carbohydrates on spe- lomas and tissue destruction through fibrosis. Some parasitic products
cific cells. Malarial parasites attach to erythrocytes that express Duffy (T. brucei, malarial parasites) activate macrophages to overproduce
blood group antigens. Thus Duffy-negative individuals are resistant cytokines, which leads to exacerbated inflammation.
to malaria. T. cruzi can infect both CD4- and CD8-positive T cells
through a T cell surface receptor. Several parasites express surface Clinical Manifestations of Infection
glycoproteins that facilitate preferential entrance into monocytes/ The progression from infection to infectious disease follows predictable
macrophages using various receptors. Leishmania expresses a surface stages (infection, incubation, symptoms, shedding of the microorgan-
glycoprotein (gp63) that binds complement components (e.g., C3b) ism). Clinical manifestations of infectious disease vary, depending on
and uses the macrophage complement receptors to gain entrance to the pathogen and the organ system affected. Manifestations can arise
the macrophage. directly from the infecting microorganism or its products; however,
Tissue damage may result directly by parasitic infestation in the the majority of the clinical symptoms result from the host’s inflamma-
tissue or be secondary to the individual’s immune and inflammatory tory and immune responses. Infectious diseases typically begin with
responses. The particular process depends a great deal on the burden the nonspecific or general symptoms of fatigue, malaise, weakness, and
of parasites infesting the site and the sensitivity of the particular site loss of concentration. Generalized aching and loss of appetite are com-
to damage. Large infestations may lead to physical loss of function in mon complaints. However, the hallmark of most infectious diseases
a tissue or organ. For instance, a large number of intestinal parasites is fever.
(e.g., the roundworm Ascaris lumbricoides, tapeworms, Giardia spp.) Fever resulting from cytokines has been discussed in Chapter 5. Exoge-
compete for and prevent uptake of nutrients, leading to various forms nous pyrogens produced by an infectious agent may not cause fever directly
of malabsorption, blocked uptake of fats, or anemia from malab- but induce the production of endogenous pyrogens during inflammation.
sorption of vitamin B12 or from large amounts of blood loss. Filarial Endogenous pyrogens include interleukin-1 (IL-1), interleukin-6 (IL-6),
parasites (e.g., Wuchereria bancrofti and Brugia malayi, which causes interferon, tumor necrosis factor-alpha (TNF-α), and other cytokines.
elephantiasis) block the lymphatics and cause accumulation of lymph It is generally accepted that fever has a beneficial effect against infection,
in tissues. The larvae of tapeworms (e.g., Taenia solium) encyst in and although the mechanisms have not been fully established.
prevent normal function of organs (e.g., muscle, liver, eye), which is
particularly dangerous in the human brain. Countermeasures Against Pathogenic Defenses
Toxins released from the parasite may cause significant irreversible The body’s innate and acquired responses against microorganisms are
organ damage. Proteolytic enzymes from E. histolytica are very cyto- numerous and involve an interaction between the immune and inflam-
lytic, leading to ulceration of intestinal walls, bloody diarrhea, amoebic matory systems. Pathogenic microorganisms, however, have developed
176 CHAPTER 7  Infection and Defects in Mechanisms of Defense

TABLE 7-9 REDUCTION IN VACCINE- TABLE 7-10 CHEMICALS OR

PREVENTABLE DISEASES ANTIMICROBIALS
IN THE UNITED STATES IDENTIFIED THAT PREVENT
BASELINE 20TH GROWTH OF OR DESTROY
CENTURY ANNUAL 2009 % MICROORGANISMS
DISEASE CASES* CASES REDUCTION
MECHANISM OF ACTION AGENT
Diphtheria 175,885 0 100
Inhibits synthesis of cell wall Penicillins, cephalosporins, mono-
Measles 503,282 61 99.9
bactams, carbapenems, vancomycin,
Mumps 152,209 982 99.4
bacitracin, cycloserine, fosfomycin
Pertussis 147,271 13,506 90.8
Damages cytoplasmic membrane Polymyxins, polyene antifungals,
Smallpox 48,164 0 100
imidazoles
Polio 16,316 0 100
Alters metabolism of nucleic acid Quinolones, rifampin, nitrofurans,
Rubella 47,745 4 99.9
nitroimidazoles
Tetanus 1,314 14 98.9
Inhibits protein synthesis Aminoglycosides, tetracyclines, chlor-
Haemophilus 20,000 25 99.9
amphenicol, macrolides, clindamy-
­influenzae type
cin, spectinomycin, sulfonamides
b, invasive
Alters energy metabolism Trimethoprim, dapsone, isoniazid
From Centers for Disease Control and Prevention: MMWR Morb
Modified from Ellner PD, Neu HCP: Understanding infectious disease,
Mortal Wkly Rep 48(12):243–248, 1999; Morb Mortal Wkly Rep
St Louis, 1992, Mosby.
58(11):289–291, 2008; 2009 data from Provisional cases of selected
notifiable diseases, MMWR Morb Mortal Wkly Rep 58(51,52):1446–
1456, 2010.
*Average number of reported cases over multiple years before initia-
gonorrhea, salmonellosis, shigellosis, and staphylococcal infections.
tion of vaccine. Streptococcus pneumoniae, which causes pneumonia, meningitis, and
acute otitis media (middle ear infection), was once routinely suscep-
tible to penicillin. Since the 1980s, however, the incidence of penicil-
means of circumventing the individual’s protective defenses. Therefore lin-resistant microorganisms has risen to greater than 30% in some
prophylactic or interventive procedures have been developed either to populations.
prevent the pathogen from initiating disease (vaccines) or to destroy Antibiotic resistance is usually a result of genetic mutations that
the pathogen once the disease process has started (antimicrobials). can be transmitted directly to neighboring microorganisms by plas-
Most vaccine development has focused on preventing the most severe mid exchange. Microorganisms commonly develop the capacity to
and common infections (Table 7-9). With the initial success of antibi- inactivate antibiotics. Penicillin resistance, for example, results from
otic therapy, there was no perceived need for vaccination against many the production of an enzyme (β-lactamase) that breaks down the
common and non–life-threatening infections. The increasing problem structure of the antibiotic. Other forms of resistance result from
of antibiotic-resistant pathogens, however, has forced a reappraisal of modification of the target molecule. Azidothymidine (AZT) is a
that strategy, and a greater emphasis now is being placed on the devel- family of antivirals that suppresses the enzymatic activity of reverse
opment of new vaccines.11 transcriptase, a viral-specific enzyme responsible for the replica-
tion of viral RNA and production of a DNA copy. HIV frequently
Antimicrobials mutates and produces an AZT-resistant reverse transcriptase. A third
Since initiation of the widespread use of penicillin during World War mechanism of resistance is mediated by multidrug transporters in
II, antibiotics have shown the greatest impact on successful resistance the microorganism’s membrane. These transporters affect the rate
to infection. Antibiotics are natural products of fungi, bacteria, and of intracellular accumulation of the antimicrobial by preventing
related microorganisms that affect the growth of other microorgan- entrance or, more commonly, by increasing active efflux of the anti-
isms. Some antibacterial antibiotics are bactericidal (kill the micro- biotic. Antibiotic-resistant strains of M. tuberculosis are protected
organism), whereas others are bacteriostatic (inhibit growth until from aminoglycosides and tetracycline by a multidrug pump that
the microorganism is destroyed by the individual’s own protective increases efflux.
mechanisms). The mechanisms of action of most antibiotics are (1) A rapid emergence of multiple antibiotic–resistant bacteria has been
inhibition of the function or production of the cell wall, (2) prevention observed. These microorganisms are resistant to almost all currently
of protein synthesis, (3) blockage of DNA replication, or (4) interfer- available antibiotics. For example, Streptococcus pneumoniae, which
ence with folic acid metabolism (Table 7-10). Because viruses use the initially was only resistant to penicillin, is now resistant to multiple
enzymes of the host’s cells, there has been far less success in developing antibiotics. In some areas, more than 20% of tuberculosis cases are
antiviral antibiotics. caused by multiple antibiotic–resistant M. tuberculosis. Methicillin-
Immediately after antibiotics became widely used, microorgan- resistant Staphylococcus aureus (MRSA) incorporates several differ-
isms mutated and developed resistance.12 By 1944 an adequate sup- ent mechanisms of resistance and has become a major health problem
ply of penicillin allowed its widespread use to treat infections. In in hospitals. Also, the incidence of drug-resistant malaria, pneumo-
1946 a hospital in Britain reported that 14% of all Staphylococcus coccal disease, salmonellosis, shigellosis, and staphylococcal infections
aureus infections were penicillin resistant. By 1950 the same hos- has increased dramatically (see Health Alert: The Continued Rise of
pital reported an increase to 59% and to greater than 89% in the Antibiotic-Resistant Microorganisms).
1990s. Over the past few decades healthcare providers have observed Why have multiple antibiotic–resistant microorganisms appeared?
increasing incidences of drug-resistant malaria, tuberculosis, Lack of compliance concerning the necessity of completing the
 CHAPTER 7  Infection and Defects in Mechanisms of Defense 177

of vaccination is to induce long-lasting protective immune responses

HEALTH ALERT
under conditions that will not result in disease in a healthy recipient
The Continued Rise of Antibiotic-Resistant of the vaccine. The primary immune response from vaccination is
Microorganisms generally short lived; therefore booster injections are used to push the
immune response through multiple secondary responses that result in
The existence of antibiotic-resistant pathogenic bacteria was observed soon
large numbers of memory cells and sustained protective levels of anti-
after the advent of antibiotic therapy during World War II. In most cases
body or T cells, or both.
alternative antibiotics were readily available. Many common pathogenic
Mass vaccination programs have been tremendously successful and
bacteria and yeast have since developed resistance to multiple antibiotics:
have led to major changes in the health of the world’s population. In
Mycobacterium tuberculosis, Enterococcus, Clostridium difficile, Streptococ-
the early 1950s an estimated 50 million cases of smallpox occurred
cus pneumoniae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Candida,
each year, with about 15 million deaths. The World Health Organi-
and others. A major example has been Staphylococcus aureus. S. aureus
zation (WHO) conducted a smallpox immunization campaign from
is part of the normal bacterial flora present in healthy individuals; about
1967 to 1977 that resulted in the global eradication of smallpox by
30% of healthy individuals have asymptomatic colonization in the nostrils.
1979.13 Many vaccines are used in the United States to protect against
­Penicillin-resistant S. aureus was reported in the 1950s and methicillin-resis-
pathogens. The Centers for Disease Control and Prevention (CDC)
tant S. aureus (MRSA) organisms were reported in the early 1960s. Currently,
provides updated vaccine schedules at their website: www.cdc.gov/vac
the prevalence of MRSA with resistance to other antibiotics (multidrug resis-
cines/recs/schedules/default.htm.
tant) is increasing. In the past MRSA was observed primarily in hospitals and
Development of a successful vaccine is costly and depends on sev-
nursing homes in persons whose defenses had been compromised. Now it is
eral factors. These include identification of the protective immune
becoming the primary microorganism found in community-acquired infections,
response and the appropriate antigen to induce that response. For
primarily skin infections such as cellulitis and abscesses, of healthy individu-
instance, individuals with ongoing HIV infection produce a great deal
als. Community-acquired MRSA has not yet developed multiple antibiotic
of antibody against several HIV antigens. But, for development of a
resistance.
successful vaccine, we must first understand which antibody will pro-
The situation may be about to become considerably worse. Very recently
tect against an initial infection.
strains of multiple antibiotic-resistant Neisseria gonorrhoeae have
Once a good candidate antigen is identified, it must be developed
emerged. The incidence of gonorrhea has been relatively stable in the
into an effective, cost-efficient, stable, and safe vaccine. For instance,
United States with more than 260,000 new cases of gonorrhea reported
most vaccines against viral infection (measles, mumps, rubella, vari-
for 2009, which may be considerably underestimated. In 2007 27% of
cella [chickenpox]) contain live viruses that are weakened (attenuated
isolates were resistant to a large variety of antibiotics, and the CDC had
virus) so they continue to express appropriate antigens but establish
recommended cephalosporins as the only class of antibiotics for treating
only a limited and easily controlled infection. For most common vac-
gonorrhea. Recently investigators from Australia and England have identi-
cines against viral infections, limited replication of the virus appears
fied strains that are resistant to cefiximine and ceftriaxone, widely used
to afford better long-term protection than using viral antigen. One
cephalosporins.
current exception is the hepatitis B vaccine, which uses a recombinant
Data from DeLeo FR: Community-associated methicillin-resistant viral protein. The hepatitis A vaccine is an inactivated (killed) virus
Staphylococcus aureus, Lancet 375(9725):1557–1568, 2010; Centers and normally should not cause an infection.
for Disease Control and Prevention (CDC): Provisional cases of selected Even attenuated viruses can establish life-threatening infections
notifiable diseases, MMWR Morb Mortal Wkly Rep 58(51,52):1446– in individuals whose immune systems are congenitally deficient or
1456, 2010; Centers for Disease Control and Prevention (CDC): Update
suppressed. The risk of infection by the vaccine strain of virus is
to CDC’s sexually transmitted diseases treatment guidelines, 2006:
extremely small, but it may affect the choice of recommended vac-
fluoroquinolones no longer recommended for treatment of gonococcal
infections, MMWR Morb Mortal Wkly Rep 56(14):332–336, 2007. cines.14 For instance, the Sabin vaccine was an attenuated virus that
was administered orally. It provided systemic protection and induced
a secretory immune response to prevent growth of the poliovirus in
the intestinal tract. Being a live virus, the vaccine could cause polio
therapeutic regimen with antibiotics allows the selective resurgence in some children who had unsuspected immune deficiencies (about 1
of microorganisms that are more relatively resistant to the antibi- case in 2.4 million doses). The Salk vaccine was a completely inacti-
otic. Overuse of antibiotics can lead to the destruction of the normal vated virus administered by injection. It induced protective systemic
flora, allowing the selective overgrowth of antibiotic-resistant strains immunity but did not provide adequate secretory immunity. There-
or pathogens that had previously been controlled. For example, after fore even if the individual was protected from systemic infection by
treatment with the antibiotic clindamycin, the normal intestinal flora poliovirus, the virus could transiently infect the individual’s intesti-
can become compromised, allowing the overgrowth of Clostridium nal mucosa, be shed, and spread to others. When polio was epidemic,
difficile and the development of pseudomembranous colitis (a bacte- the oral vaccine was preferred. Vaccination has been extremely effec-
rial infection of the intestines). C. difficle infections are often acquired tive: 2525 cases of paralytic polio were reported in the United States
in hospitals or other healthcare institutions with a long-term patient in 1960, 61 cases were reported in 1965, and no cases of polio have
population and the number of deaths is rising steadily; reported been reported since 1979. In 1994 the disease polio was declared offi-
deaths rose from 793 in 1999 to 6372 deaths in 2007, with 92% of the cially eradicated in all the Americas. The goal of the World Health
deaths occurring in individuals age 65 years or older.1 Organization is to eradicate polio worldwide in the next few years.
However, the live attenuated vaccine itself caused about eight cases
Vaccines of paralytic polio per year in the United States in individuals with
Vaccines are biologic preparations of weakened or dead pathogens inadequate immune systems. As a result, the current recommenda-
that when administered stimulate production of antibodies or cellular tion of the Centers for Disease Control and Prevention is vaccination
immunity against the pathogen without causing disease. The purpose with the killed virus.
178 CHAPTER 7  Infection and Defects in Mechanisms of Defense

Some common bacterial vaccines are killed microorganisms or recalled.16 More commonly the reluctance is based on inadequate
extracts of bacterial antigens. The vaccine against pneumococcal pneu- information. A commonly discussed fear is related to the presence
monia consists of a mixture of capsular polysaccharides from 10 strains of the preservative thimerosal in vaccines. Thimerosal is a mercury-
of Streptococcus pneumoniae. Of the more than 90 known strains of this containing compound that has been used as a preservative since the
microorganism, only these 10 cause the most severe illnesses. How- 1930s. Although no cases of mercury toxicity have been reported sec-
ever, the capsular vaccine is not very immunogenic in young children. ondary to vaccination, thimerosal was removed from all vaccines in
A conjugated vaccine is available that contains capsular polysaccharides 2001, with the exception of some inactivated influenza vaccines.17 In
from seven strains that are conjugated to carrier proteins in order to 2003 groups in northern Nigeria claimed that the oral polio vaccine
increase immunogenicity. A similar vaccine is available for Haemophi- was unsafe and were tainted with antifertility drugs (estradiol), HIV,
lus influenzae type b (Hib). and cancer-causing agents. The reasoning appeared to be secondary
Some bacterial pathogens are not invasive, but do colonize muco- to mounting distrust of Western nations because of conflicts in the
sal membranes or wounds and release potent toxins that act locally or Middle East. The effect was suspension of polio immunization for
systemically. These include the bacteria that cause diphtheria, chol- almost 1 year in two states and reduction of immunization in three
era, and tetanus. Vaccination against systemic toxins (e.g., diphtheria, other states.18 The incidence of polio rose dramatically and more than
tetanus) has been achieved using toxoids—purified toxins that have 27,000 cases of paralysis resulted. By 2006 Nigeria accounted for 51%
been chemically detoxified without loss of immunogenicity. Pertussis of the global polio cases, and this region acted as a reservoir for the
(whooping cough) vaccine has been changed from a killed whole-cell dissemination of polio to previously polio-free areas in neighboring
vaccine to cellular extract (acellular) vaccine that contains the pertussis countries.19 After renewal of immunization programs the number of
toxoid and additional bacterial antigens. This change has dramatically cases of polio in Nigeria has since dropped by more than 90% to only
reduced adverse side effects (fever, local inflammatory reactions, and 388 new cases in 2009.20
others).
With so many available vaccines there has been an effort to com-
bine vaccines in order to minimize the number of required injections.
One of the first licensed vaccine mixtures was DPT, which now usually 4 QUICK CHECK 7-1
contains diphtheria (D) and tetanus (T) toxoids and acellular pertus- 1. How do antigenic changes in viral pathogens promote disease?
sis vaccine (aP). More recent mixtures include DTaP with inactivated 2. What are three mechanisms pathogens use to block the immune system?
poliovirus, either with Hib conjugate to tetanus toxoid or with hepa- 3. What is the difference between an endotoxin and an exotoxin?
titis B vaccine.
A common problem is compliance of the susceptible population
in vaccination programs. Even with successful development of a vac-
DEFICIENCIES IN IMMUNITY
cine, however, a certain percentage of the population will be geneti-
cally unresponsive to vaccination and therefore will not produce a An immune deficiency is the failure of the immune or inflammatory
protective immune response. With most vaccines, the percentage of response to function normally, resulting in increased susceptibility
unresponsive individuals is low, and they will benefit from successful to infections. Primary (congenital) immune deficiency is caused by
immunization of the rest of the population. Depending on the micro- a genetic defect, whereas secondary (acquired) immune deficiency
organism, a certain percentage of the population (usually about 85%) is caused by another condition, such as cancer, infection, or normal
should be immunized in order to achieve protection of the total popu- physiologic changes, such as aging. Acquired forms of immune defi-
lation. This is referred to as herd immunity. If this level of immuniza- ciency are far more common than the congenital forms.
tion is not achieved, outbreaks of infection can occur. For instance,
an effective measles (rubeola) vaccine was made available in 1963 and Initial Clinical Presentation
resulted in a dramatic decrease in the number of measles cases. Many The clinical hallmark of immune deficiency is a tendency to develop
parents became complacent and did not obtain measles vaccination for unusual or recurrent, severe infections. Preschool and school-age chil-
their preschool children. As a result, a large increase in the number of dren normally may have 6 to 12 infections per year, and adults may
cases and deaths in 1989 and 1990 occurred, which initiated a reem- have 2 to 4 infections per year. Most of these are not severe and are
phasis on complete immunization before children could start school.15 limited to viral infections of the upper respiratory tract, recurrent
More recently resistance to immunization with measles has increased, streptococcal pharyngitis, or mild otitis media (middle ear infections).
and in early 2008 the number of measles cases in the United States Potential immune deficiencies should be considered if the indi-
increased by about fourfold. In several European countries immuniza- vidual has experienced severe, documented bouts of pneumonia, otitis
tion programs have been disrupted by antivaccine groups. As a result media, sinusitis (sinus infection), bronchitis, septicemia (blood infec-
the incidence of pertussis (whooping cough) increased by 10 to 100 tion), or meningitis or infections with opportunistic microorganisms
times compared with neighboring countries that maintained a high that normally are not pathogenic (e.g., Pneumocystis carinii). Infec-
incidence of immunization. tions are generally recurrent with only short intervals of relative health,
The reluctance to vaccinate has generally been based on poten- and multiple simultaneous infections are common. Individuals with
tial vaccine dangers. As with any medicine, complications can arise. immune deficiencies often have eight or more ear infections, two or
In the case of vaccines, these include pain and redness at the injec- more serious sinus infections, and two or more pneumonias, recurrent
tion site, fever, allergic reactions to vaccine ingredients, infection abscesses, or persistent fungal infections (particularly thrush) within
associated with attenuated viruses in immune-deficient individu- a year. Recurrent internal infections, such as meningitis, osteomy-
als, and others. Some dangers do exist, although extremely rarely. elitis, or sepsis, are common. Prolonged antibiotic use is commonly
For instance, a rotavirus vaccine approved more than a decade ago ineffective by oral or injected routes and may necessitate intravenous
was found to increase the risk for a life-threatening bowel obstruc- administration. A familial history of immune deficiency may be found
tion resulting from twisting of the intestines, and the vaccine was in some types of primary deficiency.
 CHAPTER 7  Infection and Defects in Mechanisms of Defense 179

The type of recurrent infections may indicate the type of immune with the onset of symptoms appearing in the second or third decade
defect.21 Deficiencies in T cell immune responses are suggested when of life.
recurrent infections are caused by certain viruses (e.g., varicella, vac- Many immune deficiencies also are associated with other charac-
cinia, herpes, cytomegalovirus), fungi and yeasts (e.g., Candida, His- teristic defects, some of which appear to be unrelated to the immune
toplasma), or certain atypical microorganisms (e.g., P. carinii). B cell system yet may be life-threatening by themselves. Examples are given
deficiencies and phagocyte deficiencies, however, are suggested if the in the following discussion. These associated symptoms can be useful
individual has documented, recurrent infections with microorgan- diagnostically and can clarify the pathophysiology of the disease.
isms that require opsonization (e.g., encapsulated bacteria) or with Individually, primary immune deficiencies are rare. For instance,
viruses against which humoral immunity is normally effective (e.g., only 30 to 50 new cases of severe combined immunodeficiency (SCID)
rubella). Some complement deficiencies resemble defects in antibody are diagnosed in the United States yearly. However, more than 70 dif-
or phagocyte function, but others are associated with disseminated ferent deficiencies have been identified. Together, primary immune
infections with bacteria of the genus Neisseria (Neisseria meningitides deficiencies are more common than cystic fibrosis, hemophilia, child-
and ­Neisseria gonorrhoeae). hood leukemia, or many other well-known diseases. The distribution
between genders is about even, although some specific diseases have a
Primary (Congenital) Immune Deficiencies male or female predominance. The three most commonly diagnosed
Most primary immune deficiencies are the result of a single gene deficiencies are common variable immune deficiency (34%), selective
defect (Table 7-11). Generally, the mutations are sporadic and not immunoglobulin A (IgA) deficiency (24%), and IgG subclass defi-
inherited: a family history exists in only about 25% of individuals. ciency (17%).
The sporadic mutations occur before birth, but the onset of symp- Primary immune deficiencies are classified into five groups, based
toms may be early or later, depending on the particular syndrome.21 on which principal component of the immune or inflammatory sys-
In some instances, symptoms of immune deficiency appear within tems is defective: defects of B lymphocytes, T lymphocytes, both B and
the first 2 years of life. Other immune deficiencies are progressive, T lymphocytes (combined), phagocytes, or complement.

TABLE 7-11 EXAMPLES OF PRIMARY IMMUNE DEFICIENCIES

CLASSIFICATION EXAMPLE IMMUNE DEFICIENCY OUTCOME

B Lymphocyte Deficiencies
Defective development of B cells in Bruton agammaglobulinemia Lack of B cells, little or no antibody Recurrent, life-threatening bacterial
central lymphoid organ (bone marrow) ­production infections
Defect in class-switch Selective IgA deficiency Little or no production of IgA, with normal Mild infections of gastrointestinal and
production of other classes of antibody respiratory tracts

T Lymphocyte Deficiencies
Defective development of T cells in DiGeorge syndrome Lack of T cells Recurrent, life-threatening fungal and viral
central lymphoid organ (thymus) infections
Defect in development of cellular Chronic mucocutaneous Lack of T cell response to Candida Recurrent and disseminated infections
­immunity against specific antigen candidiasis with fungus Candida albicans

Combined Immune Deficiencies

Defective development of both B and Severe combined Lack of both T and B cells, little or no Recurrent, life-threatening infections with
T cells ­immunodeficiencies (SCIDs) ­antibody production or cellular immunity variety of microorganisms
Defects in cooperation among B cells, Bare lymphocyte syndrome No antigen presentation because of lack Recurrent, life-threatening infections with
T cells, and antigen-presenting cells of MHC class I or MHC class II molecules variety of microorganisms
on cell surface
Large variety of defects that affect Wiskott-Aldrich syndrome Cytoskeletal defect resulting in selective Recurrent infections with select groups of
­function of B or T cells decrease in IgM production microorganisms; in this example bacteria
with polysaccharide capsules

Complement Deficiencies
Defective production of one early C3 deficiency Little or no C3 produced Recurrent, life-threatening bacterial
­component of complement system infections
Defective production of component C6 deficiency Little or no C6 produced Recurrent disseminated infections with
of membrane attack complex Neisseria gonorrhoeae or N. meningitidis

Phagocyte Deficiencies
Defects in production of neutrophils Severe congenital neutropenia Lack of neutrophils Recurrent, life-threatening bacterial
infections
Defects in bacterial killing Chronic granulomatous disease Lack of production of oxygen products Recurrent infections with bacteria that are
(e.g., hydrogen peroxide) sensitive to killing by oxygen-dependent
mechanisms
180 CHAPTER 7  Infection and Defects in Mechanisms of Defense

B Lymphocyte Deficiencies
B lymphocyte deficiencies result from defects in antibody produc-
tion.21 Because T cell immunity rarely depends on competent B cell
responses, T cell immune responses are not affected in pure B lympho-
cyte deficiencies. The results are lower levels of circulating immuno-
globulins (hypogammaglobulinemia) or occasionally totally or nearly
absent immunoglobulins (agammaglobulinemia).22
Some defects may involve a particular class of antibody, such as
selective IgA deficiency. This occurs in 1 in 700 to 1 in 400 individu-
als. Individuals with this deficiency produce other classes of immu-
noglobulins but not IgA. This suggests a failure to class-switch to IgA
and mature into IgA-producing plasma cells. Many individuals are
asymptomatic, although others have a history of severe, recurring A B
sinus, pulmonary, and gastrointestinal infections. Individuals with
FIGURE 7-4  Facial Anomalies Associated With DiGeorge Syn-
IgA deficiency often have chronic intestinal candidiasis (infection
drome. Note the wide-set eyes, low-set ears, and shortened
with C. albicans). Complications of IgA deficiency include severe structure of the upper lip. (From Male D et al: Immunology, ed 7,
allergic disease and autoimmune diseases. Studies of these indi- St Louis, 2006, Mosby.)
viduals show that secretory IgA normally may prevent the uptake
of allergens from the environment. Therefore IgA deficiency may
lead to increased allergen uptake and a more intense challenge to the responses, whereas others are partial and more adversely affect T cells
immune system because of prolonged exposure to environmental than B cells. The most severe disorders are called severe combined
antigens. immunodeficiencies (SCIDs). Most individuals with SCIDs have few
Bruton agammaglobulinemia is caused by blocked development detectable lymphocytes in the circulation and secondary lymphoid
of mature B cells in bursal-equivalent tissue. There are few or no cir- organs (spleen, lymph nodes). The thymus usually is underdeveloped
culating B cells, although T cell number and function are normal, because of the absence of T cells. Immunoglobulin levels, especially
resulting in repeated infections, such as otitis media, streptococcal IgM and IgA, are absent or greatly reduced. Several forms of SCID
sore throat, and conjunctivitis, and more serious conditions, such as are caused by autosomal recessive enzymatic defects that result in the
septicemia. accumulation of toxic metabolites to which rapidly dividing cells, such
as lymphocytes, are especially sensitive. For instance, deficiency of
T Lymphocyte Deficiencies adenosine deaminase (ADA deficiency) results in the accumulation
T lymphocyte deficiencies are defects in the development and function of toxic purines.
of cell-mediated immunity.21 Because Th cells are obligatory in the devel- Even if nearly adequate numbers of B and T cells are produced,
opment of many B lymphocyte responses, antibody production is often their cooperation may be defective. The bare lymphocyte syndrome
diminished, although the B cells are fully capable of producing an adequate is an immune deficiency characterized by an inability of lympho-
antibody response. Immunodeficiency of T cell function contributes to cytes and macrophages to produce major histocompatibility complex
failure to thrive (severely diminished rate of growth), oral infections (e.g., (MHC) class I or class II molecules. Without MHC molecules, antigen
candidiasis), chronic diarrhea, pneumonia, and skin rashes. presentation and intercellular cooperation cannot occur effectively.
Some immune deficiencies are characterized by a defect in the Children with this deficiency develop serious, life-threatening infec-
capacity to produce an immune response against a particular antigen. tions and usually die before the age of 5 years.
In chronic mucocutaneous candidiasis, the T lymphocytes cannot Some combined immune deficiencies result in depressed devel-
respond to a specific infectious agent, C. albicans. These individuals opment of a small portion of the immune system. For instance, an
usually have mild to extremely severe recurrent Candida infections individual can be unable to produce a certain class of antibody, as
involving the mucous membranes and skin. in Wiskott-Aldrich syndrome (an X-linked recessive disorder),
DiGeorge syndrome (congenital thymic aplasia or hypoplasia and where IgM antibody production is greatly depressed. Antibody
diminished parathyroid gland development) is caused by the lack or responses against antigens that elicit primarily an IgM response,
partial lack of the thymus, resulting in greatly decreased T cell num- such as polysaccharide antigens from bacterial cell walls (e.g., of
bers and function. The cause is defective development of several tis- P. aeruginosa, S. pneumoniae, Haemophilus influenzae, and other
sues originating from the third and fourth pharyngeal pouches during microorganisms with polysaccharide outer capsules), are deficient.
embryonic development. Lack of the parathyroid gland causes an In addition, there are defects in platelets presumably because of the
inability to regulate calcium concentration. Low blood calcium levels absence of certain glycoproteins. Clinical manifestations include
cause the development of tetany or involuntary rigid muscular con- bleeding because of decreases in circulating platelets, eczema, and
traction. DiGeorge syndrome is frequently associated with abnormal recurrent infections (e.g., otitis media, pneumonia, herpes simplex,
development of facial features that are controlled by the same embry- cytomegalovirus).
onic pouches; these include low-set ears, fish-shaped mouth, and other
altered features (Figure 7-4). Complement Deficiencies
Many complement deficiencies have been described.21 C3
Combined Deficiencies deficiency is the most severe defect. C3 unites all pathways of
Combined deficiencies result from defects that directly affect the complement activation, and complement component C3b is a
development of both T and B lymphocytes.21 Some combined defi- major opsonin. Persons with C3 deficiency are at risk for recur-
ciencies result in major defects in both the T and B cell immune rent life-threatening infections with encapsulated bacteria
 CHAPTER 7  Infection and Defects in Mechanisms of Defense 181

(e.g., Haemophilus influenzae and Streptococcus pneumoniae) at an

BOX 7-2 SOME CONDITIONS KNOWN TO
early age. Deficiencies of terminal components of the complement
cascade (C5, C6, C7, C8, or C9 deficiencies) are associated with
BE ASSOCIATED WITH ACQUIRED
increased infections with only one group of bacteria—those of the IMMUNE DEFICIENCIES
genus Neisseria (Neisseria meningitides or N. gonorrhoeae). Neis- Normal Physiologic Conditions
seria usually cause localized infections (meningitis or gonorrhea), Pregnancy
but those with terminal pathway defects have more than an 8000- Infancy
fold increased risk for systemic infections with atypical strains of Aging
these microorganisms.
Psychologic Stress
Phagocytic Deficiencies Emotional trauma
Phagocytic deficiencies usually result in recurrent infections with Eating disorders
the same group of microorganisms (encapsulated bacteria) associ-
ated with antibody and complement deficiencies.21 A variety of defects Dietary Insufficiencies
in the destruction of microorganisms have been described. Chronic Malnutrition caused by insufficient intake of large categories of nutrients,
granulomatous disease (CGD) is a severe defect in the myeloperox- such as protein or calories
idase-hydrogen peroxide system. A major means of bacterial destruc- Insufficient intake of specific nutrients, such as vitamins, iron, or zinc
tion uses the enzyme myeloperoxidase, halides (e.g., chloride ion), and Infections
hydrogen peroxide (H2O2). As a result of phagocytosis, neutrophils Congenital infections, such as rubella, cytomegalovirus, hepatitis B
and other phagocytes switch much of their glucose metabolism to the Acquired infections, such as AIDS
hexose-monophosphate shunt. A by-product of this pathway is the
Malignancies
conversion of molecular oxygen by nicotinamide adenine dinucleotide
Malignancies of lymphoid tissues, such as Hodgkin disease, acute or chronic
phosphate (NADPH) oxidase into highly reactive oxygen derivatives,
leukemia, or myeloma
including hydrogen peroxide. Mutations in NADPH oxidase result in
Malignancies of nonlymphoid tissues, such as sarcomas and carcinomas
deficient production of hydrogen peroxide and other oxygen products.
Thus affected individuals have adequate myeloperoxidase and halide
Physical Trauma
but lack the necessary hydrogen peroxide, resulting in recurrent severe
Burns
pneumonias; tumor-like granulomata in lungs, skin, and bones; and
other infections with some normal, relatively innocuous microorgan- Medical Treatments
isms, such as Staphylococcus aureus, Serratia marcescens, Aspergillus Stress caused by surgery
spp., and others. Anesthesia
Immunosuppressive treatment with corticosteroids or antilymphocyte
Secondary (Acquired) Immune Deficiencies antibodies
Secondary, or acquired, immune and inflammatory deficiencies are Splenectomy
far more common than primary deficiencies. These deficiencies are Cancer treatment with cytotoxic drugs or ionizing radiation
not related to genetic defects but are complications of other physi-
ologic or pathophysiologic conditions.23 Some conditions that are Other Diseases or Genetic Syndromes
known to be associated with acquired deficiencies are summarized in Diabetes
Box 7-2. Alcoholic cirrhosis
Although secondary deficiencies are common, many are not clini- Sickle cell disease
cally relevant. In many cases, the degree of the immune deficiency is Systemic lupus erythematosus (SLE)
relatively minor and without any apparent increased susceptibility to Chromosome abnormalities, such as trisomy 21
infection. Alternatively, the immune system may be substantially sup-
pressed, but only for a short duration, thus minimizing the incidence
of clinically relevant infections. Some secondary immune deficiencies
(e.g., AIDS), however, are extremely severe and may result in recurrent
life-threatening infections. of the individual, including age, gender, family history, the presence
of any associated anomalies, the types of infections (bacterial, viral,
Evaluation and Care of Those With Immune Deficiency or fungal, and the specific microorganisms involved), and risk factors
Routine care of individuals with primary or secondary immune associated with secondary immune deficiencies.21 A variety of labora-
deficiencies must be tempered with the knowledge that the immune tory tests are available to evaluate specific immune deficiencies (Table
system may be totally ineffective. It is unsafe to administer con- 7-12). A review of clinical characteristics can help select the appro-
ventional immunizing agents or blood products to many of these priate tests.24 A basic screening test is a complete blood count (CBC)
individuals because of the risk of causing an uncontrolled infec- with a differential. The CBC provides information on the numbers of
tion. Uncontrolled infection is a particular problem when attenu- red blood cells, white blood cells, and platelets, and the differential
ated vaccines that contain live but weakened microorganisms are indicates the quantities of lymphocytes, granulocytes, and monocytes
used (e.g., live polio vaccine; vaccines against measles, mumps, and in the blood. Quantitative determination of immunoglobulins (IgG,
rubella). IgM, IgA) is a screening test for antibody production, and an assay
The most common presenting symptom of immune deficiencies for total complement (total hemolytic complement, CH50) is useful
is recurrent severe infections. Significant information on the specific if a complement defect is suspected. Further testing is described in
immune deficiency can be obtained by noting certain characteristics Table 7-12.
182 CHAPTER 7  Infection and Defects in Mechanisms of Defense

TABLE 7-12 LABORATORY EVALUATION OF IMMUNE DEFICIENCIES

FUNCTION TESTED LABORATORY TEST SIGNIFICANCE OF TEST

Tests of Humoral Immune Function

Antibody production Total immunoglobulin levels, including IgG, IgM, Decrease or absence of total antibody production or of specific classes
and IgA of antibody, which is associated with many B cell and combined
­deficiencies
Levels of isohemagglutinins Production of specific IgM antibodies, which is decreased in some com-
bined deficiencies; not useful with persons who are blood type AB and do
not have naturally occurring isohemagglutinins
Levels of antibodies against vaccines—especially Production of specific IgG antibodies, which is decreased when B cells are
diphtheria and tetanus toxoids deficient or class-switch is blocked
B cell numbers Numbers of lymphocytes with surface immunoglobulin Production of circulating B cells, which is decreased in many severe B cell
or combined deficiencies
Antibody subclasses Level-specific subclasses, particularly IgG1, IgG2, Decrease or absence of a particular subclass, which is characteristic of
and IgG3 several immune deficiencies

Tests of Cellular Immune Function

Delayed hypersensitivity Skin test reaction against previously encountered Defects in antigen-responsive T cells and skin test cellular interactions
skin test antigens, especially Candida albicans or tetanus (e.g., lymphokine activity and macrophage function)
toxoid
T cell numbers Numbers of T cells expressing characteristic membrane Defects in production of circulating T cells
antigens (CD3 or CD11)
T cell proliferation Proliferative response to nonspecific mitogens General T cell defects in response to nonspecific stimulation (mitogens)
in vitro (e.g., phytohemagglutinin)
Proliferative response to antigens (e.g., tetanus toxoid) Defects in response of T cells to specific antigens
T cell subpopulations Quantify percentage of T cells with specific markers for Decrease in numbers of CD4 cells, which is related to AIDS progression
total T cells (CD3), Th cells (CD4), Tc cells (CD8)

Replacement Therapies for Immune Deficiencies Individuals with immune deficiencies are at risk for graft-ver-
Many immune deficiencies can be successfully treated by replacing sus-host disease (GVHD). This occurs if T cells in a transplanted
the missing component of the immune system. Individuals with B cell graft (e.g., transfused blood, bone marrow transplants) are mature
deficiencies that cause hypogammaglobulinemia or agammaglobulin- and therefore capable of cell-mediated immunity against the recipi-
emia usually are treated by administration of gamma globulins, which ent’s human leukocyte antigen (HLA).27 The primary targets for
are antibody-rich fractions prepared from plasma pooled from large GVHD are the skin (e.g., rash, loss or increase of pigment, thicken-
numbers of donors. Administration of gamma globulin temporarily ing of skin), liver (e.g., damage to bile duct, hepatomegaly), mouth
replaces the individual’s antibodies. Antibodies from these prepara- (e.g., dry mouth, ulcers, infections), eyes (e.g., burning, irritation,
tions are removed slowly from the person’s blood, with half of the anti- dryness), and gastrointestinal tract (e.g., severe diarrhea), and
bodies being removed by 3 to 4 weeks. Thus individuals must be treated the disease may lead to death from infections. GVHD is less of a
repeatedly to maintain a protective level of antibodies in the blood. problem when the recipient is immunocompetent—that is, has an
Defects in lymphoid cell development in the primary lymphoid immune system that can control the donor’s lymphocytes. If, how-
organs (e.g., SCID, Wiskott-Aldrich syndrome, leukocyte adhesion ever, the recipient’s immune system is deficient, the grafted T cells
defect) can sometimes be treated by replacement of stem cells through remain unchecked and attack the recipient’s tissues. Most cases of
transplantation of bone marrow, umbilical cord cells, or other cell GVHD should be prevented by the current practices of irradiating
populations that are rich in stem cells.25 Thymic defects (e.g., DiGeorge blood to destroy white blood cells before transfusion or removing
syndrome, ataxia-telangiectasia, or chronic mucocutaneous candidia- mature T cells from tissue used to treat individuals with immune
sis) may be treated by transplantation of fetal thymus tissue or thymic deficiencies.
epithelial cells (the cells that produce the thymic hormones). However, Steroids are commonly used to suppress GVHD in recipients of
in most cases improvement is only temporary. bone marrow transplants to treat certain malignancies or primary
Enzymatic defects that cause SCID (e.g., adenosine deaminase immune deficiencies. In cases where steroids are ineffective, promis-
deficiency) have been treated successfully with transfusions of glyc- ing new data support the use of mesenchymal stem cells (MSCs).27,28
erol frozen-packed erythrocytes. The donor erythrocytes contain Stem cells are relatively undifferentiated cells and can be obtained from
the needed enzyme and can, at least temporarily, provide sufficient a variety of sources (e.g., embryos, bone marrow, adult tissues). MSCs
enzyme for normal lymphocyte function. The first successful gene are present in all adult tissues.29 These particular stem cells undergo
therapy was performed in ADA deficiency, resulting in reconstitution differentiation into other cell types and, more importantly, have
of the immune systems.26 This procedure is being used experimentally potent immunosuppressive properties. Several recent clinical trials
to treat X-linked SCID, ADA-deficient SCID, and X-linked chronic have demonstrated complete suppression of GVHD in a large number
granulomatous disease. of recipients of MSCs.
 CHAPTER 7  Infection and Defects in Mechanisms of Defense 183

gp41 p17 matrix

gp120

p24 capsid
Lipid bilayer
Integrase

Protease

RNA
Reverse
transcriptase

gag pol Env

Large protein processed Polymerase Envelope (gp160)
by viral protease into Encodes viral enzymes Large protein processed by cellular
Matrix protein (p17), Protease, Reverse protease into
Capsid protein (p24), transcriptase, Integrase, Transmembrane protein (gp41) and
and others. and RNAse H Surface protein (gp120) that binds to
CD4 and chemokine receptors

nef
gag vif vpu env
LTR LTR
pol vpr tat
rev

LTR vif, vpr, vpu, tat, rev, nef

Long Terminal Repeat Regulatory Proteins
Required for the initiation Affect transcription activity, rate of the release of new
of transcription virions, integration of viral DNA, and other activities
FIGURE 7-5  The Structure and Genetic Map of HIV-1. The HIV-1 virion consists of a core of two
identical strands of viral RNA molecules of viral enzymes (reverse transcriptase [RT], protease [PR],
integrase [IN]) encoated in a core capsid structure consisting primarily of the structural viral protein p24.
The capsid is further encased in a matrix consisting primarily of viral protein p17. The outer surface is
an envelope consisting of the plasma membrane of the cell from which the virus budded (lipid bilayer)
and two viral glycoproteins: a transmembrane glycoprotein, gp41, and a noncovalently attached surface
protein, gp120. The HIV-1 genome contains regions that encode the structural proteins (gag), the viral
enzymes (pol), and the envelope proteins (env). The genome of complex retroviruses, like HIV-1, often
contains a variety of small regions that regulate expression of the virus. (Modified from Kumar V et al:
Robbins and Cotran pathologic basis of disease, ed 8, Philadelphia, 2009, Saunders.)

Despite major efforts by healthcare agencies around the world, the

Acquired Immunodeficiency Syndrome (AIDS) number of cases and deaths from HIV infection and AIDS (HIV/AIDS)
Acquired immunodeficiency syndrome is a secondary immune remains a major health concern. The WHO estimated that in 2008 33.4
deficiency that develops in response to viral infection. The human million people were living with HIV/AIDS worldwide and 2.7 million
immunodeficiency virus (HIV) infects and destroys the Th cell, were newly infected.30 Approximately 3 million deaths occur each year
which is necessary for the development of both plasma cells and from AIDS. Since 1980 it is estimated that more than 24 million indi-
cytotoxic T cells. Therefore HIV suppresses the immune response viduals have died from AIDS worldwide.
against itself and secondarily creates a generalized immune defi- The majority of cases are still in sub-Saharan Africa, but the epi-
ciency by suppressing the development of immune responses demic is worldwide, and the number of new cases is increasing rapidly,
against other pathogens and opportunistic microorganisms, lead- particularly in Asia. As an example of the prevalence of HIV/AIDS,
ing to the development of acquired immunodeficiency syndrome in sub-Saharan Africa approximately 1.3 million pregnant women are
(AIDS). HIV infected.30
184 CHAPTER 7  Infection and Defects in Mechanisms of Defense

In the United States the spread of HIV/AIDS remains somewhat

HEALTH ALERT
stable. The Centers for Disease Control and Prevention (CDC) esti-
mated in 2008 (the most recent data) that approximately 56,300 peo- Risk of HIV Transmission Associated With Sexual
ple were newly infected with HIV and about 38,000 were diagnosed Practices
with AIDS.31 Deaths related to HIV/AIDS continue at about 18,000
High Risk (in descending order of risk)
per year. The cumulative number of HIV/AIDS-related deaths in the
Receptive anal intercourse with ejaculation (no condom)
United States is in excess of 600,000, and more than 470,000 individu-
Receptive vaginal intercourse with ejaculation (no condom)
als are currently living with AIDS.
Insertive anal intercourse (no condom)
Before the implementation of massive public health campaigns
Insertive vaginal intercourse (no condom)
and the use of antiviral drugs in the United States, the progression
Receptive anal intercourse with withdrawal before ejaculation
from HIV infection to AIDS and death was unrelenting. In 1995
Insertive anal intercourse with withdrawal before ejaculation
AIDS became the number one killer of individuals between the ages
Receptive vaginal intercourse (with spermicidal foam but no condom)
of 25 and 44 years. With the advent of effective therapy to stabi-
Insertive vaginal intercourse (with spermicidal foam but no condom)
lize progression of the disease in the mid-1990s, HIV infection has
Receptive anal or vaginal intercourse (with a condom)*
become a chronic disease in the United States, with many fewer
Insertive anal or vaginal intercourse (with a condom)*
deaths.
Some Risk (in descending order of risk)
Epidemiology of AIDS Oral sex with men with ejaculation
HIV is a blood-borne pathogen with the typical routes of transmission: Oral sex with women
blood or blood products, intravenous drug abuse, both heterosexual Oral sex with men with preejaculation fluid (precum)
and homosexual activity, and maternal-child transmission before or Oral sex with men, no ejaculation or precum
during birth. Although the disease first gained attention in the United Oral sex with men (with a condom)
States related to sexual transmission between males, the most common
route worldwide is through heterosexual activity (see Health Alert: Risk Some Risk (depending on situation, intactness of mucous
of HIV Transmission Associated With Sexual Practices). Worldwide, membranes, etc.)
women constitute more than half of those living with HIV/AIDS. In Mutual masturbation with external or internal touching
the United States, as in the rest of the world, the predominant means Sharing sex toys
of transmission to women is through heterosexual contact, and the Anal or vaginal fisting
incidence of HIV/AIDS is increasing faster in women than men, par-
ticularly in the adolescent age groups. Hundreds of thousands of cases No Risk
of HIV/AIDS have been reported in children who contracted the virus Masturbating with another person without touching one another
from their mothers across the placenta, through contact with infected Hugging/massage/dry kissing
blood during delivery, or through the milk during breast-feeding. Frottage (rubbing genitals while remaining clothed)
Masturbating alone
Pathogenesis of AIDS Abstinence
HIV is a member of a family of viruses called retroviruses, which carry
genetic information in the form of RNA rather than DNA (Figure 7-5). Unresolved Issues
Retroviruses use a viral enzyme, reverse transcriptase, to convert RNA The role of precum in transmission
into double-stranded DNA. Using a second viral enzyme, an integrase, The protection offered by covering female genitals with a dental dam during
the new DNA is inserted into the infected cell’s genetic material, where oral sex on the women
it may remain dormant. If the cell is activated, translation of the viral The risk of transmission from wet kissing
information may be initiated, resulting in the formation of new viri- Data from Grimes DE, Grimes RM: HIV infection: progression and
ons, lysis and death of the infected cell, and shedding of infectious HIV management. Mosby’s clinical nursing series, St Louis, 1994, Mosby;
particles. During that process the viral protease is essential in pro- modified from Schram NR: Refusing safer sex, Focus 5(7):3–4, 1990.
cessing proteins needed from the viral internal structure (capsid). If, *Risk lower if no ejaculation or if spermicidal foam is used.
however, the cell remains relatively dormant, the viral genetic material
may remain latent for years and is probably present for the life of the
individual. (positive for antibody against HIV proteins) but asymptomatic, early
The primary surface receptor on HIV is the envelope protein stages of HIV disease, or AIDS (Figure 7-7).
gp120, which binds to the molecule CD4 on the surface of Th cells. The presence of circulating antibody against the HIV protein p24
Several other necessary co-receptors, particularly the chemokine followed by more complex tests for antibodies against additional HIV
receptor CCR5, have been identified on target cells. Thus the major proteins (e.g., Western blot analysis) or for HIV DNA (e.g., polymerase
immunologic finding in AIDS is the striking decrease in the number of chain reaction) indicates infection by the virus, although many of these
CD4-positive (CD4+) Th cells (Figure 7-6). individuals are asymptomatic.22 Antibody appears rather rapidly after
infection through blood products, usually within 4 to 7 weeks. After
Clinical Manifestations of AIDS sexual transmission, however, the individual can be infected yet sero-
Depletion of CD4+ cells has a profound effect on the immune system, negative for 6 to 14 months or longer. The period between infection
causing a severely diminished response to a wide array of infectious and the appearance of antibody is referred to as the window period.
pathogens and malignant tumors (Box 7-3). At the time of diagnosis, Although a person does not have antibody against HIV, he or she may
the individual may present with one of several different conditions: have virus growing, have virus in the blood and body fluids, and be
serologically negative (no detectable antibody), serologically positive infectious to others.
 CHAPTER 7  Infection and Defects in Mechanisms of Defense 185

Virion binding to CD4 Fusion of HIV membrane New HIV

and chemokine receptor with host cell membrane; virion
entry of viral genome
HIV virion into cytoplasm HIV
gp120/
gp41
Chemokine
receptor Cytokine
Budding
Cytokine and release
Plasma
receptor of mature
membrane
virion

CD4 HIV RNA

genome
Entrance inhibitors
Reverse
transcriptase
Reverse transcriptase inhibitors
Cytokine activation of
cell; transcription of HIV
Proviral DNA genome; transport of
Integrase inhibitors HIV core
viral RNAs to cytoplasm
structure
Integration of provirus
Synthesis of HIV
into host cell genome
proteins; assembly
of virion core Protease
inhibitors
HIV DNA
HIV RNA
provirus
Nucleus transcript
FIGURE 7-6  Life Cycle and Possible Sites of Therapeutic Intervention of Human Immunodefi-
ciency Virus (HIV). The HIV virion consists of a core of two identical strands of viral RNA encoated in
a protein structure with viral proteins gp41 and gp120 on its surface (envelope). HIV infection begins
when a virion binds to CD4 and chemokine co-receptors on a susceptible cell and follows the process
described here. The provirus may remain latent in the cell’s DNA until it is activated (e.g., by cyto-
kines). The HIV life cycle is susceptible to blockage at several sites (see the text for further informa-
tion), including entrance inhibitors, reverse transcriptase inhibitors, integrase inhibitors, and protease
inhibitors. (Modified from Kumar V, Abbas A, Fausto N: Robbins and Cotran pathologic basis of disease,
ed 7, Philadelphia, 2005, Saunders.)

BOX 7-3 AIDS-DEFINING OPPORTUNISTIC INFECTIONS AND NEOPLASMS FOUND

IN INDIVIDUALS WITH HIV INFECTION
Infections Nocardiosis (pneumonia, meningitis, disseminated)
Protozoal and Helminthic Infections Salmonella infections (disseminated)
Cryptosporidiosis or isosporiasis (enteritis)
Pneumocystosis (pneumonia or disseminated infection) Viral Infections
Toxoplasmosis (pneumonia or CNS infection) Cytomegalovirus (pulmonary, intestinal, retinitis, or CNS)
Herpes simplex virus (localized or disseminated)
Fungal Infections Progressive multifocal leukoencephalopathy
Candidiasis (esophageal, tracheal, or pulmonary) Varicella-zoster virus (localized or disseminated)
Coccidioidomycosis (disseminated)
Cryptococcosis (CNS infection) Neoplasms
Histoplasmosis (disseminated) Invasive cancer of the uterine cervix
Kaposi sarcoma
Bacterial Infections Non-Hodgkin lymphomas (Burkitt, immunoblastic)
Mycobacteriosis (“atypical,” e.g., Mycobacterium avium-intracellulare, dissemi- Primary lymphoma of brain
nated or extrapulmonary; M. tuberculosis, disseminated or extrapulmonary)

From Kumar V et al: Robbins and Cotran pathologic basis of disease, ed 8, Philadelphia, 2009, Saunders.
CNS, Central nervous system.
186 CHAPTER 7  Infection and Defects in Mechanisms of Defense

CD4+
T cells
1200
Possible acute HIV syndrome Death
1100 Wide dissemination of virus Anti-envelope
1000 Seeding of lymphoid organs Opportunistic 1:512 antibody
900 diseases 1:256
800 Clinical latency 1:128
700 Anti-p24
1:64 antibody
600
Constitutional 1:32
500 symptoms
1:16
400
300 1:8
CTLs specific
200 1:4 for HIV peptides Viral particles
in plasma
100 1:2
0 0
A 0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11 B 0 3 6 9 12 2 4 6 8 10 12 14 16
Weeks Years Weeks Years
Plasma viremia titer
CD4+ T cells/mm3
FIGURE 7-7  Typical Progression from HIV Infection to AIDS in Untreated Persons. A, Clinical pro-
gression begins within weeks after infection; the person may experience symptoms of acute HIV
syndrome. During this early period, the virus progressively infects T cells and other cells and spreads to
the lymphoid organs, with a sharp decrease in the number of circulating CD4+ T cells. During a period
of clinical latency, the virus replicates and T cell destruction continues, although the person is generally
asymptomatic. The individual may develop HIV-related disease (constitutional symptoms)—a variety of
symptoms of acute viral infection that do not involve opportunistic infections or malignancies. When
the number of CD4+ cells is critically suppressed, the individual becomes susceptible to a variety of
opportunistic infections and cancers with a diagnosis of AIDS. The length of time for progression from
HIV infection to AIDS may vary considerably from person to person. B, Laboratory tests are changing
throughout infection. Antibody and Tc cell (cytotoxic T lymphocytes [CTLs]) levels change during the
progression to AIDS. During the initial phase antibodies against HIV-1 are not yet detectable (window
period), but viral products, including proteins and RNA, and infectious virus may be detectable in the
blood a few weeks after infection. Most antibodies against HIV are not detectable in the early phase.
During the latent phase of infection antibody levels against p24 and other viral proteins, as well as
HIV-specific CTLs, increase, and then remain constant until the development of AIDS. (A redrawn from
Fauci AS, Lane HC: Human immunodeficiency virus disease: AIDS and related conditions. In Fauci AS
et al, editors: Harrison’s principles of internal medicine, ed 14, New York, 1997, McGraw-Hill; B from
Kumar V, Abbas A, Fausto N: Robbins and Cotran pathologic basis of disease, ed 7, Philadelphia, 2005,
Saunders.)

Those with the early stages of HIV disease (early-stage disease) Treatment and Prevention of AIDS
usually initially present with relatively mild and nonspecific symp- Approved AIDS medications are classified by mechanism of action:
toms resembling influenza, such as headaches, fever, or fatigue.23 nucleoside and nonnucleoside inhibitors of reverse transcriptase
These symptoms disappear after 1 to 6 weeks, and although individu- (reverse transcriptase inhibitors), inhibitors of the viral protease
als appear to be in clinical latency the virus is actively proliferating in (protease inhibitors), inhibitors of cell fusion (cell fusion inhibitors),
lymph nodes. inhibitors of viral entrance into the target cell (entrance inhibitors),
The currently accepted definition of AIDS relies on both labora- and inhibitors of the viral integrase (integrase inhibitors).22 The cur-
tory tests and clinical symptoms. If the individual is positive for anti- rent regimen for treatment of HIV infection is a combination of drugs,
bodies against HIV, the diagnosis of AIDS is made in association with termed highly active antiretroviral therapy (HAART). HAART pro-
various clinical symptoms (Figure 7-8; also see Box 7-3). The symp- tocols require a combination of three synergist drugs from two dif-
toms include atypical or opportunistic infections and cancers, as well ferent classes (see Figure 7-6). The clinical benefits of HAART are
as indications of debilitating chronic disease (e.g., wasting syndrome, profound. Death from AIDS-related diseases has been reduced signifi-
recurrent fevers). Most commonly, new cases of AIDS are diagnosed cantly since the introduction of HAART.26 However, resistant variants
initially by decreased CD4+ T cell numbers. Individuals who are not to these drugs have been identified. Drug therapy for AIDS is not cura-
HIV infected typically have 800 to 1000 CD4+ cells per cubic milli- tive because HIV incorporates into the genetic material of the host
meter of blood, with a range from 600/mm3 to 1200/mm3. A diag- and may never be removed by antimicrobial therapy. Therefore drug
nosis of AIDS can be made if the CD4+ T cell numbers decrease to administration to control the virus may have to continue for the life-
less than 200/mm3. The average time from infection to development time of the individual. Additionally, HIV may persist in regions where
of AIDS has been estimated at just over 10 years. Some estimates are the antiviral drugs are not as effective, such as the CNS.
that approximately 99% of untreated HIV-infected individuals would Vaccine development is probably the most effective means of
eventually progress to AIDS. preventing HIV infection and may be useful in treating preexisting
 CHAPTER 7  Infection and Defects in Mechanisms of Defense 187

A B

C D
FIGURE 7-8  Clinical Symptoms of AIDS. A, Severe weight loss and anorexia. B, Kaposi sarcoma
lesions. C, Perianal lesions of herpes simplex infection. D, Deterioration of vision from cytomegalovirus
retinitis leading to areas of infection, which can lead to blindness. (A and D from Taylor PK: Diagnostic
picture tests in sexually transmitted diseases, London, 1995, Mosby; B and C from Morse SA, Ballard RC,
Holmes KK et al, editors: Atlas of sexually transmitted diseases and AIDS, ed 3, Edinburgh, 2003, Mosby.)

infection. Most of the common viral vaccines (e.g., rubella, mumps, Pediatric AIDS and Central Nervous System Involvement
influenza) induce protective antibodies that block the initial infection. HIV can be transmitted from mother to child during pregnancy, at the
Only one vaccine (rabies) is used after the infection has occurred.32 time of delivery, or through breast-feeding. The clinical diagnosis of
The rabies vaccine is successful because the rabies virus proliferates HIV infection in young children born of HIV-infected mothers is very
and spreads very slowly. The ability of an HIV vaccine to either suc- often a difficult task because the presence of maternal antibodies may
cessfully prevent or treat HIV infection is questionable for several rea- result in a misleading false-positive test for antibodies against HIV for
sons. First, the AIDS virus is genetically and antigenically variable, like as long as 18 months after birth.33 Testing for antibody against HIV
the influenza virus, so that a vaccine created against one variant may can be performed recurrently from birth until 18 months; if the test
not provide protection against another variant. Second, although indi- results become negative and remain so after 12 months, the child can
viduals with AIDS have high levels of circulating antibodies against the be considered uninfected.
virus, these antibodies do not appear to be protective. Therefore even The 2008 revised surveillance case definition for HIV infection in
if a circulating antibody response can be induced by vaccination, that children younger than 18 months recommends testing for HIV or viral
response might not be effective. A vaccine may have to induce both components in two separate specimens, not including cord blood.
circulating and secretory (to prevent initial infection of the mucosal These include detection of HIV nucleic acid or p24 antigen, or direct
T cell) antibody and Tc cells (see Health Alert: AIDS Vaccine Trials). isolation of HIV in viral cultures.
188 CHAPTER 7  Infection and Defects in Mechanisms of Defense

HEALTH ALERT
AIDS Vaccine Trials
Very soon after the discovery in 1983 of the virus that causes AIDS, knowledge- with HIV was 31.2%, which was regarded as modest. This is the first positive
able scientists and public officials predicted that an effective vaccine would be effect reported for an HIV vaccine. However, considerable caution was advised
marketed within a few years. The prediction was not viewed as overly optimistic in interpreting the long-term significance of these observations. The HIV vaccine
because vaccines had been produced against many other viral diseases, and the protocol consisted of four priming injections with a canarypox virus that was
technology was available to swiftly purify, test, and manufacture viral antigens. altered to prevent infection of humans and genetically engineered to express
In 2011, more than 25 years after the discovery of HIV, optimism about producing versions of HIV gag, pol, and env proteins (ALVAC-HIV vaccine), followed by two
vaccine protection against AIDS continues to vacillate. booster injections with a vaccine containing recombinant gp120 subunits (AIDS-
The goal of an AIDS vaccine is to either prevent the initial infection or enhance VAX B/E vaccine). The effects of the priming-booster protocol were surprising
the immune response of an infected individual to reduce viral load, or both. Sev- because neither vaccine appeared to be beneficial when tested separately. The
eral recent trails of promising AIDS vaccines failed to protect recipients. The ALVAC-HIV vaccine, after recurrent testing, was considered of inadequate immu-
STEP Study was a trial of vaccine V520, produced by Merck. The immunization nogenicity, and the AIDSVAX B/E vaccine was not efficacious in two previous
protocol was very complex and elicited a T cell immune response against several clinical trials. Additionally, the test population was considered low to medium
HIV antigens, including products of HIV env, gag, pol, and nef genes expressed risk for contracting HIV and was primarily heterosexual. Another drawback was
in an altered adenovirus—a common cold virus. The trial was prematurely ter- that the HIV strains used to produce the vaccine were common in Thailand,
minated in September of 2007 because the initial analysis indicated that the Europe, and the Americas, but far less common in Africa. Thus the efficacy of
vaccine neither prevented HIV infection nor lowered viral load in the blood of this protocol is unknown in the African population, in individuals at high risk for
those who became infected; in fact, the vaccine was suspected of increasing the contracting HIV infection through intravenous drug abuse, or in men who have
risk for HIV infection in some recipients. sex with men. Regardless of those limitations, this trial was the first indication
The most recent trial, however, has fostered a new, but cautious, optimism. that an HIV vaccine could affect the rate of initial infection. With further refine-
More than 16,000 men and women in Thailand were immunized with HIV vac- ments and implementation of our expanding knowledge about HIV, future vac-
cines or with placebo. The efficacy of vaccination in reducing initial infection cine efforts may approach the goal of preventing global HIV infection and AIDS.

Data from Johnston MI, Fauci AS: N Engl J Med 359(9):888–890, 2008; Editorial: HIV vaccine trials and tribulations, Lancet Infect Dis 9(11):651,
2009; Dolin R: HIV vaccine trial results—an opening for further research, N Engl J Med 361(23):2279–2280, 2009; Rerks-Ngarm S et al: Vaccination
with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand, N Engl J Med 361(23):2209–2220, 2009; Bansal GP, Malaspina A, Flores J: Future
paths for HIV vaccine research: exploiting results from recent clinical trials and current scientific advances, Curr Opin Mol Ther 12(1):39–46, 2010.

HIV infection of babies is generally more aggressive than in adults;

on average an untreated child will die by his or her second birthday. 4 QUICK CHECK 7-2
Neurologic involvement occurs more commonly in children than 1. Why is the development of recurrent or unusual infections the clinical hall-
in adults and results from CNS involvement, rather than effects on mark of immunodeficiency?
peripheral portions of the nervous system. HIV encephalopathy occurs 2. Compare and contrast the most common infections in individuals with
with varying degrees of severity and is a clinical component in the diag- defects in cell-mediated immune response and those with defects in
nosis of AIDS in children. Most HIV-infected newborns appear nor- humoral immune response.
mal, but may progressively develop signs of CNS involvement. These 3. What are the new treatments for HIV?
usually appear as failure to attain, or loss of, developmental milestones
or loss of intellectual ability, verified by standard developmental scale
or neuropsychologic tests; acquired symmetric motor deficits, seen in HYPERSENSITIVITY: ALLERGY, AUTOIMMUNITY,
children older than age 1 month; impaired brain growth or acquired
microcephaly, demonstrated by head circumference measurements; or
AND ALLOIMMUNITY
brain atrophy, demonstrated by computed tomography (CT) or mag- Allergy, autoimmunity, and alloimmunity are classified as hypersensi-
netic resonance imaging (MRI) with serial imaging and required in tivity reactions. Hypersensitivity is an altered immunologic response to
children younger than 2 years of age. an antigen that results in disease or damage to the individual. Allergy,
It may be difficult to completely differentiate the effect of HIV autoimmunity, and alloimmunity (also termed isoimmunity) can be
infection on the CNS from other risk factors, including prenatal drug most easily understood in relationship to the source of the antigen
exposure, prematurity, chronic illness, and a chaotic social atmo- against which the hypersensitivity response is directed (Table 7-13).
sphere. The pathogenesis of HIV encephalopathy in children is poorly Allergy refers to a hypersensitivity to environmental antigens. These
understood, but the presence of inflammatory mediators may be a can include medicines, natural products (e.g., pollens, bee stings),
contributing factor. infectious agents, and any other antigen that is not naturally found in
Because HIV infection in infants progresses very rapidly, treatment the individual.
must begin at the diagnosis of infection. In older children the criteria Autoimmunity is a disturbance in the immunologic tolerance of
for treatment are similar to those used in adults. A growing number of self-antigens. The immune system normally does not strongly rec-
investigational protocols are available for treatment of children with ognize the individual’s own antigens. Healthy individuals of all ages,
HIV. In general, treatment is focused on the preservation and main- but particularly the elderly, may produce low quantities of antibodies
tenance of the immune system, aggressive response to opportunistic against their own antigens (autoantibodies) without developing overt
infections, support and relief of symptomatic occurrences, and admin- autoimmune disease. Therefore the presence of low quantities of auto-
istration of HAART. antibodies does not necessarily indicate a disease state. Autoimmune
 CHAPTER 7  Infection and Defects in Mechanisms of Defense 189

TABLE 7-13 RELATIVE INCIDENCE AND EXAMPLES OF HYPERSENSITIVITY DISEASES*

MECHANISM
TYPE I TYPE II TYPE III TYPE IV
TARGET ANTIGEN (IGE MEDIATED) (TISSUE SPECIFIC) (IMMUNE COMPLEX MEDIATED) (CELL MEDIATED)
Allergy ++++ + + ++
Environmental antigens Hay fever Hemolysis in drug allergies Gluten (wheat) allergy Poison ivy allergy
Autoimmunity + ++ +++ ++
Self-antigens May contribute to some Autoimmune thrombocytopenia Systemic lupus erythematosus Hashimoto thyroiditis
type III reactions
Alloimmunity + ++ + ++
Another person’s May contribute to some Hemolytic disease of the Individuals who do not make their own IgA Graft rejection
antigens type III reactions newborn may have an anaphylactic response against
IgA in human immune globulin

*The frequency of each reaction is indicated in a range from rare (+) to very common (++++). An example of each reaction is given.

TABLE 7-14 EXAMPLES OF AUTOIMMUNE DISORDERS

SYSTEM DISEASE ORGAN OR TISSUE PROBABLE SELF-ANTIGEN

Endocrine System
Hyperthyroidism (Graves disease) Thyroid gland Receptors for thyroid-stimulating hormone on plasma membrane of thyroid cells
Hashimoto hypothyroidism Thyroid gland Thyroid cell-surface antigens, thyroglobulin
Insulin-dependent diabetes Pancreas Islet cells, insulin, insulin receptors on pancreatic cells
Addison disease Adrenal gland Surface antigens on steroid-producing cells; microsomal antigens
Male infertility Testis Surface antigens on spermatozoa

Skin
Pemphigus vulgaris Skin Intercellular substances in stratified squamous epithelium
Bullous pemphigoid Skin Basement membrane
Vitiligo Skin Surface antigens on melanocytes (melanin-producing cells)

Neuromuscular Tissue
Multiple sclerosis Neural tissue Surface antigens of nerve cells
Myasthenia gravis Neuromuscular junction Acetylcholine receptors; striations of skeletal and cardiac muscle
Rheumatic fever Heart Cardiac tissue antigens that cross-react with group A streptococcal antigen
Cardiomyopathy Heart Cardiac muscle

Gastrointestinal System
Ulcerative colitis Colon Mucosal cells
Pernicious anemia Stomach Surface antigens of parietal cells; intrinsic factor
Primary biliary cirrhosis Liver Cells of bile duct
Chronic active hepatitis Liver Surface antigens of hepatocytes, nuclei, microsomes, smooth muscle

Eye
Sjögren syndrome Lacrimal gland Antigens of lacrimal gland, salivary gland, thyroid, and nuclei of cells

Connective Tissue
Ankylosing spondylitis Joints Sacroiliac and spinal apophyseal joint
Rheumatoid arthritis Joints Collagen, IgG
Systemic lupus erythematosus Multiple sites Numerous antigens in nuclei, organelles, and extracellular matrix

Renal System
Immune complex glomerulonephritis Kidney Numerous immune complexes
Goodpasture syndrome Kidney Glomerular basement membrane

Hematologic System
Idiopathic neutropenia Neutrophil Surface antigens on polymorphonuclear neutrophils
Idiopathic lymphopenia Lymphocytes Surface antigens on lymphocytes
Autoimmune hemolytic anemia Erythrocytes Surface antigens on erythrocytes
Autoimmune thrombocytopenic purpura Platelets Surface antigens on platelets

Respiratory System
Goodpasture syndrome Lung Septal membrane of alveolus
190 CHAPTER 7  Infection and Defects in Mechanisms of Defense

diseases occur when the immune system reacts against self-antigens is an allergic reaction to bee stings. Cutaneous anaphylaxis results in
to such a degree that autoantibodies or autoreactive T cells damage local symptoms, such as pain, swelling, and redness, which occur at
the individual’s tissues. Many clinical disorders are associated with the site of exposure to an antigen (e.g., a painful local reaction to an
autoimmunity and are generally referred to as autoimmune diseases injected vaccine or drug).
(Table 7-14).
Alloimmune diseases occur when the immune system of one indi- Type I: IgE-Mediated Hypersensitivity Reactions
vidual produces an immunologic reaction against tissues of another Type I reactions are mediated by antigen-specific IgE and the prod-
individual. Alloimmunity can be observed during immunologic reac- ucts of tissue mast cells (Figure 7-9). Most common allergic reactions
tions against transfusions, transplanted tissue, or the fetus during are type I reactions. In addition, most type I reactions occur against
pregnancy. environmental antigens and are therefore allergic. Because of this
The mechanism that initiates the onset of hypersensitivity, whether strong association, many healthcare professionals use the term allergy
allergy, autoimmunity, or alloimmunity, is not completely understood. to indicate only IgE-mediated reactions. However, IgE can contribute
It is generally accepted that genetic, infectious, and possibly environ- to some autoimmune and alloimmune diseases, and many common
mental factors contribute to development of hypersensitivity reactions. allergies (e.g., poison ivy) are not mediated by IgE.
IgE has a relatively short life span in the blood because it rap-
Mechanisms of Hypersensitivity idly binds to Fc receptors on mast cells.35 Unlike Fc receptors on
Diseases caused by hypersensitivity reactions can be characterized also phagocytes, which bind IgG that has previously reacted with anti-
by the particular immune mechanism that results in the disease (Table gen, the Fc receptors on mast cells specifically bind IgE that has
7-15). These mechanisms are apparent in most hypersensitivity reac- not previously interacted with antigen. After a large amount of IgE
tions and have been divided into four distinct types: type I (IgE-medi- has bound to the mast cells, an individual is considered sensitized.
ated reactions), type II (tissue-specific reactions), type III (immune Further exposure of a sensitized individual to the allergen results in
complex–mediated reactions), and type IV (cell-mediated reactions). degranulation of the mast cell and the release of mast cell products
This classification is artificial and seldom is a particular disease associ- (see Chapter 5).
ated with only a single mechanism. The four mechanisms are inter- Mechanisms of IgE-mediated hypersensitivity. The most potent
related, and in most hypersensitivity reactions several mechanisms can mediator of IgE-mediated hypersensitivity is histamine, which affects
be functioning simultaneously or sequentially. several key target cells. Acting through H1 receptors, histamine con-
As with all immune responses, hypersensitivity reactions require sen- tracts bronchial smooth muscles (bronchial constriction), increases
sitization against a particular antigen that results in a primary immune vascular permeability (edema), and causes vasodilation (increased
response. Disease symptoms appear after an adequate secondary blood flow) (see Chapter 5). The interaction of histamine with H2
immune response occurs. Hypersensitivity reactions are immediate or receptors results in increased gastric acid secretion. Some type I aller-
delayed, depending on the time required to elicit clinical symptoms after gic responses can be controlled by blocking histamine receptors with
reexposure to the antigen. Reactions that occur within minutes to a few antihistamines.
hours after exposure to antigen are termed immediate hypersensitivity Clinical manifestations of IgE-mediated hypersensitivity. The
reactions. Delayed hypersensitivity reactions may take several hours to clinical manifestations of type I reactions are attributable mostly to
appear and are at maximal severity days after reexposure to the antigen. the biologic effects of histamine. The tissues most commonly affected
Generally, immediate reactions are caused by antibody, whereas delayed by type I responses contain large numbers of mast cells and are sensi-
reactions are caused by cells (e.g., T cells, NK cells, macrophages). tive to the effects of histamine released from them. These tissues are
The most rapid and severe immediate hypersensitivity reaction is found in the gastrointestinal tract, the skin, and the respiratory tract
anaphylaxis. Anaphylaxis occurs within minutes of reexposure to the (Figure 7-10 and Table 7-16).
antigen and can be either systemic (generalized) or cutaneous (local- Gastrointestinal allergy is caused primarily by allergens that enter
ized).34 Symptoms of systemic anaphylaxis include pruritus, erythema, through the mouth—usually foods or medicines. Symptoms include
vomiting, abdominal cramps, diarrhea, and breathing difficulties. vomiting, diarrhea, or abdominal pain. Foods most often implicated
Severe anaphylactic reactions may include contraction of bronchial in gastrointestinal allergies are milk, chocolate, citrus fruits, eggs,
smooth muscle, edema of the throat, breathing difficulties, decreased wheat, nuts, peanut butter, and fish. The most common food allergy
blood pressure, shock, and death. An example of systemic anaphylaxis in adults is a reaction to shellfish, which may initiate an anaphylactic

TABLE 7-15 IMMUNOLOGIC MECHANISMS OF TISSUE DESTRUCTION

CLASS OF PRINCIPAL
RATE OF ANTIBODY EFFECTOR PARTICIPATION EXAMPLES
TYPE NAME DEVELOPMENT INVOLVED CELLS INVOLVED OF COMPLEMENT OF DISORDERS
I IgE-mediated reaction Immediate IgE Mast cells No Seasonal allergic rhinitis
Asthma
II Tissue-specific reaction Immediate IgG Macrophages in Frequently Autoimmune thrombocytopenic
IgM tissues purpura, Graves disease, auto-
immune hemolytic anemia
III Immune complex–­ Immediate IgG Neutrophils Yes Systemic lupus erythematosus
mediated reaction IgM
IV Cell-mediated reaction Delayed None Lymphocytes No Contact sensitivity to poison
Macrophages ivy and metals (jewelry)
 CHAPTER 7  Infection and Defects in Mechanisms of Defense 191

Sensitizing exposure Reexposure

Mucosal
Allergen cells

IL-4
IL-13 Edema
Smooth muscle contraction
APC Mucous secretion
Th2 cell
B cell

Plasma cell Mast cell

Histamine degranulation

IgE Mast cell

IgE Fc
receptor
FIGURE 7-9  Mechanism of Type I, IgE-Mediated Reactions. First exposure to an allergen leads to anti-
gen processing and presentation of antigen by an antigen-presenting cell (APC) to B lymphocytes, which
is under the direction of T-helper 2 (Th2) cells. Th2 cells produce specific cytokines (e.g., IL-4, IL-13, and
others) that favor maturation of the B lymphocytes into plasma cells that secrete IgE. The IgE is adsorbed
to the surface of the mast cell by binding with IgE-specific Fc receptors. When an adequate amount of
IgE is bound the mast cell is sensitized. During a reexposure, the allergen cross-links the surface-bound
IgE and causes degranulation of the mast cell. Contents of the mast cell granules, primarily histamine,
induce local edema, smooth muscle contraction, mucous secretion, and other characteristics of an acute
inflammatory reaction. (See Chapter 5 for more details on the role of mast cells in inflammation.)

response and death.36 When food is the source of an allergen, the active Symptoms are caused by vasodilation, hypersecretion of mucus,
immunogen may be an unidentifiable product of food breakdown by edema, and swelling of the respiratory mucosa. Because the mucous
digestive enzymes. Sometimes the allergen is a drug, an additive, or a membranes lining the respiratory tract are continuous, they are all
preservative in the food. For example, cows treated for mastitis with adversely affected. The degree to which each is affected determines the
penicillin yield milk containing trace amounts of this antibiotic. Thus symptoms of the disease.
hypersensitivity apparently caused by milk proteins may instead be the The central problem in allergic diseases of the lung is obstruction
result of an allergy to penicillin. of the large and small airways (bronchi) of the lower respiratory tract
Urticaria, or hives, is a dermal (skin) manifestation of allergic reac- by bronchospasm (constriction of smooth muscle in airway walls),
tions (see Figure 7-10). The underlying mechanism is the localized release edema, and thick secretions. This leads to ventilatory insufficiency,
of histamine and increased vascular permeability, resulting in limited wheezing, and difficult or labored breathing (see Chapter 26).39
areas of edema. Urticaria is characterized by white fluid-filled blisters Certain individuals are genetically predisposed to develop allergies
(wheals) surrounded by areas of redness (flares). This wheal and flare and are called atopic.40 In families in which one parent has an allergy,
reaction is usually accompanied by pruritus. Not all urticarial symptoms allergies develop in about 40% of the offspring. If both parents have aller-
are caused by immunologic reactions. Some, termed nonimmunologic gies, the incidence may be as high as 80%. Atopic individuals tend to pro-
urticaria, result from exposure to cold temperatures, emotional stress, duce higher quantities of IgE and have more Fc receptors for IgE on their
medications, systemic diseases, or malignancies (e.g., lymphomas). mast cells. The airways and the skin of atopic individuals have increased
Effects of allergens on the mucosa of the eyes, nose, and respiratory responsiveness to a wide variety of both specific and nonspecific stimuli.
tract include conjunctivitis (inflammation of the membranes lining Evaluation and treatment of IgE hypersensitivity. Allergic reactions
the eyelids) (see Figure 7-10), rhinitis (inflammation of the mucous can be life-threatening; therefore it is essential that severely allergic
membranes of the nose),37 and asthma (constriction of the bronchi).38 individuals be informed of the specific allergen against which they are
192 CHAPTER 7  Infection and Defects in Mechanisms of Defense

Itching

Conjunctivitis
Rhinitis
Angioedema
Laryngeal edema
Urticaria Hypotension

Bronchospasm
(asthma)

Dysrhythmias

Gastrointestinal
cramps and
malabsorption
Angioedema

FIGURE 7-10  Type I Hypersensitivity Reactions. Manifestations of allergic reactions as a result of

type I hypersensitivity include pruritus, angioedema (swelling caused by exudation), edema of the
larynx, urticaria (hives), bronchospasm (constriction of airways in the lungs), hypotension (low blood
pressure), and dysrhythmias (irregular heartbeat) because of anaphylactic shock, and gastrointestinal
cramping caused by inflammation of the gastrointestinal mucosa. Photographic inserts show a diffuse
allergic-like eye and skin reaction on an individual. The skin lesions have raised edges and develop
within minutes or hours, with resolution occurring after about 12 hours. (From Roitt I, Brostoff J, Male
D: Immunology, ed 6, St Louis, 2001, Mosby.)

TABLE 7-16 CAUSES OF CLINICAL ALLERGIC REACTIONS

MECHANISM
TYPICAL ALLERGEN OF HYPERSENSITIVITY CLINICAL MANIFESTATION

Ingestants
Foods Type I Gastrointestinal allergy
Drugs Types I, II, III Urticaria, ­immediate drug reaction, ­hemolytic anemia, serum sickness

Inhalants
Pollens, dust, molds Type I Allergic rhinitis, ­bronchial asthma
Aspergillus fumigatus Types I, III Allergic bronchopulmonary aspergillosis
Thermophilic ­actinomycetes* Types III, IV Extrinsic allergic alveolitis

Injectants
Drugs Types I, II, III Immediate drug reaction, hemolytic anemia, serum sickness
Bee venom Type I Anaphylaxis
Vaccines Type III Localized Arthus ­reaction
Serum Types I, III Anaphylaxis, serum sickness

Contactants
Poison ivy, metals Type IV Contact dermatitis

Modified from Bellanti JA: Immunology III, Philadelphia, 1985, Saunders.

*An order of fungi that grows best at high temperatures (between 45o and 80o C [113o and 176o F]).
 CHAPTER 7  Infection and Defects in Mechanisms of Defense 193

sensitized and instructed to avoid contact with that material. Several The fifth mechanism does not destroy the target cell but rather
tests are available to evaluate allergic individuals.41 These include food causes the cell to malfunction. The antibody is usually directed against
challenges, skin tests with allergens, and laboratory tests for total IgE antigenic determinants associated with specific cell-surface receptors
and allergen-specific IgE. (see Figure 7-11, E). The antibody changes the function of the recep-
Clinical desensitization to allergens can be achieved in some tor by preventing interactions with their normal ligands, replacing the
individuals.42 Minute quantities of the allergen to which the person ligand and inappropriately stimulating the receptor, or destroying the
is sensitive are injected in increasing doses over a prolonged period. receptor. For example, in the hyperthyroidism (excessive thyroid activ-
This procedure may reduce the severity of the allergic reaction in ity) of Graves disease, autoantibody binds to and activates receptors for
the treated individual. However, this form of therapy is associ- thyroid-stimulating hormone (TSH) (a pituitary hormone that con-
ated with a risk of systemic anaphylaxis, which can be severe and trols the production of the hormone thyroxine by the thyroid).43 In
life-threatening. this way, the antibody stimulates the thyroid cells to produce thyrox-
ine. Under normal conditions, the increasing levels of thyroxine in the
Type II: Tissue-Specific Hypersensitivity Reactions blood would signal the pituitary to decrease TSH production, which
Type II hypersensitivities are generally reactions against a specific cell would result in less stimulation of the TSH receptor in the thyroid and
or tissue. Cells express a variety of antigens on their surfaces, some of a concomitant decrease in thyroxine production. Increasing amounts
which are called tissue-specific antigens because they are expressed of thyroxine in the blood have no effect on antibody levels, and thy-
on the plasma membranes of only certain cells. Platelets, for example, roxine production continues to increase despite decreasing amounts of
have groups of antigens that are found on no other cells of the body. TSH (see Chapter 18).
The symptoms of many type II diseases are determined by which tis-
sue or organ expresses the particular antigen. Environmental antigens Type III: Immune Complex–Mediated Hypersensitivity
(e.g., drugs or their metabolites) may bind to the plasma membranes Reactions
of specific cells (especially erythrocytes and platelets) and function as Mechanisms of type III hypersensitivity. Most type III hypersen-
targets of type II reactions. The five general mechanisms by which type sitivity diseases are caused by antigen-antibody (immune) complexes
II hypersensitivity reactions can affect cells are shown in Figure 7-11. that are formed in the circulation and deposited later in vessel walls
All of these mechanisms begin with antibody binding to tissue-specific or other tissues (Figure 7-12). The primary difference between type
antigens or antigens that have attached to particular tissues. II and type III mechanisms is that in type II hypersensitivity antibody
In the first mechanism, the cell may be destroyed by antibody and binds to antigen on the cell surface, whereas in type III antibody binds
complement. The antibody (IgM or IgG) reacts with an antigen on to soluble antigen that was released into the blood or body fluids, and
the surface of the cell, causing activation of the complement cascade the complex is then deposited in the tissues. Type III reactions are not
through the classical pathway. Formation of the membrane attack organ specific, and symptoms are mostly unrelated to the particular
complex (C5-9) damages the membrane and may result in lysis of the antigenic target of the antibody. The harmful effects of immune com-
cell (see Figure 7-11, A). For example, erythrocytes are destroyed by plex deposition are caused by complement activation, particularly
complement-mediated lysis in individuals with autoimmune hemo- through the generation of chemotactic factors for neutrophils. The
lytic anemia (see Chapters 20 and 21) or as a result of an alloimmune neutrophils bind to antibody and C3b contained in the complexes and
reaction to mismatched transfused blood cells. attempt to ingest the immune complexes. They are often unsuccess-
In the second mechanism, antibody may cause cell destruction ful because the complexes are bound to large areas of tissue. During
through phagocytosis by macrophages. The antibody may additionally the attempted phagocytosis, large quantities of lysosomal enzymes are
activate complement, resulting in the deposition of C3b on the cell released into the inflammatory site instead of into phagolysosomes.
surface. Receptors on the macrophage recognize and bind opsonins The attraction of neutrophils and the subsequent release of lysosomal
(e.g., antibody or C3b) and increase phagocytosis of the target cell (see enzymes cause most of the resulting tissue damage.
Figure 7-11, B; phagocytosis is illustrated in Chapter 5). For example, Immune complex disease. Two prototypic models of type III
antibodies against platelet-specific antigens or against red blood cell hypersensitivity help explain the variety of diseases in this category.
antigens of the Rh system cause their removal by phagocytosis in the Serum sickness is a model of systemic type III hypersensitivities, and
spleen. the Arthus reaction is a model of localized or cutaneous reactions.
The third mechanism involves toxic products produced by neutro- Serum sickness–type reactions are caused by the formation of
phils. Soluble antigens such as medications, molecules released from immune complexes in the blood and their subsequent generalized
infectious agents, or molecules released from an individual’s own cells deposition in target tissues. Typically affected tissues are the blood ves-
may enter the circulation. In some instances, the antigens are deposited sels, joints, and kidneys.44 Symptoms include fever, enlarged lymph
on the surface of tissues, where they bind antibody (see Figure 7-11, C). nodes, rash, and pain at sites of inflammation. Serum sickness was
The antibody may activate complement, resulting in the release of C3a initially described as a complication of therapeutic administration of
and C5a, which are chemotactic for neutrophils, and the deposition of horse serum that contained antibody against tetanus toxin. Foreign
complement component C3b. Neutrophils are attracted, bind to the serum generally is not administered to individuals today, although
tissues through receptors for the Fc portion of antibody (Fc receptor) serum sickness reactions can be caused by the repeated intravenous
or for C3b, and release their granules onto the healthy tissue. The com- administration of other antigens, such as drugs, and the characteris-
ponents of neutrophil granules, as well as the toxic oxygen products tics of serum sickness are observed in systemic type III autoimmune
produced by these cells, will damage the tissue. diseases.
The fourth mechanism is antibody-dependent cell-mediated A form of serum sickness is Raynaud phenomenon, a condition
cytotoxicity (ADCC) (see Figure 7-11, D). This mechanism involves caused by the temperature-dependent deposition of immune com-
natural killer (NK) cells. Antibody on the target cell is recognized by Fc plexes in the capillary beds of the peripheral circulation. Certain
receptors on the NK cells, which release toxic substances that destroy immune complexes precipitate at temperatures below normal body
the target cell. temperature, particularly in the tips of the fingers, toes, and nose, and
194 CHAPTER 7  Infection and Defects in Mechanisms of Defense

Complement-mediated lysis
C1 C3b
Phagocytosis
C3b
receptor IgG
Fc
IgM receptor

Erythrocyte Cell
antigen antigen

Lysosomal
granule
Membrane
attack
A complex Osmotic lysis B Cell debris

Macrophage
Neutrophil-mediated damage

3. Complement 4. Neutrophil
activated chemotaxis
2. Antibody
5. Neutrophil
binds
Lysosomal adherence and
IgG granule degranulation
1. Antigen
deposits C1
in tissues Antigen
C5a C3b
Fc
receptor receptor
C3b

C
Enzymes, reactive
oxygen species

Motor end-plate in
myasthenia gravis

ADCC

Apoptosis Perforin

Fas Antibody to
acetylcholine
IgG Granzymes receptor
Ag
Acetylcholine Acetylcholine
FcR receptor
FasL
NK Antireceptor antibodies
D E
FIGURE 7-11  Mechanisms of Type II, Tissue-Specific Reactions. Antigens on the target cell bind
with antibody and are destroyed or prevented from functioning by one of the following mechanisms:
(A) complement-mediated lysis (an erythrocyte target is illustrated here); (B) clearance (phagocytosis)
by macrophages in the tissue; (C) neutrophil-mediated immune destruction; (D) antibody-dependent
cell-mediated cytotoxicity (ADCC) (apoptosis of target cells is induced by natural killer [NK] cells by
two mechanisms: by the release of granzymes and perforin, which is a molecule that creates pores
in the plasma membrane, and enzymes [granzymes] that enter the target through the perforin pores;
by the interactions of Fas ligand [FasL; a molecule similar to TNF-α] on the surface of NK cells with
Fas [the receptor for FasL] on the surface of target cells); or (E) modulation or blocking of the normal
function of receptors by antireceptor antibody. This example of mechanism (E) depicts myasthenia
gravis in which acetylcholine receptor antibodies block acetylcholine from attaching to its receptors
on the motor end-plates of skeletal muscle, thereby impairing neuromuscular transmission and caus-
ing muscle ­weakness. C1, Complement component C1; C3b, complement fragment produced from
C3, which acts as an opsonin; C5a, complement fragment produced from C5, which acts as a chemo-
tactic factor for neutrophils; Fcγ receptor, cellular receptor for the Fc portion of IgG; FcR, Fc receptor.
 CHAPTER 7  Infection and Defects in Mechanisms of Defense 195

Large immune
Small immune IgG complex
complex
Antigen 3. Neutrophil
chemotaxis

Intermediate Lysosomal
C5a granule
immune
complexes 4. Neutrophil
C1 adherence and
degranulation
Fc
receptor
C3b
C3b receptor

1. Intermediate-sized 2. Complement Enzymes, reactive

immune complexes activated oxygen species
deposited in the tissue

FIGURE 7-12  Mechanism of Type III, Immune Complex–Mediated Reactions. Immune complexes
form in the blood from circulating antigen and antibody. Both small and large immune complexes are
removed successfully from the circulation and do not cause tissue damage. Intermediate-sized com-
plexes are deposited in certain target tissues in which the circulation is slow or filtration of the blood
occurs. The complexes activate the complement cascade through C1 and generate fragments includ-
ing C5a and C3b. C5a is chemotactic for neutrophils, which migrate into the inflamed area and attach
to the IgG and C3b in the immune complexes. The neutrophils attempt unsuccessfully to phagocytose
the tissue and in the process release a variety of degradative enzymes that destroy the healthy tissues.
Fcγ receptor is the cellular receptor for the Fc portion of IgG.

are called cryoglobulins. The precipitates block the circulation and Th1 cell
cause localized pallor and numbness, followed by cyanosis (a bluish Tc cell
tinge resulting from oxygen deprivation) and eventually gangrene if TCR
FasL
the circulation is not restored.
An Arthus reaction is caused by repeated local exposure to an CD8
Granzymes TCR
antigen that reacts with preformed antibody and forms immune com- CD4
plexes in the walls of the local blood vessels. Symptoms of an Arthus
MHC
reaction begin within 1 hour of exposure and peak 6 to 12 hours later. Perforin Fas class I
The lesions are characterized by a typical inflammatory reaction, with MHC IFN-
increased vascular permeability, an accumulation of neutrophils, class II
edema, hemorrhage, clotting, and tissue damage. Apoptosis
Target IFNR
Arthus reactions may be observed after injection, ingestion, or cell
inhalation of allergens. Skin reactions can follow subcutaneous or
intradermal inoculation with drugs, fungal extracts, or antigens used Lysosomal enzymes and
in skin tests. Gastrointestinal reactions, such as gluten-sensitive enter- toxic oxygen species
opathy (celiac disease), follow ingestion of antigen, usually gluten from
wheat products (see Chapter 35).45 Allergic alveolitis (farmer lung, Lysosomal granule
pigeon breeder disease) is an Arthus-like acute hemorrhagic inflam-
mation of the air sacs (alveoli) of the lungs resulting from inhalation of Activated
macrophage
fungal antigens, usually particles from moldy hay or pigeon feces (see
Chapter 26).46 FIGURE 7-13  Mechanism of Type IV, Cell-Mediated Reactions.
Antigens from target cells stimulate T cells to differentiate into
Type IV: Cell-Mediated Hypersensitivity Reactions T-cytotoxic cells (Tc cells), which have direct cytotoxic activity,
and T-helper cells (Th1 cells) involved in delayed hypersensitivity.
Whereas types I, II, and III hypersensitivity reactions are mediated by The Th1 cells produce lymphokines (especially interferon-γ [IFNγ])
antibody, type IV reactions are mediated by T lymphocytes and do not that activate the macrophage through specific receptors (e.g., IFNγ
involve antibody (Figure 7-13). Type IV mechanisms occur through receptor [IFNγR]). The macrophages can attach to targets and
either cytotoxic T lymphocytes (Tc cells) or cytokine-producing Th1 release enzymes and reactive oxygen species that are responsible
cells. Tc cells attack and destroy cellular targets directly. Th1 cells for most of the tissue destruction.
196 CHAPTER 7  Infection and Defects in Mechanisms of Defense

produce cytokines that recruit and activate phagocytic cells, especially In 1891 Ehrlich was the first to thoroughly describe a type IV hyper-
macrophages. Destruction of the tissue is usually caused by direct killing sensitivity reaction in the skin, leading to the development of a diag-
by Tc cells or the release of soluble factors, such as lysosomal enzymes nostic skin test for tuberculosis. The reaction follows an intradermal
and toxic reactive oxygen species, from activated macrophages. injection of tuberculin antigen into a suitably sensitized individual
Clinical examples of type IV hypersensitivity reactions include graft and is called a delayed hypersensitivity skin test because of its slow
rejection, the skin test for tuberculosis, and allergic reactions resulting onset—24 to 72 hours to reach maximal intensity. The reaction site is
from contact with such substances as poison ivy and metals. A type IV infiltrated with T lymphocytes and macrophages, resulting in a clear
component also may be present in many autoimmune diseases. For hard center (induration) and a reddish surrounding area (erythema).
example, T cells against type II collagen (a protein present in joint tis- Allergic type IV reactions are elicited by some environmental anti-
sues) contribute to the destruction of joints in rheumatoid arthritis; T gens that are haptens (Chapter 5) and become immunogenic after
cells against a thyroid cell-surface antigen contribute to the destruction binding to larger (carrier) proteins in the individual.47 In allergic con-
of the thyroid in autoimmune thyroiditis (Hashimoto disease); and T tact dermatitis, the carrier protein is in the skin.48 The best-known
cells against an antigen on the surface of pancreatic beta cells (the cell example is poison ivy (Figure 7-14). The antigen is a plant catechol,
that normally produces insulin) are responsible for beta-cell destruc- urushiol, which reacts with normal skin proteins and evokes a cell-
tion in insulin-dependent (type 1) diabetes mellitus. mediated immune response. Skin reactions to industrial chemicals,

Catechol Skin
molecules protein

7—10 days 1—2 days

T cells T memory cells T memory cells Many active cells

No dermatitis Catechols combined Dermatitis

with skin proteins

Primary contact Secondary contact

B
FIGURE 7-14  Development of Allergic Contact Dermatitis. A, The development of allergy to poison ivy.
The first (primary) contact with allergen sensitizes (produces reactive T cells) the individual but does not
produce a rash (dermatitis). Secondary contact activates a type IV cell-mediated reaction that causes der-
matitis. B, Contact dermatitis caused by a delayed hypersensitivity reaction leading to vesicles and scaling
at the sites of contact. (From Damjanov I, Linder J: Anderson’s pathology, ed 10, St Louis, 1996, Mosby.)
 CHAPTER 7  Infection and Defects in Mechanisms of Defense 197

cosmetics, detergents, clothing, food, metals, and topical medicines same disease, but several members may have different disorders char-
(such as penicillin) are elicited by the same mechanism. Contact der- acterized by a variety of hypersensitivity reactions, including auto-
matitis consists of lesions only at the site of contact with the allergen, immune and allergic. Although most autoimmune diseases appear
such as a metal allergy to jewelry. as isolated events without a positive family history, susceptibility for
developing such diseases appears to be linked to a combination of

4 QUICK CHECK 7-3

multiple genes.
Breakdown of tolerance. An individual is usually tolerant to his or
1. Distinguish among the four types of hypersensitivity mechanisms. her own antigens. Tolerance is a state of immunologic control so that
2. What is the mechanism of anaphylaxis? the individual does not make a detrimental immune response against
3. What are some clinical examples of type IV hypersensitivity? his or her own cells and tissues. Autoimmune disease results from a
breakdown of this tolerance.
Although many theories exist concerning the initial cause of auto-
Antigenic Targets of Hypersensitivity Reactions immune diseases,50 only one example is known: acute rheumatic fever.
Allergy In a small number of individuals with group A streptococcal sore
Allergens. Environmental antigens that cause allergic responses are throats, the M proteins in the bacterial capsule mimic (antigenic mim-
called allergens. It is not known why some antigens are allergens and icry) normal heart antigens and induce antibodies that also react with
others are not. Typical allergens include pollens (e.g., ragweed), molds proteins in the heart valve, damaging the valve.51 Thus rheumatic fever
and fungi (e.g., Penicillium notatum), foods (e.g., milk, eggs, fish), ani- is a type II autoimmune hypersensitivity. Additionally, some strepto-
mals (e.g., cat dander, dog dander), cigarette smoke, and components coccal skin or throat infections release bacterial antigens into the blood
of house dust (e.g., fecal pellets of house mites). Often the allergen is that form circulating immune complexes. The complexes may deposit
contained within a particle that is too large to be phagocytosed or is in the kidneys and initiate an immune complex-mediated glomerulo-
surrounded by a protective nonallergenic coat. The actual allergen is nephritis (inflammation of the kidney). Thus streptococcal antigens
released after enzymatic breakdown (e.g., by lysozyme in secretions) (an environmental antigen) may also cause a type III allergic hypersen-
of the larger particle. sitivity (poststreptococcal glomerulonephritis).
Allergic disease: bee sting allergy. Allergies are the most common Autoimmune disease: systemic lupus erythematosus. Systemic
hypersensitivity diseases. The majority of allergies are type I reactions lupus erythematosus (SLE) is the most common, complex, and serious
that lead to annoying symptoms, including rhinitis, sneezing, and of the autoimmune disorders.52 SLE is characterized by the production
other relatively mild reactions. In some individuals, however, these of a large variety of antibodies (autoantibodies) against self-antigens,
reactions can be excessive and life-threatening (anaphylaxis). Anaphy- including nucleic acids, erythrocytes, coagulation proteins, phos-
lactic reactions have been described against peanuts and other nuts, pholipids, lymphocytes, platelets, and many other self-­components.
shellfish, fish, milk, eggs, and some medications. The most characteristic autoantibodies are against nucleic acids
Bee venoms contain a mixture of enzymes and other proteins that (e.g., single-stranded DNA, double-stranded DNA), histones, ribonu-
may serve as allergens. About 1% of children may have an anaphylactic cleoproteins, and other nuclear materials. Approximately 98% of per-
reaction to bee venom. Within minutes they may develop excessive sons with SLE have detectable antibodies against nuclear ­antigens.53
swelling (edema) at the bee sting site, followed by generalized hives, The blood normally contains many of these products of cellular turn-
pruritus, and swelling in areas distal from the sting (e.g., eyes, lips), over and breakdown. Excessive levels of autoantibodies react with
and other systemic symptoms including flushing, sweating, dizziness, the circulating antigen and form circulating immune complexes. The
and headache. The most severe symptoms may include gastrointesti- deposition of circulating DNA/anti-DNA complexes in the kidneys
nal (e.g., stomach cramps, vomiting), respiratory (e.g., tightness in the can cause severe kidney inflammation. Similar reactions can occur in
throat, wheezing, difficulty breathing), and vascular (e.g., low blood the brain, heart, spleen, lung, gastrointestinal tract, peritoneum, and
pressure, shock) reactions. Severe respiratory and vascular reactions skin. Thus some of the symptoms of SLE result from a type III hyper-
may lead to death. sensitivity reaction. Other symptoms, such as destruction of red blood
For an individual with known bee sting hypersensitivity, life-style cells (anemia), lymphocytes (lymphopenia), and other cells, may be
changes include avoidance of stinging or biting insects. If a child has type II hypersensitivity reactions.
experienced a previous anaphylactic reaction, the chance of having SLE, like most autoimmune diseases, occurs more often in women
another is about 60%. The primary life-threatening symptoms result (approximately a 10:1 predominance of females), especially in the 20-
from contraction of respiratory smooth muscle. Autonomic nervous to 40-year-old age group. Blacks are affected more often than whites
system mediators, such as epinephrine, bind to specific receptors on (about an eightfold increased risk). A genetic predisposition for the dis-
smooth muscle and reverse the effects of histamine, resulting in mus- ease has been implicated on the basis of increased incidence in twins
cle relaxation. Thus most individuals carry self-injectable epinephrine. and the existence of autoimmune disease in the families of individuals
The administration of antihistamines will have little effect because his- with SLE.
tamine has already bound H1 receptors and initiated severe bronchial Clinical manifestations of SLE include arthralgias or arthritis (90%
smooth muscle contraction. Long-term protection may be afforded by of individuals), vasculitis and rash (70% to 80% of individuals), renal
desensitization in most individuals. disease (40% to 50% of individuals), hematologic abnormalities (50%
of individuals, with anemia being the most common complication),
Autoimmunity and cardiovascular diseases (30% to 50% of individuals). (See Discoid
It is fairly well established that most autoimmune diseases originate lupus erythematosus in Chapter 39.) As with most autoimmune dis-
from a genetic predisposition to mount a hypersensitivity reaction eases, SLE is characterized by frequent remissions and exacerbations.
to an environmental stimulus.49 Some autoimmune diseases can be Because the signs and symptoms affect almost every body system and
familial and attributed to the presence of a very small number of sus- tend to vacillate, SLE is extremely difficult to diagnose. This has led to
ceptibility genes; affected family members may not all develop the the development of a list of 11 common clinical findings.54 The serial
198 CHAPTER 7  Infection and Defects in Mechanisms of Defense

or simultaneous presence of at least four of these findings indicates ABO system. The ABO blood group consists of two major carbo-
that the individual has SLE. The findings are as follows: hydrate antigens, labeled A and B (Figure 7-15), that are expressed on
1. Facial rash confined to the cheeks (malar rash) virtually all cells. These are co-dominant so that both A and B can be
2. Discoid rash (raised patches, scaling) simultaneously expressed, resulting in an individual having any one
3. Photosensitivity (development of skin rash as a result of exposure of four different blood types. The erythrocytes of persons with blood
to sunlight) type A have the type A carbohydrate antigen (i.e., carry the A antigen),
4. Oral or nasopharyngeal ulcers those with blood type B carry the B antigen, those with blood type AB
5. Nonerosive arthritis of at least two peripheral joints carry both A and B antigens, and those of blood type O carry neither
6. Serositis (inflammation of membranes of lung [pleurisy] or heart the A nor the B antigen. A person with type A blood also has circulat-
[pericarditis]) ing antibodies to the B carbohydrate antigen. If this person receives
7. Renal disorder (proteinuria of 0.5 g/day or cellular casts) blood from a type AB or B individual, a severe transfusion reaction
8. Neurologic disorders (seizures or psychosis) occurs, and the transfused erythrocytes are destroyed by agglutination
9. Hematologic disorders (hemolytic anemia, leukopenia, lympho- or complement-mediated lysis. Similarly, a type B individual (whose
penia, or thrombocytopenia) blood contains anti-A antibodies) cannot receive blood from a type A
10. Immunologic disorders (positive lupus erythematosus [LE] cell or AB donor. Type O individuals, who have neither antigen but have
preparation, anti–double-stranded DNA, anti-Smith [Sm] anti- both anti-A and anti-B antibodies, cannot accept blood from any of
gen, false-positive serologic test for syphilis, or antiphospholipid the other three types. These naturally occurring antibodies, called iso-
antibodies [anticardiolipin antibody or lupus anticoagulant]) hemagglutinins, are IgM immunoglobulins and are induced early in
11. Presence of antinuclear antibody (ANA) life against similar antigens expressed on naturally occurring bacteria
There is no cure for SLE or most other autoimmune diseases. The in the intestinal tract.
goals of treatment are to control symptoms and prevent further damage Because individuals with type O blood lack both types of antigens,
by suppressing the autoimmune response. Nonsteroidal anti-inflam- they are considered universal donors, meaning that anyone can accept
matory drugs, such as aspirin, ibuprofen, or naproxen, reduce inflam- their red blood cells. Similarly, type AB individuals are considered uni-
mation and relieve pain. Corticosteroids are often prescribed for more versal recipients because they lack both anti-A and anti-B antibodies
serious active disease. Immunosuppressive drugs (e.g., methotrexate, and can be transfused with any ABO blood type. Agglutination and
azathioprine, or cyclophosphamide) are used to treat severe symp- lysis cause harmful transfusion reactions that can be prevented only
toms involving internal organs. Ultraviolet light can worsen symptoms by complete and careful ABO matching between donor and recipient.
(known as flares), and protection from sun exposure is helpful. Pro- Rh system. The Rh blood group is a group of antigens expressed
longed use of certain drugs can cause transient SLE-like symptoms, only on red blood cells. This is most diverse group of red cell antigens,
and the medication history is important for differential diagnosis. consisting of at least 45 separate antigens, although only one is consid-
Improved outcomes may be available in the future with the continued ered of major importance: the D antigen. Individuals who express the D
advances in medical research and the use of stem cell treatments. antigen on their red cells are Rh-positive, whereas individuals who do
Other therapeutic approaches have been used for SLE and other not express the D antigen are Rh-negative. When discussing the gene
autoimmune diseases. Several decades ago preparations of intravenous for the Rh antigen, the letter d is used to indicate lack of D. Rh-positive
immune globulin (IVIg), which was routinely used to replenish anti- individuals can have either a DD or Dd genotype, whereas Rh-negative
bodies in persons with hypogammaglobulinemia, were administered individuals have the dd genotype. About 85% of North Americans are
to children with autoimmune thrombocytopenia (an autoimmune Rh-positive. Rh-negative individuals can make an IgG antibody to the
disease in which platelets were destroyed by an autoantibody).55 IVIg D antigen (anti-D) if exposed to Rh-positive erythrocytes.
therapy resulted in a rebound of platelet levels and temporary resolu- A disease called hemolytic disease of the newborn was most com-
tion of the thrombocytopenia. IVIg is currently being used for a variety monly caused by IgG anti-D alloantibody produced by Rh-negative
of autoimmune diseases, including SLE. More recently, monoclonal mothers against erythrocytes of their Rh-positive fetuses (see Chapter
antibodies and other reagents have specifically targeted B and T cells 21). The mother’s antibody crossed the placenta and destroyed the red
that are participating in autoimmune responses.56,57 This approach blood cells of the fetus. The occurrence of this particular form of the
has been somewhat successful in SLE, rheumatoid arthritis, and other disease has decreased dramatically because of the use of prophylactic
autoimmune diseases. anti-D immunoglobulin (i.e., RhoGAM). By mechanisms that are still
not completely understood, administration of anti-D antibody within
Alloimmunity a few days of exposure to RhD-positive erythrocytes completely pre-
Alloantigens. Genetic diversity is the norm in humans. Diversity is vents sensitization against the D antigen.58 Because hemolytic disease
also observed among self-antigens, so that two individuals may have of the newborn related to the D antigen has been controlled, alloanti-
different antigens on their tissues and, therefore, be able to establish an bodies against the other Rh antigens have become more important. In
immune response against each other’s tissues. Some self-antigens, such general, these alloantibodies are associated with a less severe hemolytic
as the ABO blood group, have limited diversity with very few different disease.
antigens being expressed in the population, whereas others, such as the Alloimmune disease: transplant rejection
HLA system, have tremendous diversity. Major histocompatibility complex. Molecules of the major
Alloimmune disease: transfusion reactions. Red blood cells (eryth- histocompatibility complex (MHC) were discussed in Chapter 5 as
rocytes) express several important surface antigens, known collectively antigen-presenting molecules. MHC molecules are also a major target
as the blood group antigens, which can be targets of alloimmune reac- of transplant rejection. As a result of studies of transplantation, the
tions. More than 80 different red cell antigens are grouped into several human MHC molecules are also referred to as human leukocyte anti-
dozen blood group systems. The most important of these, because they gens (HLAs) and the different MHC genetic loci are commonly called
provoke the strongest humoral alloimmune response, are the ABO and HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ, and HLA-DP (Figure
Rh systems. 7-16). Additional genes for complement components (e.g., C4, factor B)
 CHAPTER 7  Infection and Defects in Mechanisms of Defense 199

Blood Type
O A B AB

Erythrocyte

Antibody in
None
serum

Anti-A and Anti-B Anti-A

Anti-B
FIGURE 7-15  ABO Blood Types. This figure shows the relationship of antigens and antibodies associ-
ated with the ABO blood groups. The surfaces of erythrocytes of individuals with blood group O have a
core carbohydrate that is present on cells of all ABO blood groups (H antigen). The sera of blood group
O individuals contain IgM antibodies against both A and B carbohydrates. In individuals of the blood
group A, some of the H antigens have been modified into A antigens. The sera of these individuals have
IgM antibodies against the B antigen. In individuals with blood group B, some of the H antigens have
been modified into B antigens. These individuals have IgM antibodies against the A antigen in their
sera. In individuals of the blood group AB, some of the H antigens have been modified into both the A
and B antigens. These individuals do not have antibody to either A or B antigens.

Chromosome 6: Site of genes that encode HLA antigens that are co-dominant so that molecules encoded by each parent’s genes
are expressed on the cell surface. Within an individual, each locus will
express only one allele. For instance, each person will have at most two
different HLA-A proteins (one from each parent). However, with the
tremendous number of possible alleles that can be expressed through-
out the population, it is likely that any two unrelated individuals will
have different MHC antigens and would reject organs transplanted
MHC from one to another.
Class II Class III Class I Transplantation. The diversity of MHC molecules becomes
antigens proteins antigens clinically relevant during organ transplantation.25 The recipient of a
transplant can mount an immune response against the foreign MHC
HLA- HLA- HLA- HLA- C4a C4b HLA-B HLA-CHLA-A antigens on the donor tissue, resulting in rejection. To minimize the
DP DZ/DO DQ DR C2 Bf chance of tissue rejection, the donor and recipient are often tissue-typed
FIGURE 7-16  Human Leukocyte Antigens (HLAs). The major his- beforehand to identify differences in HLA antigens. Because of the large
tocompatibility complex (MHC) is located on chromosome 6 and number of different alleles, it is highly unlikely that a perfect match
contains genes that code for class I antigens, class II antigens, and can be found between someone who needs a transplant and a potential
class III proteins (i.e., complement proteins and cytokines). (From donor from the general population. The more similar two individuals
Mudge-Grout C: Immunologic disorders, St Louis, 1992, Mosby.) are in their HLA tissue type, the more likely a transplant from one to the
other will be successful. Clearly, the most successful transplants would
are also contained in the MHC region and are referred to as class III be between identical twins because they are identical genetically.
loci. The class I (HLA-A, -B, and -C) and class II MHC loci (HLA-DR, The specific combination of alleles at the six major HLA loci on one
-DQ, and -DP) are the most genetically diverse (polymorphic) of any chromosome (A, B, C, DR, DQ, and DP) is termed a haplotype. Each
human genetic loci. Within the human population, the number of pos- individual has two HLA haplotypes, one from the paternal chromo-
sible different alleles (i.e., forms of the gene) expressed by each locus some 6 and another from the maternal chromosome (Figure 7-17).
is astounding. For example, more than 300 different HLA-A antigens Each parent passes on one set of HLA antigens to each of his or her
are expressed in the population. These numbers are based on the poly- offspring, meaning that children usually share half their HLA antigens
morphism of observed DNA sequences and may not reflect differences with each parent. Odds dictate that children will share one haplotype
in function. with half their siblings and either no haplotypes or both haplotypes
Clearly, not every allele is expressed in the same individual. Humans with a quarter of their siblings. Thus the chance of finding a match
have two copies of each MHC locus (one inherited from each parent) among siblings is much higher (25%) than the general population.
200 CHAPTER 7  Infection and Defects in Mechanisms of Defense

A3 B12 A28 B7

A10 B5 A1 B35

A3 B12 A3 B12 A10 B5 A10 B5

A28 B7 A1 B35 A28 B7 A1 B35

Child 1 Child 2 Child 3 Child 4

FIGURE 7-17  Inheritance of HLA. HLA alleles are inherited in a co-dominant fashion; both maternal
and paternal antigens are expressed. Specific HLA alleles are commonly given numbers to indicate
different antigens. In this example, the mother has linked genes for HLA-A3 and HLA-B12 on one chro-
mosome 6 and genes for HLA-A10 and HLA-B5 on the second chromosome 6. The father has HLA-A28
and HLA-B7 on one chromosome and HLA-A1 and HLA-B35 on the second chromosome. The children
from this pairing may have one of four possible combinations of maternal and paternal HLA.

Transplant rejection. Transplant rejection may be classified as rejected organ usually shows an infiltration of lymphocytes and mac-
hyperacute, acute, or chronic, depending on the amount of time that rophages characteristic of a type IV reaction.
elapses between transplantation and rejection.25 Hyperacute rejection Chronic rejection may occur after a period of months or years of
is immediate and rare. When the circulation is reestablished to the normal function. It is characterized by slow, progressive organ failure.
grafted area, the graft may immediately turn white (the so-called white Chronic rejection may result from a weak cell-mediated (type IV) reac-
graft) instead of a normal pink color. Hyperacute rejection usually tion against minor histocompatibility antigens on the grafted tissue.
occurs because of preexisting antibody (type II reaction) to antigens
on the vascular endothelial cells in the grafted tissue.
Acute rejection is a cell-mediated immune response that occurs
4 QUICK CHECK 7-4
1. Why do certain drugs become immunogenic to the host?
within days to months after transplantation. This type of rejection 2. Why is SLE considered an autoimmune disease?
occurs when the recipient develops an immune response against 3. Define the different types of graft rejection.
unmatched HLA antigens after transplantation. A biopsy of the

DID YOU UNDERSTAND?

Infection 7. Fungi release toxins and enzymes that are damaging to tissue.
1. Bacteria injure cells by producing exotoxins or endotoxins. Exotoxins are 8. Parasitic microorganisms range from unicellular protozoa to large worms.
enzymes that can damage the plasma membranes of host cells or can inac- Although less common in the United States, parasites and protozoa are
tivate enzymes critical to protein synthesis, and endotoxins activate the common causes of infection worldwide.
inflammatory response and produce fever. 9. Parasitic and protozoal infections are rarely transmitted from human to
2. Septicemia is the proliferation of bacteria in the blood. Endotoxins released human. Infection mainly spreads through vectors (e.g., by mosquito bites)
by blood-borne bacteria cause the release of vasoactive enzymes that or through contaminated water or food.
increase the permeability of blood vessels. Leakage from vessels causes 10. The most effective means to prevent infection is vaccination; the adminis-
hypotension that can result in septic shock. tration of an antigen specific for the infectious agent in order to induce a
3. Viruses enter host cells and use the metabolic processes of host cells to long-term and protective secondary immune response.
proliferate.
4. Viruses that have invaded host cells may decrease protein synthesis, disrupt Deficiencies in Immunity
lysosomal membranes, form inclusion bodies where synthesis of viral nucleic 1. Immunodeficiency is the failure of mechanisms of self-defense to function
acids is occurring, fuse with host cells to produce giant cells, alter antigenic in their normal capacity.
properties of the host cell, and transform host cells into cancerous cells. 2. Immunodeficiencies are either congenital (primary) or acquired (secondary).
5. Diseases caused by fungi are called mycoses, and they occur in two forms: Congenital immunodeficiencies are caused by genetic defects that disrupt
yeasts (spheres) and molds (filaments or hyphae). lymphocyte development, whereas acquired immunodeficiencies are sec-
6. Dermatophytes are fungi that infect skin, hair, and nails with diseases such ondary to disease or other physiologic alterations.
as ringworm and athlete’s foot.
 CHAPTER 7  Infection and Defects in Mechanisms of Defense 201

DID YOU UNDERSTAND?—cont’d

3. The clinical hallmark of immunodeficiency is a propensity to unusual or 3. Hypersensitivity reactions can be immediate (developing within seconds or
recurrent severe infections. The type of infection usually reflects the hours) or delayed (developing within hours or days).
immune system defect. 4. Anaphylaxis, the most rapid immediate hypersensitivity reaction, is an
4. The most common infections in individuals with defects of cell-mediated explosive reaction that occurs within minutes of reexposure to the antigen
immune response are fungal and viral, whereas infections in individuals and can lead to cardiovascular shock.
with defects of the humoral immune response or complement function are 5. Allergens are antigens that cause allergic responses.
primarily bacterial. 6. Type I (IgE-mediated) reactions occur after antigen reacts with IgE on mast
5. Severe combined immunodeficiency (SCID) is a total lack of T cell function cells, leading to mast cell degranulation and the release of histamine and
and a severe (either partial or total) lack of B cell function. other inflammatory substances.
6. DiGeorge syndrome (congenital thymic aplasia or hypoplasia) is character- 7. Type II (tissue-specific) reactions are caused by four possible mechanisms:
ized by complete or partial lack of the thymus (resulting in depressed T complement-mediated lysis, opsonization and phagocytosis, antibody-
cell immunity), frequently associated with diminished or parathyroid gland dependent cell-mediated cytotoxicity, and modulation of cellular function.
activity (resulting in hypocalcemia) and cardiac anomalies. 8. Type III (immune complex–mediated) reactions are caused by the forma-
7. Defects in B cell function are diverse, ranging from a complete lack of the tion of immune complexes that are deposited in target tissues, where they
human bursal equivalent, the lymphoid organs required for B cell matura- activate the complement cascade, generating chemotactic fragments that
tion (as in Bruton agammaglobulinemia), to deficiencies in a single class of attract neutrophils into the inflammatory site.
immunoglobulins (e.g., selective IgA deficiency). 9. Immune complex disease can be a systemic reaction, such as serum sick-
8. Acquired immunodeficiencies are caused by superimposed conditions, ness (e.g., Raynaud phenomenon), or localized, such as the Arthus reaction.
such as malnutrition, medical therapies, physical or psychologic trauma, or 10. Type IV (cell-mediated) reactions are caused by specifically sensitized T
infections. cells, which either kill target cells directly or release lymphokines that acti-
9. Immunodeficiency syndromes usually are treated by replacement ther- vate other cells, such as macrophages.
apy. Deficient antibody production is treated by replacement of miss- 11. Allergies can be mediated by any of the four mechanisms of hypersensitivity.
ing immunoglobulins with commercial gamma-globulin preparations. 12. Clinical manifestations of allergic reactions are usually confined to the
Lymphocyte deficiencies are treated by the replacement of host lympho- areas of initial intake or contact with the allergen. Ingested allergens
cytes with transplants of bone marrow, fetal liver, or fetal thymus from a induce gastrointestinal symptoms, airborne allergens induce respiratory or
donor. skin manifestations, and contact allergens induce allergic responses at the
10. AIDS is an acquired dysfunction of the immune system caused by a retrovi- site of contact.
rus (HIV) that infects and destroys CD4+ lymphocytes (T-helper cells). 13. Atopic individuals are genetically predisposed to the development of
allergies.
Hypersensitivity: Allergy, Autoimmunity, and Alloimmunity 14. Alloimmunity is the immune system’s reaction against antigens on the tis-
1. Hypersensitivity is an inappropriate immune response misdirected against sues of other members of the same species.
the host’s own tissues (autoimmunity) or directed against beneficial for- 15. Alloimmune disorders include transient neonatal disease, in which the
eign tissues, such as transfusions or transplants (alloimmunity); or it can be maternal immune system becomes sensitized against antigens expressed
exaggerated responses against environmental antigens (allergy). by the fetus, and transplant rejection and transfusion reactions, in which
2. Mechanisms of hypersensitivity are classified as type I (IgE-mediated) reac- the immune system of the recipient of an organ transplant or blood transfu-
tions, type II (tissue-specific) reactions, type III (immune complex–medi- sion reacts against foreign antigens on the donor’s cells.
ated) reactions, and type IV (cell-mediated) reactions.

 KEY TERMS
• A BO blood group  198 •  topic  191
A •  ryoglobulins  195
C
• Acquired immunodeficiency syndrome • Attenuated virus  177 • Delayed hypersensitivity reaction  190
(AIDS)  183 • Autoimmune disease  190 • Delayed hypersensitivity skin test  196
• Acute rejection  200 • Autoimmunity  188 • Dermatophyte  174
• Adenosine deaminase (ADA) • Bacteremia  171 • Desensitization  193
deficiency  180 • Bare lymphocyte syndrome  180 • DiGeorge syndrome  180
• Agammaglobulinemia  180 • Blood group antigen  198 • Dimorphic fungus (pl., fungi)  173
• Allergen  197 • B lymphocyte deficiency  180 • Endotoxic shock  171
• Allergy  188 • Bruton agammaglobulinemia  180 • Endotoxin (lipopolysaccharide [LPS])  171
• Alloimmune disease  190 • C3 deficiency  180 • Entrance inhibitor  186
• Alloimmunity  190 • Chronic granulomatous disease • Erythema  196
• Anaphylaxis  190 (CGD)  181 • Exotoxin  171
• Antibody-dependent cell-mediated cyto- • Chronic mucocutaneous candidiasis  180 • Graft-versus-host disease (GVHD)  182
toxicity (ADCC)  193 • Chronic rejection  200 • Herd immunity  178
• Antigenic drift  168 • Combined deficiency  180 • Highly active antiretroviral therapy
• Antigenic shift  168 • Communicability  167 (HAART)  186
• Antitoxin  171 • Complement deficiency  180 • Human immunodeficiency virus
• Arthus reaction  195 • Contact dermatitis  196 (HIV)  183
202 CHAPTER 7  Infection and Defects in Mechanisms of Defense

  K E Y T E R M S—cont’d
•  uman leukocyte antigen (HLA)  198
H •  arasitic microorganisms  174
P • S evere combined immunodeficiency
• Hyperacute rejection  200 • Pathogenecity  167 (SCID)  180
• Hypersensitivity  188 • Phagocytic deficiency  181 • Systemic lupus erythematosus (SLE)  197
• Hypogammaglobulinemia  180 • Portal of entry  167 • Tissue-specific antigen  193
• Immediate hypersensitivity reaction  190 • Primary (congenital) immune • T lymphocyte deficiency  180
• Immune deficiency  178 deficiency  178 • Tolerance  197
• Immunogenicity  167 • Protease  184 • Toxogenicity  167
• Induration  196 • Protease inhibitor  186 • Toxoid  178
• Infectivity  167 • Raynaud phenomenon  193 • Universal donor  198
• Integrase inhibitor  186 • Reverse transcriptase  184 • Universal recipient  198
• Isohemagglutinin  198 • Reverse transcriptase inhibitor  186 • Urticaria (hives)  191
• Major histocompatibility complex • Rh blood group  198 • Vaccination  177
(MHC)  198 • Secondary (acquired) immune • Vaccine  177
• Mesenchymal stem cell (MSC)  182 deficiency  178 • Virulence  167
• Methicillin-resistant Staphylococcus aureus • Selective IgA deficiency  180 • Wheal and flare reaction  191
(MRSA)  176 • Septicemia  171 • Wiskott-Aldrich syndrome  180
• Mycosis (pl., mycoses)  174 • Serum sickness  193

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CHAPTER

8
Stress and Disease
Margaret F. Clayton, Kathryn L. McCance, and Beth A. Forshee*

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Historical Background and General Concepts, 204 Stress, Personality, Coping, and Illness, 216
Stress Overview: Multiple Mediators and Systems, 207 Coping, 217
The Stress Response, 209 GERIATRIC CONSIDERATIONS: Aging & The Stress-Age
Neuroendocrine Regulation, 209 Syndrome, 218
Role of the Immune System, 215

Modern society is full of stress. Stress experiences involve daily hassles popularized these same findings, viewing stress as a biologic phenom-
(e.g., fast-paced scheduling, the pressure to remain in constant contact enon.4 During Selye’s original attempts to discover a new sex hormone
through social media or cell phones, or both), major life events (e.g., by injecting crude ovarian extracts into rats, he discovered the biologic
loss of family member, loss of job), abuse, and trauma (Figure 8-1). syndrome of stress.4 He repeatedly found that three structural changes
Americans have become accustomed to an accelerated way of life with occurred: (1) enlargement of the cortex of the adrenal gland, (2) atro-
chronic stress by adopting behaviors (e.g., smoking, drinking, drug phy of the thymus gland and other lymphoid structures, and (3) devel-
abuse, sleep disturbances) that may result in the so-called stress-related opment of bleeding ulcers in the stomach and duodenal lining. Selye
disorders. In general, stress begins with a stimulus that the brain per- soon discovered that these manifestations were not specific to injected
ceives as stressful and in turn promotes adaptation- and ­survival-related ovarian extracts but also occurred after exposure of the rats to other
physiologic responses. These responses can become dysregulated and noxious stimuli, such as cold, surgical injury, and restraint. He called
cause pathophysiologic consequences.1,2 Another way to think about these stimuli stressors. Selye concluded that this triad or syndrome of
this is that acute stress is considered to enhance immunity whereas manifestations represented a nonspecific response to noxious stimuli,
chronic stress is now considered to suppress immunity.2 naming it the general adaptation syndrome (GAS).
Three successive stages of the GAS were identified: (1) the alarm
HISTORICAL BACKGROUND AND GENERAL stage or reaction, in which the central nervous system (CNS) is aroused
and the body’s defenses are mobilized (e.g., “fight or flight”) (Figure
­CONCEPTS 8-2); (2) the stage of resistance or adaptation, during which mobiliza-
Walter B. Cannon used the term stress in both a physiologic and a psy- tion contributes to “fight or flight;” and (3) the stage of exhaustion,
chologic sense as early as 1914.3 He applied the engineering concept where continuous stress causes the progressive breakdown of compen-
of stress and strain in a physiologic context and believed that emo- satory mechanisms (acquired adaptations) and homeostasis. Exhaus-
tional stimuli were also capable of causing stress. In 1946 Hans Selye tion marks the onset of certain diseases (diseases of adaptation).
Interactions among the sympathetic branch of the autonomic
nervous system (ANS) and the hypothalamus, pituitary, and adrenal
*Beth A. Forshee, RN, PhD, contributed to this chapter in the previous edition. glands (HPA axis, see Figure 8-4) produce the nonspecific physiologic

204
 CHAPTER 8  Stress and Disease 205

Environmental stressors
Major life events Trauma, abuse
(work, home, neighborhood)

Perceived stress
(threat, helplessness,
vigilance)
Behavioral responses
Individual differences (fight or flight; personal
(genes, development, behavior — diet,
experience) smoking, drinking, exercise)

Physiologic
responses
Allostasis Adaptation

Allostatic load

FIGURE 8-1  Physiologic and Behavioral Stress Responses. Stress processes arise from bidirec-
tional communication patterns between the brain and other physiologic systems (autonomic, immune,
neural, and endocrine). Importantly, these bidirectional mechanisms are protective, promoting short-
term adaptation (allostasis). Chronic stress mechanisms, however, can lead to long-term dysregulation
and promote behavioral responses and physiologic responses that lead to stress-induced disorders/
diseases (allostatic load), compromising health. (From McEwen BS: Central effects of stress hormones
in health and disease: understanding the protective and damaging effects of stress and stress media-
tors, Eur J Pharmacol 583[2–3]:174–185, 2008.)

responses identified by Selye. The alarm phase begins when a stressor

Adrenal activates the hypothalamus and sympathetic nervous system (see Fig-
gland ures 8-2 and 8-3). The resistance or adaptation phase begins with the
actions of the adrenal hormones cortisol, norepinephrine, and epi-
Kidney nephrine. Exhaustion (also known as allostatic overload; discussed
Nerve signal later) occurs if stress continues and adaptation is not successful, ulti-
mately causing impairment of the immune response, heart failure, and
kidney failure leading to death.
ACTH Physiologic stress is a chemical or physical disturbance produced
by a change, either in the external environment or within the body itself,
Medulla that elicits a response to counteract the disturbance (i.e., begins the GAS).
Cortex Selye identified three components of physiologic stress: (1) the ­exogenous
or endogenous stressor initiating the disturbance, (2) the chemical or
physical disturbance produced by the stressor, and (3) the body’s coun-
Glucocorticoids Adrenaline teracting (adaptational) response to the disturbance.
(cortisol) (epinephrine) Although Selye’s identification of the GAS is regarded as tremen-
dously important and the cornerstone of stress research, the idea that
stress is a purely physiologic response is oversimplified. In the mid-
1950s, studies showed that activation of the adrenal cortex occurred in
Liver releases Increased heart rate, humans in response to psychologic stressors,5 in monkeys with con-
glucose breathing rate,
blood sugar ditioned emotional responses,6 and in humans subjected to a stressful
interview technique.7 Mason later demonstrated that occurrence of the
GAS depended on psychologic factors surrounding the stressors.8 He
FIGURE 8-2  The Alarm Reaction. The alarm reaction includes
also showed that factors, such as degrees of discomfort, unpleasant-
increased secretion of glucocorticoids (cortisol) by the adrenal cortex
and increased secretion of epinephrine and small amounts of nor- ness, or suddenness of the stress, could account for the presence or
epinephrine from the adrenal medulla. The response to the release absence of physiologic stress responses.8
of cortisol and sympathetic nerve activation is summarized in Figure Research conducted since the 1970s has shown the remarkable
8-3. ACTH, Adrenocorticotropic hormone. (From Thibodeau GA, Pat- sensitivity of the CNS and endocrine systems to emotional, psycho-
ton KT: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.) logic, and social influences. Psychologic stressors can elicit a reactive or
 206
Stressor

Central nervous system

CHAPTER 8  Stress and Disease

Hypothalamus

Corticotropin-releasing hormone (CRH)

Sympathetic nervous Posterior Anterior*

system pituitary pituitary

↑ADH/vasopressin ↑ACTH
Neuropeptide Epinephrine
Y (NPY) Norepinephrine

↑H2O retention Adrenal cortex

↑Blood ↑Pupil Piloerection Bronchodilation Increased lipolysis Liver

pressure dilation (goosebumps) Cortisol†

↑Sweat gland ↑Arteriole smooth Increased force and rate Decreased glycogen
of cardiac contraction synthesis ↑Blood pressure ↓Luteinizing ↑Blood
action muscle contraction
and cardiac hormones, levels of
(armpits and palms)
output estradiol, amino acids‡
testosterone
Increased cardiac
Increased
output Pancreas
Vasoconstrictor glycogenolysis
↑Lipolysis Atrophy of ↑Lipogenesis
Vascular growth extremities lymphoid face and
factor tissue trunk
Increased circulating Decreased Increased
Angiogenic free fatty acids insulin glucagon
factor
Anti-inflammatory Immunosuppression
Decreased glucose Increased or or enhanced
*Variable changes in β-endorphins, growth hormone, and prolactin uptake in skeletal gluconeogenesis proinflammatory humoral immunity†
*(see text). muscle and adipose
†Effects may be dependent on amount of cortisol and nature of the
†stressor.
‡Caused by protein catabolism in muscle, adipose tissue, skin, bones,
‡lymphoid tissue. Increased blood glucose
ADH, Antidiuretic hormone; ACTH, adrenocorticotropic hormone.
FIGURE 8-3  The Stress Response.
 CHAPTER 8  Stress and Disease 207

anticipatory stress response. The reactive response is a physiologic

response derived from psychologic stressors. For example, the stress
of an examination may produce an increased heart rate and dry
mouth. Although there is no physical stressor, the psychologic stress +
of an examination elicits a reactive physiologic response. Anticipatory Stress
responses occur when physiologic responses develop in anticipation
of disruption of the optimal steady state, also known as homeosta-
sis. Anticipatory responses can be generated by fears (such as a fear of
predators) or memories.9 In a conditioned response, a person learns
that specific events are associated with danger. Anticipation of experi- Hypothalamus
encing these events produces a physiologic stress response. For exam-
ple, a child who is abused by a parent may experience a physiologic CRH +
stress response in anticipation of further abuse when that parent enters
the room. Another well-known example of a conditioned response is
the development of post-traumatic stress disorder (PSTD) experienced
by military personnel and survivors of natural disasters.
Today there is evidence implicating stress both as a precipitating – –
factor for some diseases and conditions and as a contributor to wors- Anterior
pituitary
ening symptoms and outcomes in other diseases, such as atherosclero-
sis, irritable bowel syndrome, ulcers, asthma, autoimmune disorders,
anxiety, delayed wound healing, chronic pain and fatigue syndromes,
reproductive dysfunction, diabetes, and depression.10-12 In addition,
ACTH –
evidence published since 2000 generally supports a role for stress in
human immunodeficiency virus (HIV) progression.13
The concept that stress may influence immunity and resistance to Adrenal glands
disease has been considered and investigated since the 1950s. Research
in the 1970s determined that life changes or emotions resulting from Kidneys
life changes and occurring over a prolonged time were associated with Cortisol
decreased immune function. More recently, studies have been con-
ducted to investigate the interactions among social, psychologic, and
+
biologic factors and their role in causing and prolonging or shortening Metabolic
the course of disease. What is emerging from the various disciplines effects
involved—molecular biology, immunology, neurology, endocrinol- FIGURE 8-4  Hypothalamic-Pituitary-Adrenal (HPA) Axis. The
ogy, and behavioral science—is a more holistic and complex model that response to stress begins in the brain. The hypothalamus is the
involves biochemical relationships of the central nervous system (CNS), control center in the brain for many hormones including corticotro-
autonomic nervous system (ANS), endocrine system, and immune sys- pin-releasing hormone (CRH).
tem. More simply, these relationships are often cited together as the
hypothalamic-pituitary-adrenal (HPA) axis (Figure 8-4). In sequence,
the hypothalamus secretes corticotropin-releasing hormone (CRH), depression, anger, fear, loss, and excitement), obesity, advanced age,
which binds to specific receptors on pituitary cells that, in turn, pro- drugs, disease, surgery, and medical treatment.
duce adrenocorticotropic hormone (ACTH). ACTH is then trans- Although the field of PNI is relatively new it has elicited strenuous
ported through the blood to the adrenal glands located on the top of the scientific debate, especially with respect to the causal role of personal-
kidneys. After binding to specific receptors on the adrenal glands, the ity in cancer mortality and morbidity.16 For example, mouse models
glucocorticoid hormones (primarily cortisol) are released. Cortisol ini- suggest a strong link between stress and breast cancer progression,
tiates a series of metabolic changes (discussed in the section Glucocor- yet this effect has not been consistently found in humans.16,17 What
ticoids: Cortisol), but overall these hormones are thought to enhance is certain, however, is that hormones released by the stress response
immunity during acute stress and to suppress immunity during chronic influence many metabolic systems and corresponding physiologic
stress because of prolonged exposure and increased concentration.2 events, even if the mechanisms and subsequent physiologic events are
Psychoneuroimmunology (PNI) is the study of how the con- yet to be fully understood. Further, sufficient data now exist to con-
sciousness (psycho), the brain and spinal cord (neuro), and the body’s clude that immune modulation by psychosocial stressors or interven-
defenses against infection and abnormal cell division (immunology) tions is directly related to health outcomes.1,11,18-31 Along with a greater
interact. Psychoneuroimmunology assumes that all immune-medi- understanding of the relationship between the human stress response
ated diseases result from interrelationships among psychosocial, emo- and disease, new strategies for treatment of stress-related disorders are
tional, genetic, neurologic, endocrine, immunologic, and behavioral emerging.
­factors.14,15 The immune system is integrated with other physiologic
processes and is sensitive to changes in CNS and endocrine function- STRESS OVERVIEW: MULTIPLE MEDIATORS
ing, such as those that accompany psychologic states. Stressors can
AND SYSTEMS
elicit the stress response or stress system through the action of the
nervous and endocrine systems. Stressors include infection, noise, Psychologic stress may cause or worsen several diseases or disorders
decreased oxygen supply, pain, malnutrition, heat, cold, trauma, pro- including anxiety, depression, insomnia, chronic pain and fatigue syn-
longed exertion, radiation, responses to life events (including anxiety, dromes, obesity, metabolic syndrome, essential hypertension, type 2
208 CHAPTER 8  Stress and Disease

TABLE 8-1 EXAMPLES OF STRESS-RELATED DISEASES AND CONDITIONS

TARGET ORGAN TARGET ORGAN OR
OR SYSTEM DISEASE OR CONDITION SYSTEM DISEASE OR CONDITION
Cardiovascular system Coronary artery disease Gastrointestinal system Ulcer
Hypertension Irritable bowel syndrome
Stroke Diarrhea
Disturbances of heart rhythm Nausea and vomiting
Ulcerative colitis
Muscle Tension headaches Genitourinary system Diuresis
Muscle contraction backache Impotence
Frigidity
Connective tissues Rheumatoid arthritis (autoimmune disease) Skin Eczema
Related inflammatory diseases of connective tissue Neurodermatitis
Acne
Pulmonary system Asthma (hypersensitivity reaction) Endocrine system Type 2 diabetes mellitus
Hay fever (hypersensitivity reactions) Amenorrhea
Immune system Immunosuppression or deficiency Central nervous system Fatigue and lethargy
Autoimmune diseases Type A behavior
Overeating
Depression
Insomnia

diabetes, atherosclerosis and its cardiovascular consequences, osteo- Catecholamines can increase proinflammatory cytokine produc-
porosis, and autoimmune inflammatory and allergic disorders.11 Some tion, causing, for example, increased heart rate and blood pressure.
of these disorders are the leading causes of death in the United States Glucocorticoids are known to inhibit this proinflammatory produc-
(Table 8-1). Effects of stress on inflammatory and immune processes tion; however, inhibition depends on dose and cell or tissue type.24
influence coronary artery disease, depression, autoimmune disorders, Therefore glucocorticoids can also promote inflammation depending
and, possibly, virally-mediated cancers. These activated inflammatory on dose and cell type.25 The increased understanding of these effects
reactions increase what is called the “sickness syndrome,” a collection suggests the possibility that chronic and dysfunctional HPA axis stim-
of nonspecific symptoms caused by excessive levels of inflammatory ulation (as may occur during chronic inflammation) increases inflam-
cytokines during infectious or inflammatory illness. Additionally, mation in the brain and other tissue, possibly contributing to other
stress disrupts the biologic process of sleep and the long-term func- diseases including osteoporosis, metabolic disease (e.g., diabetes, obe-
tions of growth and reproduction.11 sity), and cardiovascular disease.26 Additionally, these interactions are
Chronic inflammation, which can be stimulated by stress, may be nonlinear (see Figure 8-5) and are very complex.
important in the functional decline that leads to frailty, disability, and The parasympathetic system also plays a role in opposing the
untimely death.23 As evidence mounts concerning the important role sympathetic (catecholamine) responses and has anti-inflammatory
that stress plays in many disease processes, research has focused on the effects.25 Allostasis is considered an adaptive physiologic response to
mechanisms responsible for these mind-body interactions. stressful events (e.g., fight or flight).32 Chronic or disregulated allosta-
The term stress was used persistently and widely in the past in spe- sis (long-term or chronic exaggerated responses to stress) can lead to
cialties, such as biology, health sciences, and social sciences, despite disease (see Figure 8-1). Allostatic load is the individualized cumulative
a lack of agreement about its definition. Currently, stress is usually amounts of stressors that exist in our lives and that influence our physi-
defined as a transactional or interactional concept. Transactionally, ologic responses. Allostatic load includes our genetic makeup, life-style
stress is viewed as the state of affairs that arises when a person appraises (including damaging health behaviors), daily events, and sometimes,
and reacts to a situation. In general, a person experiences stress when dramatic events such as disasters.32 Over time this load exacts a toll on
a demand exceeds that person’s coping abilities, resulting in reactions our bodies (i.e., “wear and tear”). Because the brain is a key player in
such as disturbances of cognition, emotion, and behavior (e.g., smok- deciding what is stressful, the brain is influential in determining when
ing, drinking, loss of sleep) that can adversely affect well-being. we have reached allostatic overload. Moreover, these responses are
The physiology involved in meeting the demands and challenges individualized—that is, what would be considered normal for one per-
of daily life is an emerging topic of research. Some refer to these chal- son may be considered extremely stressful for another.33 In response
lenges as “stressors” and to the chronically stressed person as being to acute and chronic stress some regions of the brain (hippocampus,
“stressed out.” The physiology is complex, involving mechanisms of amygdala, and prefrontal cortex) may respond by undergoing struc-
both protection and injury. As previously mentioned, glucocorticoids tural remodeling that can alter behavioral and physiologic responses,
from the adrenal cortex, in response to ACTH from the pituitary gland such as cognitive impairment and depression.32 Key systems involved
(see Figure 8-4), comprise the major stress hormones along with the in allostatic overload (exaggerated pathophysiologic responses to
catecholamines epinephrine and norepineprine. Other central hor- stress) include the concentrations of cortisol, catecholamines of the
mones/mediators also play a role, including the proinflammatory and sympathetic nervous system, and proinflammatory cytokines as
anti-inflammatory cytokines that are regulated by glucocorticoids and well as a decline in parasympathetic activity. A prevalent example is
catecholamines (Figure 8-5).1 sleep deprivation from being “stressed out.”1 Sleep deprivation has
 CHAPTER 8  Stress and Disease 209

CNS function
• Cognition
• Depression
• Aging Metabolism
• Diabetes • Diabetes
• Alzheimer’s • Obesity

Cortisol

DHEA Inflammatory cytokines

Sympathetic Anti-inflammatory cytokines

Parasympathetic Oxidative stress

Cardiovascular function Immune function

• Endothelial cell damage • Immune enhancement
• Atherosclerosis • Immune suppression

FIGURE 8-5  Stress Interactions Are Nonlinear and Complex. Nonlinearity means that when one
mediator is increased or decreased, the subsequent compensatory changes in other mediators
depend on time and level of change, causing multiple interacting variables. The inevitable conse-
quences from adapting to daily life over time include changes in behavioral responses. For example,
these changes include sleeping patterns, smoking, alcohol consumption, physical activity, and social
interactions. These behavioral patterns are a part of the allostatic overload with chronic elevations in
cortisol level, sympathetic activity, and levels of proinflammatory cytokines, and a decrease in para-
sympathetic activity. (From McEwen BS: Central effects of stress hormones in health and disease:
understanding the protective and damaging effects of stress and stress mediators, Eur J Pharmacol
583[2–3]:174–185, 2008.)

significant damaging effects including elevated evening cortisol con- nerves also contain nonadrenergic mediators that amplify or antago-
centration; elevated insulin and blood glucose levels; increased blood nize the effects of these catecholamines. Simultaneously, hypothalamic
pressure; reduced parasympathetic activity; increased levels of proin- CRH stimulates the pituitary gland to release a variety of hormones,
flammatory cytokines; and increased secretion of the hormone ghrelin including antidiuretic hormone (ADH) from the posterior pituitary
(primarily by cells of the stomach and pancreas), which increases appe- gland and prolactin, growth hormone, and adrenocorticotropic hor-
tite. Altogether these alterations can lead to increased caloric intake, mone (ACTH) from the anterior pituitary gland. ACTH stimulates the
depressed mood, cognitive problems, and a host of other responses cortex of the adrenal gland to release glucocorticoids, mainly cortisol
from insomnia.28 (see Figure 8-3).

Catecholamines
4 QUICK CHECK 8-1 Circulating catecholamines essentially mimic direct sympathetic
1. Define the HPA axis. stimulation. Catecholamines cannot cross the blood-brain barrier
2. Discuss the diseases/disorders affected by stress. and are synthesized locally in the brain. The physiologic effects of
3. Briefly describe the three stages of the general adaptation syndrome. the catecholamines on organs and tissues are summarized in Table
4. Define allostatic load and allostatic overload. 8-2. Norepinephrine regulates blood pressure, promotes arousal,
and increases vigilance, anxiety, and other protective emotional
responses.
THE STRESS RESPONSE Epinephrine in the liver and skeletal muscles is rapidly metabolized.
Epinephrine influences cardiac action by enhancing myocardial con-
Neuroendocrine Regulation tractility (inotropic effect), increasing heart rate (chronotropic effect),
The sympathetic nervous system is aroused during the stress response, and increasing venous return to the heart, ultimately increasing both
releasing norepinephrine (adrenergic stimulation) and causing the cardiac output and blood pressure. Epinephrine dilates blood vessels
medulla of the adrenal gland to release catecholamines (80% epineph- supplying skeletal muscles, allowing for greater oxygenation. Meta-
rine and 20% norepinephrine) into the bloodstream. Sympathetic bolically, it causes transient hyperglycemia (high blood sugar), reduces
210 CHAPTER 8  Stress and Disease

TABLE 8-2 PHYSIOLOGIC EFFECTS HEALTH ALERT

OF CATECHOLAMINES* Psychosocial Stress and Progression to Coronary
ORGAN/TISSUE PROCESS OR RESULT Heart Disease
Brain Increased blood flow; increased glucose The link between stress and coronary heart disease was proposed as early
metabolism as the 1970s; however, it was only recently that conclusive evidence and
Cardiovascular system Increased rate and force of contraction proposed mechanisms for development of the disease were identified. Much
Peripheral vasoconstriction work continues to focus on elucidating the interaction between stress and
Pulmonary system Bronchodilation cardiovascular disease.
Skeletal muscle Increased glycogenolysis One of the primary risk factors for coronary heart disease is hypertension.
Increased contraction A new designation of prehypertension was recently created and found to be
Increased dilation of muscle vasculature a good predictor for future cardiovascular events. Prehypertension is defined
Decreased glucose uptake and utilization as a systolic blood pressure of 120 to 139 mm Hg or a diastolic blood pressure
(decreases insulin release) of 80 to 90 mm Hg. Individuals with prehypertension are much more likely to
Liver Increased glucose production develop frank hypertension and, eventually, coronary heart disease.
Increased glycogenolysis Studies show that persons with a highly reactive personality type who expe-
Adipose tissue Increased lipolysis rience high levels of anxiety with stress are much more likely to progress from
Decreased glucose uptake prehypertension to hypertension and then to develop cardiac disease, spe-
Skin Decreased blood flow cifically coronary heart disease, than those who have better coping abilities.
Gastrointestinal and Decreased protein synthesis Further long-term psychologic stress, such as experienced in a strained mar-
genitourinary tracts riage or an unhappy work environment, not only was shown to accelerate the
Decreased smooth muscle contraction progression of hypertension and coronary heart disease but also is correlated
Increased renin release with higher mortality rates from coronary heart disease.
Increased gastrointestinal sphincter tone Trait anger, defined as a stable personality trait characterized by frequency,
Lymphoid tissue Acute and chronic stress inhibits several intensity, and duration of anger, also was shown to be a factor in the develop-
components of innate immunity, particularly ment of coronary heart disease at higher rates than the general population.
decreasing natural killer cells Individuals with trait anger also experienced more strokes. Hostile individu-
Macrophages Inhibit and stimulate macrophage activity als with advanced cardiovascular disease may be particularly susceptible to
Depends on availability of type 1/proinflam- stress-induced increases in sympathetic activity and inflammation.
matory cytokines, presence or absence One popular mechanism for the interaction between psychosocial stress
of antigenic stressors, and peripheral and cardiovascular disease suggests that stress triggers an inflammatory
corticotropin-releasing hormone (CRH) response that, over time, increases the chances of developing coronary heart
Data from Elenkov IJ, Chrousos GP: Ann N Y Acad Sci 966:290–303, disease. The primary mechanisms proposed are chronically elevated cortisol
2002; Granner DK: Hormones of the adrenal medulla. In Murray levels and dysregulation of the circadian rhythm for cortisol release. Further,
RK et al, editors: Harper’s biochemistry, ed 25, New York, 2000, chronic stress alters hypothalamic-pituitary-adrenal (HPA) function, resulting
­McGraw-Hill. in an abnormal stress response pattern. This alteration in HPA activity was
*Some of these responses require glucocorticoids (e.g., cortisol) for found in persons with coronary heart disease along with increased inflamma-
maximal activity (see text for explanation). tory markers. The elevation in inflammatory markers seen with chronic stress
is important because these markers were shown to interact with lipids, spe-
cifically low-density lipoproteins, to increase the production of atherosclerotic
glucose uptake in the muscles and other organs, and decreases insulin
plaques.
release from the pancreas, thus preventing glucose uptake by periph-
Because coronary heart disease is one of the major causes of death in indus-
eral tissue and preserving it for the CNS. Epinephrine also mobilizes
trialized countries, development of successful interventional programs is of
free fatty acids and cholesterol.
high priority. Programs in which dietary changes, exercise, stress manage-
The catecholamines stimulate two major classes of receptors:
ment, and positive support systems are implemented continue to show posi-
α-adrenergic receptors (α1 and α2) and β-adrenergic receptors (β1 and
tive results for slowing the progression of heart disease and decreasing the
β2). Table 12-7 summarizes the actions of the two subclasses of adren-
risk factors for disease development. Further, individuals in these programs
ergic receptors. (A discussion of receptors can be found in Chapters 1,
report decreased levels of depression and stress as well as overall improve-
17, and 22.) Epinephrine binds with and activates both α and β recep-
ment in mental health.
tors whereas norepinephrine binds primarily with α receptors.
Data from Brydon L et al: J Psychosom Res 68(2):109–116, 2010;
Glucocorticoids: Cortisol Davidson KW: Cleve Clin J Med 75(suppl 2):S15–S19, 2008; Nijm J
During stress ACTH activates the adrenal cortex, increasing secre- et al: J Int Med 262(3):375–384, 2007; Player MS et al: Ann Fam Med
tion of glucocorticoid hormones, primarily cortisol (see Figure 8-3). 5(5):403–411, 2007; Shamaei-Tousi A et al: Cell Stress Chaperones
(Cortisol is known outside the body as hydrocortisone.) These steroid 12(4):384–392, 2007; Steptoe A, Brydon L: Neurosci Biobehav Rev
33:63–70, 2009; Vizza J et al: J Cardiopulm Rehabil Prev 27(6):376–
molecules reach all tissues, including the brain, easily penetrate cell
383, 2007.
membranes, and react with numerous intracellular glucocorticoid
receptors. Because they spare almost no tissue or organ and influ-
ence a large proportion of the human genome, they exert significant
diverse biologic actions!11 Glucocorticoids regulate many functions
of the CNS, including arousal, cognition, mood, sleep, metabolism,
 CHAPTER 8  Stress and Disease 211

maintenance of cardiovascular tone, the immune and inflammatory the body to combat the stressor. The effects of cortisol are summarized
reaction, and growth and reproduction. Thus glucocorticoids dramati- in Table 8-3.
cally affect human pathophysiology and, consequently, longevity.1,11 Cortisol also affects protein metabolism. It has an anabolic
The feedback mechanisms of the HPA axis sense and determine the effect; that is, it increases the rate of synthesis of proteins and
circulating glucocorticoid levels, while other tissues passively accept ribonucleic acid (RNA) in liver. This is countered by its catabolic
the actions of circulating ­glucocorticoids.11 Thus discrepancy in the effect on protein stores in other tissues. Protein catabolism acts to
glucocorticoid sensing network between the HPA axis and peripheral increase levels of circulating amino acids; therefore chronic expo-
tissues could possibly produce peripheral tissue hypercortisolism or sure to excess cortisol can severely deplete protein stores in muscle,
hypocortisolism.11 For example, both high HPA axis reactivity to stress bone, connective tissue, and skin. Finally, cortisol promotes gastric
and increased peripheral tissue sensitivity to glucocorticoids have been secretion in the stomach and intestines, potentially causing gas-
shown to be associated with severity of coronary artery disease (see tric ulcers. This could account for the gastrointestinal ulceration
Health Alert: Psychosocial Stress and Progression to Coronary Heart observed by Selye. This is in opposition to norepinephrine, which
­Disease).29 Chronic dysregulation of the HPA axis, especially elevated reduces gastric secretion.
levels of cortisol, has been linked to a wide variety of disorders includ- Overall, glucocorticoids have an important role in the homeostasis
ing obesity, sleep deprivation, lipid abnormalities, ­hypertension, of the CNS.1,11 These hormones regulate memory, cognition, mood,
­diabetes, ­atherosclerosis, loss of bone density, hippocampal atrophy, and sleep. They also influence brain anatomy by reducing hippo-
and cognitive impairment.33 campal volume, enlarging ventricles, and causing reversible cortical
Cortisol mobilizes substances needed for cellular metabolism and atrophy.1,11
stimulates gluconeogenesis, or the formation of glucose from noncar- Glucocorticoids contribute to the development of metabolic syn-
bohydrate sources, such as amino acids or free fatty acids in the liver. drome and the pathogenesis of obesity (see Health Alert: Glucocorti-
In addition, cortisol enhances the elevation of blood glucose levels that coids, Insulin, Inflammation, and Obesity). They can directly cause
is promoted by other hormones, such as epinephrine, glucagon, and insulin resistance and influence genetic variations that predispose to
growth hormone. Cortisol also inhibits the uptake and oxidation of obesity. Glucocorticoids also may affect fetal programming of the HPA
glucose by many body cells. Overall, cortisol’s actions on carbohydrate axis by causing an adverse intrauterine environment because of altera-
metabolism result in increased blood glucose levels, thereby energizing tions in cortisol secretion during pregnancy.30

TABLE 8-3 PHYSIOLOGIC EFFECTS OF CORTISOL

FUNCTIONS AFFECTED PHYSIOLOGIC EFFECTS
Carbohydrate and lipid Diminishes peripheral uptake and utilization of glucose; promotes gluconeogenesis in liver metabolism cells; enhances
metabolism gluconeogenic response to other hormones; promotes lipolysis in adipose tissue
Protein metabolism Increases protein synthesis in liver and decreases protein synthesis (including immunoglobulin synthesis) in muscle,
lymphoid tissue, adipose tissue, skin, and bone; increases plasma level of amino acids; stimulates deamination in liver
Anti-inflammatory effects High levels of cortisol used in drug therapy suppress inflammatory response; inhibit proinflammatory activity of many
(systemic effects) growth factors and cytokines; however, over time some individuals may develop tolerance to glucocorticoids, causing an
increased susceptibility to both inflammatory and autoimmune disease
Proinflammatory effects (possible Cortisol levels released during stress response may increase proinflammatory effects
local effects)
Lipid metabolism Lipolysis in extremities and lipogenesis in face and trunk
Immune effects Treatment levels of glucocorticoids are immunosuppressive; thus they are valuable agents used in numerous diseases/
conditions; T cell or innate immune system is particularly affected by these larger doses of glucocorticoids with suppres-
sion of Th1 function or innate immunity; stress can cause a different pattern of immune response; these nontherapeutic
levels can suppress innate (Th1) and increase adaptive (Th2) immunity—the so-called Th2 shift; several factors influ-
ence this complex physiology and include long-term adaptations, reproductive hormones (i.e., overall, androgens sup-
press and estrogens stimulate immune responses), defects of hypothalamic-pituitary-adrenal axis, histamine-generated
responses, and acute versus chronic stress; thus stress seems to cause a Th2 shift systemically whereas locally, under
certain conditions, it can induce proinflammatory activities and by these mechanisms may influence onset or course of
infections, autoimmune/inflammatory, allergic, and neoplastic disease
Digestive function Promotes gastric secretion
Urinary function Enhances excretion of calcium
Connective tissue function Decreases proliferation of fibroblasts in connective tissue (thus delaying healing)
Muscle function Maintains normal contractility and maximal work output for skeletal and cardiac muscle
Bone function Decreases bone formation
Vascular system/myocardial Maintains normal blood pressure; permits increased responsiveness of arterioles to constrictive action of adrenergic
function ­stimulation; optimizes myocardial performance
Central nervous system function Somehow modulates perceptual and emotional functioning, essential for normal arousal and initiation of daytime activity
Possible synergism with estrogen Suppresses maternal immune system to prevent rejection of fetus?
in pregnancy?
212 CHAPTER 8  Stress and Disease

HEALTH ALERT
Glucocorticoids, Insulin, Inflammation, and Obesity
The signs and symptoms of Cushing syndrome (e.g., excess glucocorticoids [GCs]) synthesis and secretion from the pancreas are inhibited by the glucocorticoids.
include truncal obesity, relatively thin extremities, a “moon face,” and a “buffalo However, increasing levels of glucocorticoids in vivo are associated with increas-
[neck] hump.” In such individuals the possibility of associated hypertension is ing insulin secretion, possibly because of an anti-insulin effect on the liver, which
high as well as increased risk of infection and metabolic syndrome or frank type 2 appears to be vulnerable to the negative effects of glucocorticoids on insulin
diabetes. In addition, the likelihood of an elevated ratio of intraabdominal subcu- action. Hepatic insulin resistance is strongly associated with abdominal obesity.
taneous fat mass to nonabdominal fat mass is high because the glucocorticoids Recent data reveal that the plasma concentration of inflammatory mediators,
mediate the redistribution of stored calories into the abdominal region. The spe- such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), is increased
cific increase in abdominal fat stores is a consequence of elevated levels of gluco- in the insulin-resistant states of obesity and type 2 diabetes. Two mechanisms
corticoids combined with increased insulin action. However, the increased levels might be involved in the pathogenesis of inflammation: (1) glucose and macronu-
of glucocorticoids need not be present in the circulation; instead, they can be gen- trient intake (i.e., which can be mediated through chronic stress) causes oxida-
erated locally in fat by conversion of inactive cortisone to active cortisol through tive stress; and (2) the increased concentrations of TNF-α and IL-6 associated
the action of the isoenzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1. with obesity and type 2 diabetes might interfere with insulin signal transduction.
This conversion is referred to as “pre-receptor” metabolism of cortisol. The active This interference might promote inflammation. Chronic overnutrition (obesity)
steroid is secreted directly to the liver through the portal vein. In  vitro insulin might thus be a proinflammatory state with oxidative stress.

Psychologic/
emotional stress
↑ Cortisol
Infection

NF-
Obesity Smoking
activation
Micronutrient intake
(may be influenced by
chronic stress) Increase glucose Genetic
Proinflammatory
in plasma factors
ROS cytokines
Increase free fatty (high
TNF?, IL-6, CRP
acids responders)
(interference)

Insulin signaling

Pancreatic -cell
destruction
Type 2 diabetes Genetic factors

Stress, Inflammation, Obesity, and Type 2 Diabetes. The induction of reactive oxygen species (ROS) generation and inflammation through the proinflammatory transcription
factor, NF-κβ, activates most proinflammatory genes. Macronutrient intake, obesity, free fatty acids, infection, smoking, psychologic stress, and genetic factors increase the
production of ROS. Interference with insulin signaling (insulin resistance) leads to hyperglycemia and proinflammatory changes. Proinflammatory changes increase levels of TNF-α
and IL-6, and also lead to the inhibition of insulin signaling and insulin resistance. Inflammation in pancreatic β cells leads to β cell dysfunction, which in combination with insulin
resistance leads to type 2 diabetes. CRP, C-reactive protein.

Data from Dallman MF et al: Endocrinology 145(6):2633–2638, 2004; Dandona P, Aljada A, Brandyopadhyay A: Trends Immunol 25(1):4–7, 2004;
Kim SP et al: Diabetes 52:2453–2460, 2003; Masuzaki H et al: Science 94:2166–2170, 2001; Padgett DA, Glaser R: Trends Immunol 24(8):444–
448, 2003; Strack AM et al: Am J Physiol 268:R142–R149, 1995; Thakore JH et al: Biol Psychiatry 47:1140–1142, 1998; Wagen Knecht LE et al:
Diabetes 52:2490–2496, 2003; Spencer SJ, Tilbrook A: Stress 14(3), 2011.

Cortisol secretion during stress exerts beneficial effects by inhib- cortisol exposure. Finally, glucocorticoids have been shown to induce
iting initial inflammatory effects, for example, vasodilation and T cell apoptosis.26
increased capillary permeability.26 Cortisol also promotes resolution Stress hormones, especially glucocorticoids (cortisol), have been
and repair. These actions are mainly accomplished by facilitating the used therapeutically as powerful anti-inflammatory/immunosuppres-
effects of glucocorticoid receptor (GR), namely, the transcription of sive agents for years. The synthetic forms of glucocorticoid hormones
genetic material (through DNA binding) within leukocytes.26 Because (exogenous types of anti-inflammatory glucocorticoids administered
GR is so widely expressed, glucocorticoids influence virtually all for a pharmaceutical reaction) are poorly metabolized when compared
immune cells. The adaptiveness or destructiveness of cortisol-induced to endogenous glucocorticoids, leading to a longer half-life and no cir-
effects may depend on the intensity, type, and duration of the stressor; cadian rhythm for these compounds. Moreover, these synthetic com-
the tissue involved; and the subsequent concentration and length of pounds bind with different targets so each has a unique effect.25
 CHAPTER 8  Stress and Disease 213

Paradoxically, elevated levels of glucocorticoids and catechol- of cytotoxic T cells, natural killer (NK) cells, and activated macro-
amines (epinephrine and norepinephrine), both endogenous and phages—the major components of innate immunity.
exogenously administered, may decrease innate immunity and Cytokines secreted by Th2 cells also act to inhibit Th1 cells and can
increase autoimmune (adaptive) responses. These effects can accen- promote adaptive immunity by stimulating growth and activation of
tuate inflammation in general and potentially increase neuronal mast cells and eosinophils, as well as the differentiation of B cell immu-
death (e.g., in stroke victims).25 This may help explain the seemingly noglobulins. Thus these cytokines are considered to be the major anti-
contradictory stress response of immunosuppression and increased inflammatory cytokines (Figure 8-6).31 The decrease in Th1 activity and
risk of infection (decreased innate immunity) with a heightened increase in Th2 activity is sometimes called a Th1 to Th2 shift.
antibody response and autoimmune disease (increased adaptive Corticotropin-releasing hormone (CRH) influences the immune
immunity). system indirectly by the activation of cortisol (glucocorticoids) and
Initially, immune responses are regulated by cells of innate immu- catecholamines (see Figure 8-4). CRH is secreted by the hypothala-
nity called antigen-presenting cells (APCs), such as monocytes/macro- mus and also peripherally at inflammatory sites (called peripheral
phages (see Chapter 6), dendritic cells, and other phagocytic cells, and or immune CRH).34,35 Peripheral (immune) CRH is proinflamma-
by Th1 and Th2 lymphocytes (cells involved in adaptive immunity). tory, causing an increase in vasodilation and vascular permeability.
These cells secrete chemical messengers, called cytokines, that regu- Therefore it appears that mast cells are the target of peripheral CRH.
late innate and adaptive immune responses. Antigen-presenting cells Mast cells release histamine, which is a well-known mediator of acute
also release cytokines that induce T cells to differentiate into Th1 cells. inflammation and allergic reactions (see Figure 8-6). Histamine
Th1 cells and APC cytokines work together to stimulate the activity induces acute inflammation and allergic reactions while suppressing

Stressors Postganglionic sympathetic nerve terminal Stressors

Cortisol
CRH NE NE epinephrine

Blood vessel
Blood Cortisol Mast cell
vessel epinephrine Monocyte
Histamine

Histamine Th1 Th2

IL-12 IL-10
Cytokines Cytokines

Acute Cellular Immunity Humoral Immunity (Th2 shift)

inflammation
allergic Tc, NK, macrophage B lymphocyte (antibody),
reaction eosinophil, mast cell

FIGURE 8-6  Effect of Corticotropin-Releasing Hormone (CRH)–Mast Cell–Histamine Axis, Cortisol,

and Catecholamines on the Th1/Th2 Balance—Innate and Adaptive Immunity. Adaptive immunity
provides protection against multicellular parasites, extracellular bacteria, some viruses, soluble toxins,
and allergens. Innate immunity provides protection against intracellular bacteria, fungi, protozoa, and
several viruses. Type 1 cytokines or proinflammatory cytokines include IL-12, interferon-gamma (IFN-γ),
and tumor necrosis factor-alpha (TNF-α). Type 2 cytokines or anti-inflammatory cytokines include IL-10
and IL-4. Solid lines (black) represent stimulation, whereas dashed lines (blue) represent inhibition (i.e.,
Th1 and Th2 are mutually inhibitory, IL-12 and IFN-γ inhibit Th2, and vice versa; IL-4 and IL-10 inhibit
Th1 responses). Stress and CRH modulate inflammatory/immune and allergic responses by stimulating
cortisol (glucocorticoid), catecholamines, and peripheral (immune) CRH secretion and by changing the
production of regulatory cytokines and histamines. CRH (peripheral, immune), corticotropin-releasing
hormone; NE, norepinephrine; Th, helper T cell; IL, interleukin; Tc, cytotoxic T cell; NK, natural killer
cell; dashed lines, decreased (inhibited); solid lines, increased (stimulation). (Redrawn from Elenkov IJ,
Chrousos GP: Stress hormones, Th1/Th2 patterns, pro/anti-inflammatory cytokines and susceptibility
to disease, Trends Endocrinol Metab 10[9]:359–368, 1999.)
214 CHAPTER 8  Stress and Disease

Th1 activity (decreasing innate immunity) and promoting Th2 activity increased or prolonged inflammatory responses.32 Researchers evalu-
(increasing adaptive immunity).36-39 ate the relative balance of the parasympathetic and sympathetic ner-
Locally, stress can exert proinflammatory or anti-inflammatory vous systems using a technique known as heart rate variability (the
effects. Moreover, some evidence indicates that stress is not a uniform, measurement of R wave variability from heartbeat to heartbeat).
nonspecific reaction.40 Different types of stressors might have variable
effects on the immune response. Thus stress may systemically cause a Other Hormones
decrease in innate immunity and enhance adaptive immunity, whereas The immune system is integrated with other physiologic processes
locally, under certain conditions, it can induce proinflammatory activi- and is sensitive to changes in CNS and endocrine functioning, such
ties that may influence the onset and cause of infection, autoimmune/ as those that accompany psychologic states.41,42 Stressors can elicit the
inflammatory, and allergic responses. In summary, stress can activate stress response through the action of the nervous and endocrine sys-
an excessive immune response and, through cortisol and the catechol- tems, specifically corticotropin-releasing hormone (CRH) from the
amines, suppress Th1 responses while enhancing Th2 responses. hypothalamus, the sympathetic nervous system, the pituitary gland,
and the adrenal gland (see Figure 8-3). CRH is also released peripher-
Parasympathetic System ally at inflammatory sites and called peripheral or immune CRH. The
The parasympathetic system balances the sympathetic nervous system processes of growth and reproduction as well as the synthesis of thy-
and thus also influences adaptation or maladaptation to stressful events. roid hormone are suppressed during stress and may conserve energy
The parasympathetic system generally opposes the sympathetic sys- during stress. Neuropeptide Y (NPY), a sympathetic neurotransmit-
tem; for example, the parasympathetic nervous system slows the heart ter, has recently been shown to be a stress mediator. Because NPY is
rate. The parasympathetic system also has anti-inflammatory effects. a growth factor for many cells, it is implicated in atherosclerosis and
Under conditions of allostatic overload, the parasympathetic system tissue remodeling. Other hormones that influence the stress response
may decrease its containment of the sympathetic system, resulting in are listed in Table 8-4.

TABLE 8-4 OTHER HORMONES THAT INFLUENCE THE STRESS RESPONSE

HORMONE SOURCE ACTION
β-Endorphins (endog- Pituitary and hypothalamus Activates endorphin (opiate) receptors on peripheral sensory nerves, leading to pain relief or
enous opiates) analgesia
Hemorrhage increases levels to inhibit blood pressure or delay compensatory changes that
would increase blood pressure1
Growth hormone (GH, Anterior pituitary gland Affects protein, lipid, and carbohydrate metabolism
somatotropin) Counters effects of insulin
Involved in tissue repair
May participate in growth and function of immune system2
Levels increase after variety of stressful stimuli (cardiac catheterization, electroshock
therapy, gastroscopy, surgery, fever, physical exercise)
Increased levels associated with psychologic stimuli (taking examinations, viewing violent or
sexually arousing films, certain psychologic performance tests)
Prolonged stress (chronic stress) suppresses growth hormone
Prolactin Anterior pituitary gland; numerous Increases in response to many stressful stimuli (including procedures such as gastroscopy,
extrapituitary tissue sites12 proctoscopy, pelvic examination, and surgery)3
Requires more intense stimuli than those leading to increases in catecholamine or cortisol
levels
Levels show little change after exercise
Oxytocin Hypothalamus Promotes bonding and social attachment
In animals associated with reduced hypothalamic-pituitary-adrenal (HPA) activation levels
and reduced anxiety4
Testosterone Leydig cells in testes Regulates male secondary sex characteristics and libido
Levels decrease after stressful stimuli (anesthesia, surgery, marathon running, mountain
climbing)5
Decreased by psychologic stimuli; however, some data indicate that psychologic stress
associated with competition (e.g., pistol shooting) increases both testosterone and cortisol
levels, especially in athletes older than 45 years6
Markedly reduced in individuals with respiratory failure, burns, and congestive heart failure7
Decreased levels occur during aging and are associated with lower cortisol responsiveness
to stress-induced inflammation8
Estrogen Ovaries Works in concert with oxytocin, exerting calming effect during stressful situations9
Melatonin Produced by pineal gland Increases during stress response; release is suppressed by light and increased in dark; recep-
tors have been identified on lymphoid cells, possibly higher density of receptors on T cells
than B cells; suppression of lymphocyte function by trauma was reversed by melatonin10
 CHAPTER 8  Stress and Disease 215

TABLE 8-4 OTHER HORMONES THAT INFLUENCE THE STRESS RESPONSE—cont’d

HORMONE SOURCE ACTION
Somatostatin (SOM) Produced by sensory nerve terminals Natural killer (NK) function and immunoglobulin synthesis decreased by SOM; growth
found in and released from lym- hormone secretion decreased by SOM
phoid cells and hypothalamus
Vasoactive intestinal Found in neurons of CNS and in VIP increases during stress; VIP-containing nerves are located in both primary and secondary
peptide (VIP) peripheral nerves lymphoid tissues, around blood vessels, and in gastrointestinal tract; VIP receptors are on
both T and B cells; VIP may influence lymphocyte maturation; cytokine production by T cells
is modified by VIP; B cell and antibody production is influenced by VIP
Calcitonin gene–related Found in spinal cord motor neurons CGRP receptors are present on T and B lymphocytes; thus it is likely that CGRP can modulate
peptide (CGRP) and in sensory neurons near immune function; CGRP may enhance acute inflammatory response because it is vasodila-
­dendritic cells of skin and in tor; maturation of immune B lymphocytes is inhibited by CGRP; IL-1 is inhibited by CGRP,
primary and secondary lymphoid which is important for activation of T cells; it has been shown to interfere with lymphocyte
tissues activation
Neuropeptide Y (NPY) Present in neurons of CNS and Lymphocytes have receptors for NPY and thus may modulate their function;11 several lines
in ­neurons throughout body; of evidence suggest that NPY is neurotransmitter and neurohormone involved in stress re-
colocalized in nerve terminals in sponse; increased levels of NPY occur in plasma in response to severe or prolonged stress;
lymphatic tissues with norepi- may be responsible for stress-induced regional vasoconstriction (splanchnic, coronary, and
nephrine cerebral); may also increase platelet aggregation2
Substance P (SP) Produced by neuropeptide classified SP increases in response to stress; receptors for SP are found on membrane of both T and
as tachykinin (increases heart B cells, mononuclear phagocytic cells, and mast cells; proinflammatory activity induces
rate subsequent to lowering blood release of histamine from mast cells during stress response; causes smooth muscle
pressure) found in brain, as well contraction, causes macrophages and T cells to release cytokines, and increases antibody
as nerves innervating secondary production
lymphoid tissues

1. Amico JA et al: Anxiety and stress responses in female oxytocin deficient mice (review), J Neuroendocrinol 16(4):319–324, 2004.
2. Rabin BS: The nervous system—immune system connection. In Stress, immune function, and health: the connection, New York, 1999,
­Wiley-Liss.
3. Rohleder N et al: Age and sex steroid-related changes in glucocorticoid sensitivity of proinflammatory cytokine production after psychosocial
stress, J Neuroimmunol 126(1–2):69–77, 2002.
4. Marucha PT, Kiecolt -Glaser JK, Favagehi M: Mucosal wound healing is impaired by examination stress, Psychosom Med 60(3):362–365, 1998.
5. Chesnokova V, Melmed S: Mini review: neuro-immmuno-endocrine modulation of the hypothalamic-pituitary-adrenal axis (HPA) by gp130 signal-
ing molecules (review), Endocrinology 143(5):1571–1574, 2002.
6. Guezennec CY et al: Effect of competition stress on tests used to assess testosterone administration in athletes, Int J Sports Med 16(6):368–
372, 1995.
7. Bauer-Wu SM: Psychoneuroimmunology. Part I: Physiology, Clin J Oncol Nurs 6(3):167–170, 2002.
8. Bauer-Wu SM: Psychoneuroimmunology. Part II: Mind-body interventions, Clin J Oncol Nurs 6(4):243–246, 2002.
9. Repka-Ramirez MS, Baraniuk JN: Histamine in health and disease, Clin Allergy Immunol 17:1–17, 2002.
10. Maestroni GJ: MLT and the immune-hematopoietic system, Adv Exp Med Biol 460:396, 1999.
11. Petito JM, Huang Z, McCarthy DB: Molecular cloning of NPY-Y1 receptor cDNA from rat splenic lymphocytes: evidence of low levels of mRNA
expression and [125I]NPY binding sites, J Neuroimmunol 54:81, 1994.
12. Cacioppo JT et al: Autonomic, neuroendocrine, and immune responses to psychological stress: the reactivity hypothesis, Ann N Y Acad Sci
840:664–673, 1998.

Role of the Immune System regulatory interactions between the immune system (including cell-
Several conditions with variable pathophysiologic characteristics derived cytokines) and the nervous and endocrine systems.
appear to have a common origin15,43 relating to chronic inflammatory The immune, nervous, and endocrine systems communicate
processes. These conditions include cardiovascular disease, osteoporo- through similar pathways using hormones, neurotransmitters, neuro-
sis, arthritis, type 2 diabetes mellitus, chronic obstructive pulmonary peptides, and immune cell products.26 The complexity of this system
disease (COPD), other diseases associated with aging, and some can- can be daunting. Various components of immune system responses
cers; all are characterized by the prolonged presence of proinflamma- can be affected by neuroendocrine-produced factors involved in the
tory cytokines.15,43 (Inflammation is discussed in Chapter 5.) stress reaction. Conversely, immune cell–derived cytokines and other
It is important to remember that inflammation is associated with products affect neurocrine and endocrine cells.41,47,48 Several pathways
impairment of normal tissue function. Although inflammation is a regulate communication among these systems (Figure 8-7).
normal response and considered beneficial, an excessive inflammatory The stress response directly influences the immune system through
response can damage tissue. Stress and negative emotions are asso- hypothalamic and pituitary peptides and through products of the sym-
ciated directly with the production of increased levels of proinflam- pathetic branch of the ANS. Immune cells have surface receptors for
matory cytokines, providing a possible link between stress, immune ACTH, CRH, endorphins, norepinephrine, growth hormone, steroids,
function, and disease.44-46 More recent research is focused on the and other products of the stress response.42 There is direct innervation
216 CHAPTER 8  Stress and Disease

systemic production of these cytokines also induces other CNS and

Stress
behavior changes during an acute infectious episode.57-60
and/or
Neuropeptides and hormones have a significant effect on the
circadian rhythms
immune response. Whether this impact on immune function is sup-
pressive or potentiating depends on the type of factor secreted (some
factors enhance, some suppress, and some both enhance and suppress),
the concentration and length of exposure, the target cell, and the spe-
Nervous system cific immune function studies.57 Neuropeptides and neuroendocrine
hormones may directly control biochemical events affecting cell prolif-
eration, differentiation, and function or may indirectly control immune
cell behavior by affecting the production or activity of cytokines.47,48
In summary, stress-induced immune changes affect many immune
cell functions, including decreased natural killer cell and T cell cyto-
Endocrine Immune toxicity and impaired B cell function.61 These impairments in immune
system system function may have health consequences for stressed individuals,
including increased risk of infection and some types of cancer.62,63

STRESS, PERSONALITY, COPING, AND ILLNESS

FIGURE 8-7  Nervous System/Endocrine System/Immune
­System Interactions. Interconnections or pathways of communi- Extreme physiologic stressors, such as severe burn injury, represent
cation among the immune, nervous, and endocrine systems. a predictable stimulus for stress responses. A less severe and defined
event or situation, however, can be a stressor for one person and not
for another. Many stressors, such as fasting or temperature changes, do
of the thymus, spleen, lymph nodes, and bone marrow.47 Choliner- not necessarily cause a physiologic stress response if psychologic fac-
gic, adrenergic, and peptidergic nerve terminals are present in the tors are minimized. Stress itself is not an independent entity but a sys-
lymphoid organs and tissues. Endogenous opiates are released during tem of interdependent processes moderated by the nature, intensity,
stress and have concentration-dependent, enhancing, and suppressive and duration of the stressor and the perception, appraisal, and cop-
effects on various immune cells (see Table 8-4).47,49-52 ing efficacy of the affected individual, all of which in turn mediate the
The pineal gland regulates immune response and mediates the appar- psychologic and physiologic response to stress. Further, adjustment to
ent effects of circadian rhythm on immunity. When melatonin produc- repetitive stressors is known to be individualized, based on a person’s
tion is blocked (by continuous light or by pharmacologic means), the appraisal of a situation.64 Illustrating the influence of an individualized
immune response is suppressed, whereas administration of melatonin stress appraisal on physiologic processes, a meta-analysis of the rela-
reverses these effects.53 This immunomodulation pathway may effect tionships between stressors and immunity found that a higher percep-
immune changes found with sleep disturbance and dysregulated circa- tion of stress was associated with reduced Tc cell cytotoxicity, although
dian rhythm,54 which are common among acutely ill and stressed persons. not with levels of circulating T-helper or Tc lymphocytes.65
The hypothalamic-pituitary-adrenal (HPA) axis may produce indi- Psychosocial distress may be predictive of psychologic, social, and
rect effects on the CNS that modulate immune responses. The result is physical health outcomes (see Health Alert: Acute Emotional Stress and
profound with prolonged severe stress,41 including enlargement of the Adverse Heart Effects). In psychologic distress, the individual feels a
adrenal gland with simultaneous involution of the thymus and lymph general state of unpleasant arousal after life events that manifests as
nodes. Increased levels of circulating glucocorticosteroids (GCSs) may physiologic, emotional, cognitive, and behavior changes.66 Periods of
be an important mechanism in stress-related immune structure altera- depression and emotional upheaval often are associated with adverse
tions and in suppression of the immune response.41 The GCS level life events and place the affected individual at risk for immunologic
increases are attributable to pituitary ACTH production—a result deficits, increasing the risk of ill health.41 Adverse life events having
of increased hypothalamic CRH. A number of stress factors initiate the most negative effect on immunity are characterized as uncontrol-
CRH production, including high levels of interleukin-1 (IL-1) and lable, undesirable, and overtaxing the individual’s ability to cope.67,68
­interleukin-6 (IL-6). Production of IL-1 by activated macrophages and A meta-analysis of studies shows a relationship between depression
monocytes is inhibited by GCSs, suggesting a feedback loop with IL-1, and reduction in lymphocyte proliferation and NK cell activity.69 Mul-
CRH, ACTH, and GCS secretion.47,55 tiple moderating factors may be important in immune modulation in
Lymphocytes also produce ACTH and endorphins in small depressed individuals, including comorbidities such as alcoholism.
amounts, which probably influences immune response in an autocrine Examples of triggering circumstances include bereavement, academic
(same cell stimulation) or paracrine (cell to cell) manner in ongoing pressures, and marital conflict. Aging also may increase psychosocial
immune responses.47,56 The T cell growth factor IL-2 can up-regulate distress and is associated with immune changes (see Health Alert: Part-
pituitary ACTH. Immune-derived cytokines have significant influ- ner’s Survival and Spouse’s Hospitalizations and/or Death).70,71
ence on neuroendocrine function, with evidence for direct and indi- Personality characteristics also are associated with individual differ-
rect cytokine effects on nervous and adrenal cell functions. Thus the ences in appraisal and response to stressors.42 Specific personality char-
immune system has an adaptive role as a signal organ to alert other acteristics, such as academic achievement, motivation, and aggression,
systems of internally threatening stimuli (e.g., infection, tissue damage, are correlated with immunologic alterations. For example, aggression
tumor cells). The release of immune inflammatory mediators (IL-6, is positively associated with changes in T and B cell numbers in male
tumor necrosis factor-beta [TNF-β], interferon) is triggered by bacte- military personnel.72
rial or viral infections, cancer, tissue injury, and other stressors that in Stressful life events and mood have been reported as important
turn initiate a stress response through the HPA pathway. Enhanced factors preceding the onset or exacerbation of symptoms in acquired
 CHAPTER 8  Stress and Disease 217

disorder (PTSD) has been described in many populations.76-78 The

HEALTH ALERT
influence of repetitive but episodic stress on cancer survivors demon-
Acute Emotional Stress and Adverse Heart Effects strates a connection between events such as mammography and acti-
Myocardial Ischemia vation of the HPA axis. Early research with breast cancer survivors by
• Individuals with coronary heart disease may develop myocardial ischemia Cordova and colleagues79 demonstrated a link between sympathetic
during mental or acute emotional stress even though their exercise or activity and HPA axis activation, noting that some women reported
chemical nuclear test results are negative. symptoms of post-traumatic stress disorder (heart palpitations, panic,
• Systemic vascular resistance increases during periods of mental or acute shakiness, nausea) when they thought about cancer recurrence or
emotional stress with concomitant increased myocardial oxygen demand. when they found themselves near the hospital where they received ini-
tial treatment.79 Further, Ma and colleagues80 reported that the threat
Left Ventricular Dysfunction of cancer recurrence (using a simulated mammography event as a
• More evidence for left ventricular dysfunction exists in older women. stressor to elicit thoughts of cancer recurrence) elicited greater altera-
• After acute emotional stress or trauma, there is an increase in sudden chest tions in heart rate variability when compared to another simulated
pain and shortness of breath. controlled stressor. These studies suggest activation of the autonomic
• Left ventricular dysfunction is more common in the cardiac apex. nervous system to events, such as mammography, that occur repeat-
• Alterations are possibly a result of increased levels of catecholamines. edly throughout breast cancer survivorship, although the timing of
onset of these autonomic activation responses to a stressor is unclear.
Ventricular Dysrhythmias These additional stresses may affect the course of illness as well
• Intense or unusual acute stress precipitates about 20% of serious ventricu- as interfere with the efficacy of the medical intervention. Identifying
lar dysrhythmias or sudden cardiac death. and reducing stress in the clinical setting have particular applicabil-
• Altered brain activity may lead to changes in ventricular repolarization and ity in both disease prevention and illness management. In addition to
electrical instability of the cardiac muscle. medical procedures, patient-provider communication also provides
an important area for future research. Recent studies of cancer com-
Data from Critchley HD et al: Brain 128(pt 1):75–85, 2005; Ramach- munication and patient-provider interaction have demonstrated a
andruni S et al: J Am Coll Cardiol 47(5):987–991, 2006; Soufer R:
link between communication events and emotional outcomes, such as
Circulation 110(13):1710–1713, 2004; Wittstein IS et al: N Engl J Med
352(6):539–548, 2005; Ziegelstein RC: JAMA 298(3):324–329, 2007.
uncertainty and mood state in breast cancer survivors.81,82 Although
a logical extension, it remains to be seen if these emotional outcomes
impact physiology-based health outcomes caused by activation of the
HEALTH ALERT HPA axis and subsequent immune processes.
Partner’s Survival and Spouse’s Hospitalizations Coping
and/or Death Coping is the process of managing stressful challenges that tax the
A Harvard study shows that a spouse’s chances of dying increase not only individual’s resources.83 A beneficial influence during stress has been
when the partner dies but also when that partner becomes seriously ill. The shown with adaptive coping strategies, especially if they are problem
9-year follow-up study consisted of 518,240 elderly couples. Mortality after focused and involve social support.83,84 Adverse consequences of stress
the partner’s hospitalization varied according to the spouse’s diagnosis. For may be minimized by coping styles. Coping styles that have been
elderly people whose spouse had been hospitalized, the short-term risk of associated with altered immunity include repression, denial, escape-
dying approaches that of an elderly person after his or her spouse’s death. avoidance, and concealment.42 Repression was associated with lower
A wife’s hospitalization increased her husband’s chances of dying within 1 monocyte counts, higher eosinophil counts, higher serum glucose
month by 35%; a husband’s hospitalization increased his wife’s chances of levels, and more self-reported medication reactions in medical outpa-
dying by 44%. Likewise, a wife’s death increased her partner’s 1-month mor- tients85 and with higher Epstein-Barr virus (EBV) antibody titers in
tality risk by 53%, and a husband’s death raised his partner’s risk by 61%. students.86 Further, a prospective long-term study found increased
The researchers commented that a spouse’s illness or death can increase a markers of accelerated human immunodeficiency virus (HIV) infec-
partner’s mortality by causing severe stress and removing a primary source of tion in gay men who concealed their homosexual identity.56
emotional, psychologic, practical, and financial support. Coping responses may be adaptive or maladaptive. Maladaptive
coping can result in a change in behavior contributing to potentially
Data from Christakis NA, Allison PD: Mortality after the hospitalization adverse health effects (e.g., increased smoking, change in eating habits).
of a spouse, N Engl J Med 354(7):719–730, 2006. Serious disturbances of the sleep-wake cycle are observed in many peo-
ple under stress and in many clinical settings. Recent work has shown
immunodeficiency syndrome (AIDS) infection, diabetes, and multiple that sleep disturbance may exacerbate the pathophysiologic status of
sclerosis.73-75 In addition, the interaction with healthcare providers in some individuals.87-89 Investigators have reported that sleep deprivation
a clinical setting, the diagnosis of a major illness, and the process of and circadian disruption, even in young otherwise healthy individuals,
undergoing various clinical procedures (e.g., blood sampling, injec- have detrimental influences on respiratory and immune system func-
tions, examinations, surgical procedures) may represent significant tion. Even partial sleep deprivation was associated with reduced NK cell
negative life events to many individuals (Figure 8-8). These additional activity in healthy subjects, and only recently have seriously ill individu-
stresses may interfere with the efficacy of the medical intervention. als been assessed for adequacy and structure of sleep during recovery.87
Identifying and reducing stress in the clinical setting have particular Adaptive coping strategies, especially those that are problem focused
applicability for both preventing disease and managing illness. and those that encourage seeking social support, are considered ben-
In the past decade, evidence has accumulated linking severe psy- eficial during stressful experiences. The extent to which an individual
chosocial stress resulting from negative life events to a chronic syn- responds to distress, using effective positive coping strategies, deter-
drome with mental and physical consequences. Post-traumatic stress mines the degree of successful moderation of the stress challenge.
218 CHAPTER 8  Stress and Disease

POTENTIAL EFFECTS IN HEALTHY INDIVIDUALS

Stressful life event

Ef
in

fe
p
co

ct
POTENTIAL EFFECTS DURING MEDICAL INTERVENTION

ive
ive

co
ct
fe

pin
ef

g
In
Symptoms
Significant stress response Transient effect − +
A Distress/illness Return to steady state
If perceived
Diagnosis as stressor
POTENTIAL EFFECTS IN SYMPTOMATIC INDIVIDUALS

Stressful life event

Treatment
C
g

Ef
in

fe
p

ct
co

ive
ive

co
ct

+  Stimulation
p
fe

in
ef

g
In

−  Inhibition
B Exacerbation of illness Little or no effect on symptoms
FIGURE 8-8  Health Outcome Determination in Stressful Life Situations Is Moderated by Numer-
ous Factors. Whether a life-challenged individual experiences distress or illness depends on the sub-
ject’s appraisal of the event and the coping strategies used during the stressful period. Models (A) and
(B) reflect possible outcomes in stressed healthy and symptomatic individuals. Model (C) illustrates the
dynamic clinical setting in which the diagnosis of a serious illness and subsequent medical interven-
tions may be perceived as stressful challenges and have potentially detrimental influences on physical
outcome.

Mediating factors that may influence stress susceptibility or resil- GERIATRIC CONSIDERATIONS
ience include age, socioeconomic status, gender, social support,
religious or spiritual factors, personality, self-esteem, genetics, past Aging & The Stress-Age Syndrome
experiences, and current health status. Evidence suggests that effec- With aging, sometimes a set of neurohormonal and immune alterations, as
tive intervention may result in greater stress resilience and improved well as tissue and cellular changes, develops. These changes have been
psychologic and physiologic outcomes.90 For example, women with defined as stress-age syndrome and include the following:
recurrent metastatic breast cancer who were provided weekly group • Alterations in the excitability of structures of the limbic system and
counseling in addition to routine medical treatment lived an average of hypothalamus
19 months longer than control subjects, suggesting a mediating influ- • Increase of the blood concentrations of catecholamines, ADH, ACTH, and
ence of additional support for these women.57,84 cortisol
The importance of social support for seriously ill individuals has • Decrease of the concentrations of testosterone, thyroxine, and others
focused attention also on the health of caregivers. Significant stress • Alterations of opioid peptides
manifested as depression, anxiety, and fatigue has been noted in family • Immunodepression and pattern of chronic inflammation
caregivers of those with cancer, Alzheimer disease, and burn trauma.91 • Alterations in lipoproteins
Enhanced social support has been shown to improve measures of • Hypercoagulation of the blood
immune function.84,92-95 • Free radical damage of cells
Interventions to potentially prevent or manage stress-related psy- Some of the alterations are adaptational, whereas others are potentially
chologic or physical problems include both short- and long-term damaging. These stress-related alterations of aging can influence the course
coping strategies. Educational components are specific to the indi- of developing stress reactions and lower adaptive reserve and coping capacity.
vidual’s problems. Relaxation techniques may include meditation,
mindfulness, imagery, massage, and biofeedback. These approaches Data from Frolkis VV: Stress-age syndrome, Mech Ageing Dev
may be used on an individual or group basis. Incorporation of these 69(1–2):93–107, 1993.
approaches into clinical training facilitates their use in the clinical ACTH, Adrenocorticotropic hormone; ADH, antidiuretic hormone.
arena. Future research should focus on the efficacy of such approaches
with various populations.
In summary, it is clear that the mind and body are connected
4 QUICK CHECK 8-2
1. Define psychoneuroimmunology.
through a multitude of complex physical and emotional interactions. 2. How does the immune system participate in stress-related diseases?
Understanding the complexity of these interactions is a challenge for 3. Why are stress-related diseases a problem?
many researchers. Areas of promise include investigating relationships 4. Why do stress-related diseases occur?
between the potential for illness with respect to stressors, as well as 5. What intervention or prevention activities reduce stress-related diseases?
developing effective stress management techniques and approaches.
 CHAPTER 8  Stress and Disease 219

DID YOU UNDERSTAND?

Concepts of Stress 7. Epinephrine exerts its chief effects on the cardiovascular system. Epi-
1. Modern society is full of stress. Stress experiences involve daily hassles nephrine increases cardiac output and increases blood flow to the heart,
(fast-paced scheduling, the pressure to remain in constant contact through brain, and skeletal muscles by dilating vessels that supply these organs.
social media or cell phones, or both), major life events (loss of family mem- It also dilates the airways, thereby increasing delivery of oxygen to the
ber, loss of job), abuse, and trauma. bloodstream.
2. Hans Selye identified three structural changes in rats subjected repeatedly 8. Norepinephrine’s chief effects complement those of epinephrine. Norepi-
to noxious stimuli (stressors): (a) enlargement of the cortex of the adrenal nephrine constricts blood vessels of the viscera and skin; this has the effect
gland, (b) atrophy of the thymus gland and other lymphoid tissues, and (c) of shifting blood flow to the vessels dilated by epinephrine. Norepinephrine
ulceration of the gastrointestinal tract. also increases mental alertness.
3. Selye believed that the three changes were caused by a nonspecific physi- 9. The glucocorticoid molecules reach all tissues, including the brain, easily
ologic response to any long-term stressor. He called this response the gen- penetrate cell membranes, and react with numerous intracellular glucocor-
eral adaptation syndrome (GAS). ticoid receptors. Because they spare almost no tissue or organ and influ-
4. The GAS occurs in three stages: (a) the alarm stage, (b) the stage of resis- ence a large proportion of the human genome, they exert significant diverse
tance or adaptation, and (c) the stage of exhaustion or allostatic overload. biologic actions. Cortisol’s chief effects involve metabolic processes. By
Diseases of adaptation develop if the stage of resistance or adaptation inhibiting the use of metabolic substances while promoting their formation,
does not restore homeostasis. Although important, this approach is now cortisol mobilizes glucose, amino acids, lipids, and fatty acids and delivers
thought to be greatly oversimplified. them to the bloodstream.
5. Selye identified three components of physiologic stress: (a) the stressor, 10. Overall, glucocorticoids have an important role in the homeostasis of the
(b) the physiologic or chemical disturbance produced by the stressor, and CNS. These hormones regulate memory, cognition, mood, and sleep.
(c) the body’s adaptational response to the stressor. 11. Glucocorticoids contribute to the development of metabolic syndrome and
6. Other investigators have shown that the physiologic stress response also the pathogenesis of obesity. They can directly cause insulin resistance and
occurs in response to psychologic or emotional stress. influence genetic variations that predispose to obesity.
7. Psychologic stressors can be anticipatory and triggered by expectations of 12. Cortisol secretion during stress exerts beneficial effects by inhibiting ini-
an upcoming stressor or can be reactive to a stressor. Both of these psycho- tial inflammatory effects, for example, vasodilation and increased capillary
logic stressors are capable of eliciting a physiologic stress response. permeability. Cortisol also promotes resolution and repair. Paradoxically,
elevated levels of glucocorticoids and catecholamines (epinephrine and
The Stress Response norepinephrine), administered both endogenously and exogenously, can
1. The stress response involves the nervous system (sympathetic branch of decrease innate immunity and increase autoimmune (adaptive) responses.
the autonomic nervous system), the endocrine system (pituitary and adre- These effects can accentuate inflammation in general and potentially
nal glands), and the immune system. More simply, these relationships are increase neuronal death (e.g., in stroke victims).
often cited together as the hypothalamic-pituitary-adrenal (HPA) axis. 13. Other hormones are affected by the stress response, for example, increased
2. The stress response is initiated when a stressor is present in the body or circulating levels of β-endorphins, growth hormone, prolactin, oxytocin, the
perceived by the mind. Psychologic stress may cause or worsen several steroid sex hormones, and antidiuretic hormone.
diseases or disorders including anxiety, depression, insomnia, chronic pain
and fatigue syndromes, obesity, metabolic syndrome, essential hyperten- Stress, Personality, Coping, and Illness
sion, type 2 diabetes, atherosclerosis and its cardiovascular consequences, 1. Stress is a system of interdependent processes that are moderated by the
osteoporosis, and autoimmune inflammatory and allergic disorders. nature, intensity, and duration of the stressor and the coping efficacy of the
3. Effects of stress on inflammatory and immune processes influence coronary affected individual, all of which in turn mediate the psychologic and physi-
artery disease, depression, autoimmune disorders, and, possibly, virally- ologic response to stress.
mediated cancers. 2. Personality characteristics are associated with individual differences in
4. The physiology involved in meeting the demands and challenges of daily appraisal and response to stressors.
life is an emerging topic of research. Some refer to these challenges as 3. Coping styles associated with altered immunity include repression, denial,
“stressors” and to the chronically stressed person as being “stressed out.” escape-avoidance, and concealment.
The physiology is complex, involving mechanisms of both protection and 4. Many studies have linked psychologic distress with altered immune func-
injury. Glucocorticoids from the adrenal cortex, in response to ACTH from tion, and there is now evidence that strengthens the association of stress
the pituitary gland, comprise the major stress hormones along with the cat- with the potential for illness in humans.
echolamines epinephrine and norepineprine.
5. The neuroendocrine response to stress consists of sympathetic stimulation GERIATRIC CONSIDERATIONS: Aging & The Stress-Age
of the adrenal medulla to secrete catecholamines (norepinephrine, epi- Syndrome
nephrine, neuropeptide Y) and stressor-induced stimulation of the pituitary 1. With aging, often a set of neurohormonal and immune alterations, includ-
to secrete ACTH, which in turn stimulates the adrenal cortex to secrete ing tissue and cellular changes, occur. These changes are collectively
steroid hormones, particularly cortisol. called stress-age syndromes.
6. In general, catecholamines prepare the body to act, and cortisol mobilizes 2. The changes are numerous, with some being adaptative whereas others
energy (glucose) and other substances needed for action. The parasympa- are potentially damaging.
thetic system balances or restrains the sympathetic system, resulting in
anti-inflammatory effects.
220 CHAPTER 8  Stress and Disease

 KEY TERMS
• A drenocorticotropic hormone •  iseases of adaptation  204
D •  eactive response  207
R
(ACTH)  207 • General adaptation syndrome (GAS)  204 • Stage of exhaustion  204
• Alarm stage  204 • Homeostasis  207 • Stage of resistance or adaptation  204
• Allostasis  208 • Hypothalamic-pituitary-adrenal • Stress response  209
• Allostatic overload  208 (HPA) axis  207 • Stressor  204
• Anticipatory response  207 • Neuropeptide Y (NPY)  214 • Th1 to Th2 shift  213
• Coping  217 • Peripheral (immune) CRH  213
• Corticotropin-releasing hormone • Physiologic stress  205
(CRH)  207 • Psychoneuroimmunology (PNI)  207

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CHAPTER

9
Biology, Clinical Manifestations,
and Treatment of Cancer
David M. Virshup

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Cancer Terminology and Characteristics, 222 Cancer Invasion and Metastasis, 241
Tumor Classification and Nomenclature, 223 Very Few Cells in a Cancer Have the Ability to Metastasize, 242
The Biology of Cancer Cells, 227 Clinical Manifestations and Treatment of Cancer, 243
Cancer Cells in the Laboratory, 227 Clinical Manifestations of Cancer, 243
The Genetic Basis of Cancer, 227 Treatment of Cancer, 248
Types of Genes Misregulated in Cancer, 234
Cancer Stem Cells, 238
Stroma-Cancer Interactions, 239
Inflammation, Immunity, and Cancer, 240

Cancer is a leading cause of suffering and death in the developed this broad category is more challenging. A definition from 1922 may
world. The incidence of cancer increases markedly with advancing summarize cancer as well as any:
age and is strongly affected by gender, life-style, ethnicity, infection,
The most generally accepted definition of a tumor is that it is a tissue over-
inflammation, and genetics. Because of intensive research, we now
growth which is independent of the laws governing the remainder of the
understand that cancer is a collection of more than 100 different dis-
body. It is usual to add as a qualifying phrase to separate tumors from
eases, each caused by a specific and often unique accumulation of reparative processes, such as bone callus, that the neoplasm overgrowth
genetic and epigenetic alterations. Environment, heredity, and behav- serves no useful purpose to the organism.1
ior interact to modify the risk of developing cancer and the response
to treatment. Improvements in treatment strategies and support- The term cancer derives from the Greek word for crab, karkinoma,
ive care, coupled with new, often individualized therapies based on which the physician Hippocrates used to describe the appendage-like pro-
advances in our fundamental understanding of the basic pathophysi- jections extending from tumors. The word tumor originally referred to
ology of malignancy, have contributed to an increasing number of any swelling that is caused by inflammation, but is now generally reserved
effective options for these diverse, often lethal, disorders collectively for describing a new growth, or neoplasm. Not all tumors or neoplasms,
called cancer. however, are cancer. The term cancer refers to a malignant tumor and is
not used to refer to benign growths such as lipomas or hypertrophy of an
organ. Yet it is important to recognize that benign neoplasms also can be
CANCER TERMINOLOGY AND CHARACTERISTICS life-threatening if they enlarge in critical locations. For example, a benign
Any discussion of cancer must start with a definition of what it is and meningioma at the base of the skull may cause symptoms by compressing
what it is not. Although most readers may have an intuitive understand- adjacent normal brain tissue. The definitions of benign versus malignant
ing of this disorder, composing an exact definition that encompasses are presented in the following text and in Table 9-1.

222
 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer 223

cancers of blood-forming cells are called leukemias. However, many

TABLE 9-1 CHARACTERISTICS OF BENIGN
cancers, such as Hodgkin disease and Ewing sarcoma, are named
VERSUS MALIGNANT TUMORS for historical reasons that do not follow this nomenclature
BENIGN TUMORS MALIGNANT TUMORS convention.
Grow slowly Grow rapidly
Have a well-defined capsule Are not encapsulated
Carcinoma in Situ
Are not invasive Invade local structures and tissues Cancers develop incrementally, as they accumulate specific genetic
Are well differentiated; look like Are poorly differentiated; may not be lesions. Careful surveillance for cancer often detects abnormal
tissue from which they arise able to determine tissue of origin growths in epithelial tissues that have atypical cells and increased pro-
Have a low mitotic index; ­dividing Have a high mitotic index; many liferation rate compared with normal surrounding tissues. These early
cells are rare dividing cells stage growths are localized to the epithelium but have not penetrated
Do not metastasize Can spread distantly, often through the local basement membrane or invaded the surrounding stroma
blood vessels and lymphatics ­(Figure 9-2). Based on these characteristics, they are not malignant
but are often called carcinoma in situ (CIS). CIS is commonly found
in a number of sites, including the cervix, skin, oral cavity, esopha-
gus, and bronchus. In glandular epithelium, in situ lesions occur in
the stomach, endometrium, breast, and large bowel. In the breast,
Tumor Classification and Nomenclature ductal carcinoma in situ (DCIS) can fill the mammary ducts but has
The careful evaluation of each cancer is important for many rea- not progressed to local tissue invasion.2 CIS lesions can have one of
sons. Different cancers will have different causes, different rates and the following three fates: they can remain stable for a long time, they
patterns of progression, and different responses to treatment. The can progress to invasive and metastatic cancers, or they can regress
classification starts with knowing the tissue and organ of origin, and disappear. CIS can vary from low-grade to high-grade dysplasia,
the extent of distribution to other sites, and the microscopic and with the high-grade lesions having the highest likelihood of becom-
immunohistochemical appearance of the lesion. Increasingly, it also ing invasive cancers. Knowing how to best treat low-grade CIS lesions
includes a detailed description of the critical genetic changes in the is challenging, because the proportion that progress to cancer versus
cancer. the proportion that will never cause clinical problems is usually not
known. Although most persons prefer removal of any CIS as opposed
Benign and Malignant to “watchful waiting,” this topic continues to be a source of great
Benign tumors, which are not referred to as cancers, are made of fairly debate.
well-differentiated cells and well-organized stroma, the surrounding
capsule of connective tissue. They retain recognizable tissue structure Classification of Tumors—Classic Histology
and do not invade beyond their capsule, nor do they spread to regional and Modern Genetics
lymph nodes or distant locations. Mitotic cells are very rarely pres- Because our knowledge about the molecular alterations in cancer
ent during microscopic analysis. Benign tumors are generally named can influence the choices of therapy, it becomes increasingly impor-
according to the tissues from which they arise, and include the suf- tant for clinicians to accurately molecularly classify each cancer
fix “-oma.” For example, a benign tumor of the smooth muscle of (Box 9-1). The classification, and hence the treatment decisions, of
the uterus is a leiomyoma, and a benign tumor of fat cells is a lipoma. cancers was originally based on gross and light microscopic appear-
Benign tumors will usually have a subset of the genetic lesions found ance, and is now commonly accompanied by immunohistochemi-
in advanced cancers. cal analysis of protein expression. Increasingly, this is supplemented
Malignant tumors are distinguished from benign tumors by more by a more extensive molecular analysis of the tumors. Sometimes
rapid growth rates and specific microscopic alterations, including a single gene is examined (for example, to determine if there is a
loss of differentiation and absence of normal tissue organization characteristic chromosomal translocation diagnostic of chronic
­(Figure 9-1). One of the microscopic hallmarks of cancer cells is ana- myelogenous leukemia [CML]), and sometimes a panel of genes
plasia, the loss of cellular differentiation. Malignant cells are also pleo- and proteins are examined (e.g., in breast cancer) to determine if
morphic, with marked variability of size and shape. They often have the tumor expresses estrogen receptor, progesterone receptor, and
large darkly stained nuclei and mitotic cells are common. Malignant the epidermal growth factor (EGF) receptor HER2, or if there are
tumors may have a substantial amount of stroma, but it is disorga- mutations in specific genes that include response to therapy. In a
nized, with loss of normal tissue structure. Malignant tumors lack a research setting, and increasingly in clinical settings, gene expres-
capsule and grow to invade nearby blood vessels, lymphatics, and sur- sion and mutation analysis can be measured using polymerase chain
rounding structures. The most important and most deadly character- reaction (PCR), microarray, or advanced DNA sequencing technol-
istic of malignant tumors is their ability to spread far beyond the tissue ogy, so that the status of a large number of genes can be assessed.
of origin, a process known as metastasis. These analyses can be used to classify tumors more precisely and
In general, cancers are named according to the cell type from may predict the most effective therapy. This detailed analysis of each
which they originate. Cancers arising in epithelial tissue are called tumor is a form of personalized medicine that offers therapy based
carcinomas, and if they arise from or form ductal or glandular on a very detailed knowledge of each individual’s characteristics and
structures are named adenocarcinomas. Hence, a malignant tumor their specific cancer.3 This enhanced molecular characterization
arising from breast glandular tissue is a mammary adenocarcinoma. subdivides cancers into therapeutically and prognostically relevant
Cancers arising from mesenchymal tissue (including connective tis- smaller groups. As an example, breast cancers can now be subclas-
sue, muscle, and bone) usually have the suffix sarcoma. For example, sified into over four types (luminal A, luminal B, basal-like, and
malignant cancers of skeletal muscle are known as rhabdomyosar- others) based on their expression of specific markers, such as estro-
comas. Cancers of lymphatic tissue are called lymphomas, whereas gen receptor, HER2/Neu, and other specific genes and proteins.
224 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer

A B C

D E F
FIGURE 9-1  Loss of Cellular and Tissue Differentiation During the Development of Cancer. The
cells of a benign neoplasm (B) resemble those of the normal colonic epithelium (A), in that they are
columnar and have an orderly arrangement. Loss of some degree of differentiation is evident in that
the neoplastic cells do not show much mucin vacuolization. Cells of the well-differentiated malignant
neoplasm (C) of the colon have a haphazard arrangement, and although gland lumina are formed they
are architecturally abnormal and irregular. Nuclei vary in shape and size, especially when compared with
(A). Cells in the poorly-differentiated malignant neoplasm (D) have an even more haphazard arrange-
ment, with very poor formation of gland lumina. Nuclei show greater variation in shape and size com-
pared with the well-differentiated malignant neoplasm in (C). Cells in anaplastic malignant neoplasms
(E) bear no relation to the normal epithelium, with no recognizable gland formation. Tremendous varia-
tion is found in the size of cells and their nuclei, with very intense staining (hyperchromatic nuclei). Not
knowing the site of origin makes it impossible to classify this tumor by microscopic appearance alone.
Well-differentiated tumors often resemble their cell of origin, as shown in the example of a benign
tumor of smooth muscles (F). (From Stevens A, Lowe J: Pathology, ed 2, London, 2000, Mosby.)
 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer 225

LOW-GRADE HIGH-GRADE
NORMAL EPITHELIUM INTRAEPITHELIAL INTRAEPITHELIAL INVASIVE CARCINOMA
NEOPLASIA NEOPLASIA
epithelium
connective tissue

A B C D

50 m
FIGURE 9-2  Progression from Normal to Neoplasm in the Uterine Cervix. A sequence of cellular
and tissue changes progressing from low-grade to high-grade intraepithelial neoplasms (also called car-
cinoma in situ) and then to invasive cancer is seen often in the development of cancer. In this example
of the early stages of cervical neoplastic changes, the presence of anaplastic cells and loss of normal
tissue architecture signify the development of cancer. The high rate of cell division and the presence of
local mutagens and inflammatory mediators all contribute to the accumulation of genetic abnormalities
that lead to cancer. (From Alberts B et al: Molecular biology of the cell, ed 5, New York, 2008, Garland.)

germ cell tumors secrete a protein known as alpha fetoprotein (AFP)

BOX 9-1 TYPES OF GENETIC LESIONS into the blood, and prostate tumors secrete prostate specific antigen
IN CANCER (PSA) into the blood. If the tumor marker itself has biologic activity,
1. Point mutations then it can cause symptoms, a phenomenon known as a paraneoplastic
2. Subtle alterations (insertions, deletions) syndrome (see Table 9-7). For example, the adrenal medulla normally
3. Chromosome changes (aneuploidy and loss of heterozygosity) secretes the catecholamine epinephrine (adrenaline). Benign tumors
4. Amplifications of the adrenal medulla (pheochromocytoma) can produce catechol-
5. Gene silencing (DNA methylation, histone modification, microRNAs) amines (e.g., adrenaline) in vast excess, leading to rapid pulse rate, high
6. Exogenous sequences (tumor viruses) blood pressure, diaphoresis (i.e., sweating), and tremors. Detection of
elevated blood or urine levels of catecholamines helps to confirm the
diagnosis, and treatment of the disease relieves the symptoms. Tumor
markers can be used in three ways: (1) to screen and identify individu-
Each subtype has a different response to therapy and a different als at high risk for cancer; (2) to help diagnose the specific type of tumor
prognosis (Figure 9-3). in individuals with clinical manifestations relating to their tumor, as in
adrenal tumors or enlarged liver or prostate; and (3) to follow the clini-
Tumor Markers cal course of a tumor. For example, a falling PSA level after radiation or
During surveillance or diagnosis of cancer as well as following therapy, surgical therapy for prostate cancer indicates successful treatment, and
specific biochemical markers of tumors have proven to be helpful. a later rise in the PSA level may indicate a recurrence.
These tumor markers are substances produced by both benign and There are several significant problems in using tumor marker
malignant cells that are either present in or on tumor cells or found assays to screen populations of healthy individuals for cancer. Test-
in blood, spinal fluid, or urine (Table 9-2). Some tumor markers have ing large populations will always detect a few normal individuals with
been known for many decades. For diseases associated with a tumor test results at the high end of the normal distribution (the “false posi-
marker, there is indeed a “blood test for cancer.” Tumor markers tives”), which can lead to expensive and invasive additional tests, and
include hormones, enzymes, genes, antigens, and antibodies. Liver and unnecessary concern. Similarly, some individuals with disease will
226 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer

G
5.6
2.8
1.4
1.4
2.8
5.6
4
2
1
2
4

No adjuvant systemic therapy

1.0
Relapse-free survival (probability)

0.8

0.6

0.4

0.2 Basal-like
HER2-enriched
Luminal A
Luminal B Log-rank P  2.26e-12
0.0
0 2 4 6 8 10
B Time (years)
FIGURE 9-3  Molecular Markers Aid in Cancer Classification and Treatment Choices. A, Cancers
can be classified based on gene expression patterns. In this breast cancer study, gene expression was
measured in tumors from 115 patients. Each row is a different gene, and each column is a different
patient sample. Red denotes high gene expression; green signifies low gene expression. Using this
molecular subtyping method, breast cancer can be subdivided into at least four molecular subtypes—
luminal A, luminal B, HER2, and basal. The group on the far right is normal breast tissue. B, Molecu-
lar classification predicts overall survival. In this group of women, breast cancer molecular subtypes
were determined by gene expression profiles in a group of women with similar stage tumors, as in  
(A). The molecular subtype is a good predictor of response to chemotherapy and survival. This molecu-
lar subtyping method can help select the best therapy for women. (A from Sorlie T et al: Repeated
observation of breast tumor subtypes in independent gene expression data sets, Proc Natl Acad Sci
U S A 100[14]:8418–8423, 2003; B from Parker JS et  al: Supervised risk predictor of breast cancer
based on intrinsic subtypes, J Clin Oncol 27[8]:1160–1167, 2009.)
 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer 227

have test results in the normal range (“false negatives”). Furthermore, THE BIOLOGY OF CANCER CELLS
some nonmalignant conditions also can produce tumor markers. The
presence of an elevated tumor marker therefore may suggest a specific Cancer Cells in the Laboratory
diagnosis, but it is not used alone as a definitive diagnostic test. Identi- Cancer cells behave differently than normal cells in several important
fication of ideal sensitive and specific tumor markers that are elevated ways. The microscopic differences were described previously in this
early in the course of common cancers remains a high priority because chapter and the genetic differences will be described next. There are
the early detection of cancer often improves the treatment outcome. also differences in cancer cell behavior that can be analyzed in the lab-
oratory. Cancer cells are sometimes described as transformed cells,
because they can be created from normal cells. Once transformed,

4 QUICK CHECK 9-1

cancer cells display distinct growth properties in the laboratory. They
often have markedly decreased requirements for external growth fac-
1. Identify the major differences between benign and malignant tumors. tors. Transformed cells, unlike normal cells, lack contact inhibition
2. Why is molecular characterization of tumors so important? and continue to crowd, eventually piling up on each other (Figure 9-4).
3. Discuss the importance of tumor markers. Normal cells usually will not grow unless they are attached to a firm
surface (such as a petri dish). However, cancer cells are often anchor-
age independent; that is, they continue to divide even when suspended
in a soft agar gel. Normal cells have a limited life span in the labo-
TABLE 9-2 EXAMPLES OF TUMOR ratory; they may divide in a petri dish 10 or 50 times, but then they
MARKERS cease growing. Cancer cells usually are immortal in that they seem to
MARKER NAME NATURE TYPE OF TUMOR have an unlimited life span and will continue to divide for years under
appropriate laboratory conditions. One of the most commonly used
Alpha fetoprotein (AFP) 70-kDa protein Hepatic, germ cell
laboratory cell lines, HeLa cells, was derived from a cervical cancer
Carcinoembryonic antigen 200-kDa glycoprotein GI, pancreas, lung,
specimen obtained in 1951 that continues to grow and divide in labo-
(CEA) breast, etc.
ratories around the world.4 Cancerous cells can be assayed in mice as
β-Human chorionic Glycopeptide hormone Germ cell
well; normal human cells injected into a special type of mouse (geneti-
­gonadotropin (β-HCG)
cally ­engineered to lack an immune system to prevent rejection of
Prostate-specific antigen 33-kDa glycoprotein Prostate
human cells) will not grow. However, transformed cells from humans
(PSA)
can continue to grow, invade normal tissues, and even metastasize in
Catecholamines Epinephrine and Pheochromocytoma
these mice.
­precursors (adrenal medulla)
Homovanillic acid/­ Catecholamine Neuroblastoma
The Genetic Basis of Cancer
vanillylmandelic ­metabolites
Cancer-Causing Mutations in Genes
acid (HVA/VMA)
Before the advent of modern molecular biology, many different causes
Urinary Bence Jones Ig light chain Multiple myeloma
of cancer were postulated, based on epidemiologic studies as well as
protein
investigations of specific carcinogens and viruses. We now understand
Adrenocorticotropic Peptide hormone Pituitary adenomas
that the stepwise accumulation of a small set of changes in the deoxy-
­hormone (ACTH)
ribonucleic acid (DNA) and chromosomes of the cancer cell cause it
GI, Gastrointestinal; Ig, immunoglobulin; kDa, kilodalton(s). to become cancerous (Figure 9-5). As our knowledge of cancer biology

Noncancerous cells are When these cells form a Cancer cells do not exhibit
anchorage dependent and complete monolayer, they contact inhibition, and
only proliferate when stop dividing due to continue to divide, piling
attached to a surface. contact inhibition. up on each other.

Normal cells suspended Cancer cells are anchorage

in soft agar cannot attach independent and can
and therefore cannot proliferate suspended
proliferate. in soft agar.
FIGURE 9-4  Cancerous Cells Show Abnormal Growth in the Laboratory. Cancer cells, unlike most
normal cells (A), usually continue to grow and accumulate on top of one another after they have formed
a confluent monolayer in culture (loss of contact inhibition) and (B) can grow without being attached to
a surface, called anchorage independence.
228 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer

Normal colonocyte
Genetic Event Cell Behavior
Inactivation Cell seems normal but is
First mutation of APC predisposed to proliferate
excessively

Mutational Cell begins to proliferate

Second mutation activation of K-ras too much but is otherwise
normal

Loss of DCC, over- Cell proliferates more

Third mutation
expression of COX-2 rapidly; it also undergoes
structural changes
Fourth Loss of TP53, activation Cell grows uncontrollably
or later of telomerase and looks obviously
mutation abnormal
Malignant cell
FIGURE 9-5  Clonal Proliferation Model of Neoplastic Progression in the Colon. During clonal prolifera-
tion, progressively altered populations of colon cells (colonocytes) arise over time. As genetic and epigenetic
changes occur, different subclones (indicated by different color cells) coexist for a time. Clones that grow the
fastest out-compete other clones, producing even more malignant, and abnormal-appearing, growths. The
sequential accumulation of mutations has been well studied in the progression from a normal colon cell to a
benign intestinal polyp to a malignant colon cancer. One of the earliest mutations in colon cancer is loss of
the tumor-suppressor gene APC. Additional mutations (often in the oncogene RAS), activation of COX-2, and
loss of the tumor suppressors DCC and TP53 occur as the lesion progresses from a benign polyp to an inva-
sive carcinoma. APC, Adenomatous polyposis coli; COX-2, cyclooxygenase-2; DCC, deleted in colon cancer;
TP53, p53 gene. (Modified from Mendelsohn I et al: The molecular basis of cancer, ed 2, Philadelphia, 2001,
Saunders; and Kumar V, Cotran RS, Robbins SL: Basic pathology, ed 6, Philadelphia, 1997, Saunders.)

continues to increase so too does our understanding of the many ways 180
that heritable changes in cells can contribute to cancer. These changes
include small and large DNA mutations that alter genes, chromo- 160
somes, and non–coding RNAs, as well as epigenetic changes, because
of altered chemical modifications of DNA and histones (also see 140
Incidence rate per 100,000

Chapters 2 and 10). Although the word mutation is used extensively

here, it can also refer to heritable changes in gene and non–coding 120
RNA expression (epigenetics) that do not involve changes in DNA
sequence (see p. 233). 100
Cancer is predominantly a disease of aging. Perhaps the most
revealing epidemiologic data are presented in Figure 9-6. The inci- 80
dence of most cancers, that is, the fraction of individuals in each
age group who develop cancer, increases dramatically with age. The 60
best explanation for these epidemiologic data is that each individual
acquires a number of genetic “hits” or mutations over time. When 40
sufficient mutations have occurred, cancer develops. These epide-
miologic data are consistent with the observation of mutations in 20
early and advanced cancers and with data obtained from the study of
experimental cancers created in the laboratory—the accumulation of 0
four to seven specific hits over time is required to cause a full-blown 10 20 30 40 50 60 70 80
cancer.5 Age
Clonal selection. As a cell accumulates specific mutations, it FIGURE 9-6  Marked Increases in Cancer With Age. The incidence
can acquire, step by step, the characteristics of a cancer cell, for of cancer increases exponentially with advancing age. For example,
example, anchorage-independent growth, lack of contact inhibi- this graph depicts the number of cases of colon cancer diagnosed
tion, and immortality.6 That mutant cell may then have a selective per 100,000 women in England and Wales in 1 year. Similar data are
advantage over its neighbors; its progeny can accumulate faster than seen for other cancers, and in men as well. These data suggest that
stepwise accumulation of genetic and epigenetic alterations over
its nonmutant neighbors. This is referred to as clonal prolifera-
time increases the risk of developing cancer. The slope of the curve
tion or clonal expansion (see Figure 9-5). As a clone with muta- predicts that five to seven mutations must accumulate before full-
tions proliferates, it may become an early stage tumor, for example, blown cancer develops. (Modified from Armitage P, Doll R: The age
a carcinoma in situ or a benign colonic polyp. Additional random distribution of cancer and a multi-stage theory of carcinogenesis,
heritable changes occur in these proliferating cells, and some of Br J Cancer 91[12]:1983–1989 [reprinted in 2004]; Alberts B et al:
these mutations favor progression to more advanced tumors. Molecular biology of the cell, ed 4, New York, 2002, Garland.)
 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer 229

TABLE 9-3 COMPARISON OF CANCER

GENE TYPES
4 QUICK CHECK 9-2
1. What are the characteristics of cancer cells in the laboratory?
GENE TYPE NORMAL FUNCTION MUTATION EFFECT 2. What are the heritable changes in cells that contribute to cancer
development?
Caretaker DNA and chromosome Chromosome instability 3. Define oncogene, proto-oncogene, and tumor-suppressor gene.
stability and increased rates
of mutation
Dominant Encode proteins that promote Overexpression or
oncogenes* growth (e.g., growth factors) amplification causes
What Types of Changes in Genes Actually Occur in Cancer?
gain of function The activation and inactivation of various genes is key in the develop-
Tumor suppres- Encode proteins that inhibit Requires loss of func- ment of cancer. The following three types of DNA changes occur in can-
sors (recessive proliferation and prevent tion of both alleles to cer: small DNA changes, large DNA changes, and epigenetic changes.
oncogenes) or repair mutations increase cancer risk Mutation of normal genes into oncogenes
Point mutations. Several types of genetic events can activate
*Nonmutant state referred to as proto-oncogene. oncogenes (Figure 9-8). Perhaps the most common events are small-
scale changes in DNA, such as point mutations, the alteration of one
or a few nucleotide base pairs (see Chapter 2). This type of mutation
The process of tumor development is a form of darwinian evolu- can have profound effects on the activity of proteins. A point muta-
tion; cells with a heritable change that confers a survival advantage tion in the RAS gene converts it from a regulated proto-oncogene to
out-compete their neighbors. The progressive accumulation of dis- an unregulated oncogene, an accelerator of cellular proliferation. Acti-
tinct advantageous (from the point of view of the cancer cell, not the vating point mutations in RAS are found in many cancers, especially
individual!) mutations leads step by step from normal cells to fully pancreatic and colorectal cancer. Specialized tests, such as direct DNA
malignant cancers. sequencing, can detect such point mutations in clinical samples.
Chromosome translocations and copy number variation.
Oncogenes and Tumor-Suppressor Genes: Accelerators Chromosome translocations are large changes in chromosome struc-
and Brakes ture in which a piece of one chromosome is translocated to another
Passengers and drivers. The previous discussion refers to the heri- chromosome. Translocations can activate oncogenes in one of two dis-
table changes in cells as being key in the development of cancer. New tinct mechanisms. First, a translocation can cause excess and inappro-
technologies that provide massive amounts of information about chro- priate production of a proliferation factor. One of the best examples is
mosome and gene structure allow us to see multiple alterations in can- the t(8;14) translocation found in many Burkitt lymphomas; t(8;14)
cer cells. These methods include massively parallel high-throughput designates a chromosome that has a piece of chromosome 8 fused to
DNA sequencing (the process by which the sequence of nucleotides a piece of chromosome 14 (see Chapter 20). Burkitt lymphoma is an
along a strand of DNA is determined), high-density single-nucleo- aggressive cancer of B lymphocytes. The MYC proto-oncogene found
tide polymorphism (SNP), and chromosome copy number analysis on chromosome 8 is normally activated at low levels in proliferating
(CNA). These approaches confirm that there are a small number of lymphocytes and is deactivated in mature lymphocytes. The MYC
very common genetic alterations in cancer and a very large number of protein is part of the positive signal for cell proliferation. If accidental
alterations that individually are rare.7 It is clear that some mutations formation of the t(8;14) translocation occurs, the MYC gene is aber-
can contribute to cancer progression (e.g., mutations in p53 or RAS). rantly placed under the control of a B cell immunoglobulin gene (IG)
These mutations are driver mutations; they drive the progression present on chromosome 14. The IG gene is very active in maturing B
of cancer. Conversely, not all mutations in cancer contribute to the lymphocytes. The t(8;14) translocation alters the control of MYC; its
malignant phenotype. Some are just random events, and are referred normal low level is switched to high levels, as directed by an IG gene
to as passenger mutations; they are just along for the ride. The increas- promoter. MYC protein, when inappropriately high, drives prolifera-
ing amount of cancer genome analysis data poses the following ques- tion and blocks differentiation. Hence, the t(8;14) translocation causes
tion: how do we determine which mutations are drivers and which are cancer of maturing B cells (see Figure 9-8, C).
passengers? Second, chromosome translocations can lead to production of
What are the driver mutations? To understand how genetic muta- novel proteins with growth-promoting properties. In a different type
tions cause cancer, first it is important to distinguish between onco- of leukemia, chronic myeloid leukemia (CML), a specific chromosome
genes and tumor-suppressor genes. Table 9-3 compares the two types translocation is almost always present. This translocation, t(9;22), was
of cancer genes. Oncogenes are mutant genes that in their normal first identified in association with CML in Philadelphia in 1960 and so
nonmutant state direct synthesis of proteins that positively regu- is often referred to as the Philadelphia chromosome.8 This transloca-
late (accelerate) proliferation. Conversely, tumor-suppressor genes tion fuses two chromosomes in the middle of two different genes: BCR
encode proteins that in their normal state negatively regulate (halt, or on chromosome 9 and ABL on chromosome 22. The result is produc-
“put the brakes on”) proliferation. Hence, they also have been referred tion of a BCR-ABL fusion protein containing the first half of BCR and
to as anti-oncogenes. the second half of ABL. BCR-ABL is a misregulated protein tyrosine
In its normal, nonmutant state, an oncogene is referred to as a kinase that promotes growth of myeloid cells. Imatinib, a drug that
proto-oncogene. An example of a proto-oncogene would be a growth specifically targets this tyrosine kinase, represents the first successful
factor (e.g., epidermal growth factor) or a growth factor receptor (e.g., chemotherapy targeted against the product of a specific oncogenic
epidermal growth factor receptor). Other positive regulators of prolif- mutation. Imatinib and related tyrosine kinase inhibitors (TKIs) are
eration are in the signal transduction pathway that transmits the signal highly effective in the treatment of CML and, because of their speci-
from the growth factor receptor to the cell nucleus. Normally, RAS is a ficity, lack the toxic side effects noted with nonspecific anticancer
proto-oncogene (Figure 9-7). drugs.9 However, imatinib is not effective in cancers that do not have
230 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer

Growth factor Farnesyl

Growth factor receptor membrane anchor Cell membrane

Active RAS
Activation
e RAS
Inactiv
GTP
GAP
GDP
Bridging
protein Inactivation by hydrolysis
of GTP to GDP
Phosphate

To nucleus
Active RAS

PLC RalGDS RAF PI3K

Calcium Multiple target MAPK Active

signaling for growth signaling and metabolism
proliferation and survival

FIGURE 9-7  Many Growth Factors Signal Through the RAS Protein. When a normal cell is stimu-
lated through a growth factor receptor, inactive (GDP-bound) RAS is activated to a GTP-bound state.
Activated RAS sends growth signals to the nucleus through cytoplasmic kinases, starting with the
activation of kinase RAF. The mutant RAS protein is permanently activated because of its inability to
hydrolyze GTP, leading to continual stimulation of the cell without any external trigger. GAP, GTPase-
activating protein; GDP, guanosine diphosphate; GTP, guanosine triphosphate; MAPK, mitogen-acti-
vated protein kinase. (From Kumar V, Cotran RS, Robbins SL: Basic pathology, ed 7, Philadelphia, 2003,
Saunders; Downward J: Nat Rev Cancer 3[1]:11–22, 2003.)

Chromosome

Promoter
Proto-oncogene

A. Point mutation B. Gene C. Chromosomal

amplification translocation

Overexpression

Translocated
promoter

Chimeric protein

Translocated
gene fragment
FIGURE 9-8  Oncogene Activation Mechanisms. Cellular genes may become cancerous oncogenes
as a result of (A) point mutations that alter one or a few nucleotide base pairs, causing the production
of a protein that is activated as a result of the altered sequence (e.g., RAS); (B) amplification of the cel-
lular gene, resulting in higher levels of protein expression (e.g., MYCN in neuroblastoma); or (C) chro-
mosomal translocations that either (1) lead to the juxtaposition of a strong promoter, causing increased
protein expression (MYC in Burkitt lymphoma), or (2) produce a novel fusion protein that is derived from
gene fragments normally present on different chromosomes (BCR-ABL in chronic myeloid leukemia).
(From Haber DA: Molecular genetics of cancer. In ACP medicine, Danbury, Conn, 2004, WebMD.)
 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer 231

A B
FIGURE 9-9  N-myc Gene Amplification in Neuroblastoma. The N-myc gene is detected in human
neuroblastoma cells using a technique called FISH (fluorescent in situ hybridization). (A) A single pair
of N-myc genes are detected in normal cells and in low-grade neuroblastoma. (B) Multiple, amplified
copies of the N-myc gene are detected in some cases of neuroblastoma. Amplification of the N-myc
gene is strongly associated with a poor prognosis in childhood neuroblastoma. (Courtesy Arthur R.
Brothman, PhD, FACMG, University of Utah School of Medicine, Salt Lake City, Utah.)

the t(9;22) translocation or related mutations. In modern personalized

cancer therapy, knowledge of the specific genetic alteration can dictate TABLE 9-4 SOME FAMILIAL CANCER
the optimal drugs for the individual. SYNDROMES CAUSED BY
Just as single nucleotides can be gained or lost, larger regions of TUMOR-SUPPRESSOR GENE
DNA encompassing entire genes can be gained or lost, a phenome- FUNCTION LOSS
non known as copy number variation (CNV).10 CNV can be inher- SYNDROME GENE
ited and accounts for a significant fraction of human genetic diversity.
Retinoblastoma RB1
CNV also can occur in the course of cancer development, where it can
Li-Fraumeni syndrome p53 (TP53)
amplify oncogenes or delete tumor-suppressor genes.
Familial melanoma p16INK4a (CDKN2A)
Gene amplification. A type of chromosome structural abnormal-
Neurofibromatosis Neurofibromin (NF1)
ity that can activate oncogenes is gene amplification (see Figures 9-8, B,
Familial adenomatous polyps APC
and 9-9). Amplifications are the result of duplication of a region of a
Breast cancer BRCA1
chromosome over and over again, so that instead of the normal two
copies of a gene, tens or even hundreds of copies are present (see Chap-
ter 2). Gene amplification results in increased expression of an onco-
gene, or in some cases drug resistance genes. The N-MYC oncogene allele of a tumor suppressor is often inactivated by point mutations.
is amplified in 25% of childhood neuroblastoma cases and confers For example, the RB gene may be inactivated on one chromosome by a
a poor prognosis.11 The epidermal growth factor receptor ERBB2 is point mutation (e.g., the copy inherited from the father). Because the
amplified in 20% of breast cancers.12 Individuals whose cancers have other copy of the retinoblastoma gene (in this example, the one from
ERBB2 amplification respond well to drugs specifically targeted to this the mother) is intact, a functional RB protein can still be made and,
oncogene.13 therefore, the cell division cycle can be regulated appropriately. If the
Tumor-suppressor genes. Tumor-suppressor genes are genes remaining gene is mutated or silenced, then all RB function is lost and
whose major function is to negatively regulate cell growth and pre- another step toward cancer occurs (see Chapter 1).
vent mutations. Tumor suppressors may normally slow the cell cycle,
inhibit proliferation resulting from growth signals, or stop cell divi-
sion when cells are damaged. Examples of several tumor suppressors 4 QUICK CHECK 9-3
are provided in (Table 9-4). One of the first discovered tumor- 1. Describe the differences between point mutations, chromosomal translo-
suppressor genes, the retinoblastoma (RB) gene, normally strongly cations, and gene amplification.
inhibits the cell division cycle (see Chapter 1). When it is inactivated, 2. Biologically, why do tumor-suppressor genes have to be inactivated
the cell division cycle can proceed unchecked. RB is mutated in child- to cause cancer?
hood retinoblastoma, and in many lung, breast, and bone cancers as
well.
Whereas oncogenes are activated in cancers, tumor suppressors Loss of heterozygosity. For the function of a tumor suppressor to
must be inactivated to allow cancer to occur (see Table 9-4 and Figure be lost, both chromosomal copies (alleles) of the gene must be inacti-
9-10). A single genetic event can activate an oncogene because it can vated. This is because they act in a recessive manner at the level of the
act in a dominant manner in the cell. However, we have two copies, cell. Although it may seem intuitive that simple inactivating mutations
or alleles, of each gene, one from each parent. It therefore takes two might disrupt both alleles, in fact this is not what usually happens.14
hits to inactivate the two alleles of a tumor-suppressor gene. The first Instead, the first allele (in the preceding example, the paternal copy) is
232 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer

DNMTs

DNA
methylation

Gene silencing
NURFs HDACs
First hit: mutation Second hit: epigenetic HMTs
A silencing or chromosome loss Nucleosome Histone
remodeling modifications

B
Active chromatin Ac Ac

TF TF

P Exon Exon Exon DNA

Nucleosome
mRNA Protein
Transcription
Histone
deacetylase
DNA
methyltransferase

Inactive chromatin TF TF

Me Me

P Exon Exon Exon

Transcription
C inhibited

Oncogenes Oncogenes
On

Carcinogens
selection Methylated CpG
Time Unmethylated CpG
Tumor suppressor genes Tumor suppressor genes

Off
D Normal cells Cancer cells
FIGURE 9-10  Silencing Tumor-Suppressor Genes. Tumor-suppressor genes can be deactivated by
a variety of mechanisms. (A) In this example, the first hit is a point mutation in a tumor-suppressor
gene (white box), followed by either epigenetic silencing or chromosome loss of the second allele (red
box). (B) Genes can normally be silenced by a variety of interacting processes including DNA methyla-
tion, histone modification, nucleosomal remodeling, and microRNA changes (not shown). A number
of cellular enzymes contribute to these modifications, including DNA methyltransferases (DNMTs),
histone deacetylases (HDACs), histone methyltransferases (HMTs), and complex nucleosomal remod-
eling factors (NURFs). Gene silencing is essential for normal development and differentiation. (C) His-
tone modification and promoter methylation regulate gene expression. Genes are transcribed when
chromatin is modified by addition of acetyl (Ac) groups to specific lysine groups in histones. Gene
expression can be turned off when specific acetyl groups are removed (by HDACs) or when the CpG-
rich promoter regions of genes are modified by direct DNA methylation (by DNA methyltransferase).
In addition, small endogenous RNA molecules (microRNAs or miRNA) can bind to mRNA and reduce
gene expression. (D) Changes in promoter methylation turn cancer genes off and on. Oncogenes can
be turned on by promoter hypomethylation, and tumor-suppressor genes can be turned off by pro-
moter hypermethylation. Each of these changes can produce selective growth and survival advantages
for the cancer cell. TF, Transcription factor; Me, methylation. (B adapted from Jones PA, Baylin SB: The
epigenomics of cancer, Cell 128:683–692, 2007; C from Gluckman PD et al: N Engl J Med 359[1]:66,
2008; D from Shames DS, Minna JF, Gazdar AF: Curr Mol Med 7:85–102, 2007.)
 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer 233

inactivated by simple mutation, but the second allele (in this example, have no function (erroneously called junk DNA). The human genome
the maternal copy) is lost because entire regions of the maternal chro- encodes more than 1000 miRs. miRs regulate diverse signaling path-
mosome are epigenetically silenced or a piece of the chromosome is ways; the miRs that stimulate cancer development and progression
simply lost (see Figure 9-10, A). Because humans have two chromo- are termed oncomirs. miRs decrease the stability and expression of
somes, one from each parent, they are always heterozygous for nearby other genes by pairing with mRNA in a process that involves the RNA-
multiple genetic markers; loss of one copy (allele) of a specific chro- induced silencing complex, or RISC. A single miR can have multiple
mosome region in a tumor is referred to as loss of heterozygosity, or mRNA targets. Changes in miR abundance can therefore affect the
LOH. Loss of heterozygosity, like silencing, can unmask inactivating expression of many genes, making miRs both powerful regulators and
mutations in recessive tumor-suppressor genes. For example, the RB challenging subjects to study.19 Beyond miRs, longer RNAs without
gene resides on chromosome 13, in a region referred to as q14 (13q14). apparent protein coding capacity also are implicated in cellular regula-
Most individuals with RB mutations have a subtle mutation in one tion with an emerging appreciation of their role in cancer.20
allele and have lost the other copy allele of RB through loss of the 13q14 miRs can play both positive and negative roles in cancer. The
chromosome region on the other chromosome. importance of miRs in cancer was first shown in chronic lympho-
Turning off genes without mutation cytic leukemia (CLL), where a chromosome region encoding miR15
Epigenetic silencing. Abnormal gene silencing is emerging as a and miR16 was found to be deleted in a large number of individu-
major factor in cancer progression. Gene expression can be regulated als. Decreased expression of these two miRs is seen in many cases of
in a heritable manner (i.e., passed from a parent to a child or from a CLL, as well as in prostate and several other cancers, and results in
single cell to its progeny) by an “epigenetic” mechanism called silenc- increased expression of a number of oncogenes. Conversely, increased
ing. Inheritance of silencing occurs during cell division and does not expression of a cluster of miRs (17-18-19-20-92) is seen in some lym-
require mutations or changes in DNA sequence (also see Chapters 2 phomas and solid tumors, causing the decreased expression of a num-
and 10). More simply, the same DNA sequence can produce dramati- ber of tumor-suppressor genes. miR expression can be easily assessed
cally different phenotypes depending on chemical modifications that with microarray technology, leading to the realization that substantial
alter the expression of genes. Epigenetic silencing is caused by revers- changes in miR expression are seen in many cancers.
ible chemical modification (methylation [addition of a methyl group]
or acetylation [addition of an acetyl group]) of histones and related Guardians of the Genome
chromatin components, as well as methylation of cytosine residues The previous discussion of mutations leads naturally to the question of
in DNA (known as DNA methylation) (see Figure 9-10, Figure 2-24 how mutations occur in the first place. The integrity of genetic infor-
[p. 49], and Chapter 10). Whole regions of chromosomes are normally mation can be compromised at several points: during each round of
shut off by silencing, so that the pattern of gene expression is differ- DNA synthesis, during each mitosis when chromosomes are segregated
ent than that seen in other cells with the same genes. In this way, the to daughter cells, and when external mutagens (e.g., chemicals and
progeny of liver cells remain liver cells, and skin cells remain skin cells. radiation) alter or disrupt DNA. Multiple mechanisms have evolved to
Notably, global changes in epigenetic silencing can turn these cells back protect and repair the genome. These repair mechanisms are directed
into stem cells.15 by caretaker genes, genes that are responsible for the maintenance of
Changes in gene silencing contribute to the development of cancer.16 genomic integrity. Caretaker genes encode proteins that are involved
Many cancers have increased methylation of DNA in the promoter in repairing damaged DNA, such as occurs with errors in DNA rep-
region of tumor-suppressor genes, often near gene promoter regions lication, mutations caused by ultraviolet or ionizing radiation, and
(see Chapters 2 and 10). They also have associated changes in the modi- mutations caused by chemicals and drugs. Loss of function of care-
fication of histones in the chromatin, often correlated with methyla- taker genes leads to increased mutation rates. If DNA damage is severe,
tion of DNA. These changes in chromatin-modifying genes alter the the cell undergoes programmed cell death, or apoptosis, rather than
promoter regions of genes, leading to their silencing. The boundaries simply dividing with damaged DNA.
of the normally silenced regions can also spread in cancer cells, thereby Inherited mutations can disrupt the caretaker genes that protect
inactivating previously active genes. In either case, silencing can shut the integrity of the genome. Examples include the disorder xeroderma
off critical tumor-suppressor genes in the absence of mutations in the pigmentosum (XP); affected individuals have defects in the repair of
gene. Early in the development of cancer, these changes in gene expres- ultraviolet light–induced DNA damage and should avoid direct sun-
sion can lead to a selective advantage for affected cells, perhaps leading light exposure. They have a very high incidence of skin cancer. Heredi-
to their immortalization and clonal expansion. Silencing of tumor sup- tary nonpolyposis colorectal cancer (HNPCC) results from an inherited
pressors may be a faster way to create cancer cells than mutational or defect in repairing DNA base pair mismatches that occur occasionally
genetic loss of tumor suppressors.17 Conversely, loss of silencing can during DNA replication. Affected individuals have an increased rate of
contribute to inappropriate expression of oncogenes. Chemotherapeu- small insertions and deletions in DNA, leading to a high rate of colon
tic drugs that can regulate gene silencing, including histone deacetylase and other cancers. Finally, there are inherited mutations that threaten the
(HDAC) inhibitors and 5-azacytidine (which reverses the effects of integrity of entire chromosomes. Bloom syndrome, caused by mutations
DNA methyltransferases [DNMTs]), have proven effective in reacti- in a DNA helicase, and Fanconi aplastic anemia, caused by loss of func-
vating silenced tumor-suppressor genes and are being evaluated for the tion of a multiprotein complex required for repair of DNA double-strand
treatment of selected cancers (see Figure 9-10).18 breaks,21 are autosomal recessive disorders in which affected individuals
MicroRNAs, oncomirs, and non–coding RNAs. Changes in demonstrate marked chromosomal instability. Chromosome breaks,
gene regulation can affect not just single genes, but also entire net- aberrant fusions, and chromosome loss are common. As a consequence,
works of signaling. Gene expression networks can be regulated by these individuals have a high risk of developing cancer at an early age.
changes in microRNAs (miRNAs, or miRs) and other non–coding The rate of individual gene mutation is probably too low to account
RNAs (ncRNAs). miRNAs are short (approximately 22 nucleotides) for the acquisition of many new mutations during the evolution of a
RNAs derived from introns of protein coding genes or transcribed as malignant cancer clone. In addition to abnormal epigenetic silencing,
independent genes from regions of the genome previously believed to chromosome instability (often referred to as CIN) also appears to
234 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer

be increased in malignant cells (also see Chapter 10). The underlying inherited breast cancer (BRCA1); and familial polyposis coli or ade-
mechanism of this instability is not clear but may be caused by mal- nomas of the colon (APC). A specific tumor-suppressor gene has been
functions in the cellular machinery that regulates chromosome seg- found in each of these cancers. In many cases, these tumor-suppressor
regation at mitosis.22 Chromosome instability results in a high rate of genes also are inactivated in sporadic (as opposed to inherited) can-
chromosome loss, as well as loss of heterozygosity and chromosome cers. For example, inherited mutations in the APC gene are rare and
amplification. Each of these events can accelerate the loss of tumor- account for only a few percent of all colon cancers. However, 85% of
suppressor genes and the overexpression of oncogenes. sporadic colon cancers also have acquired mutations of APC, which
occurred over time in the individual. Characterization of cancer-caus-

4 QUICK CHECK 9-4

ing genes and other genetic factors helps identify individuals prone to
developing cancer and contributes to our understanding of sporadic
1. Define epigenetics and epigenetic silencing. cancers. Individuals known to carry mutations in tumor-suppressor
2. What is the role of miRs in cancer development. genes (for example, women with a germline BRCA1 mutation) are
offered targeted cancer screening to facilitate early cancer detection
and therapy.24
Genetics and Cancer-Prone Families
Genetic events are the primary basis of carcinogenesis. Most of the Types of Genes Misregulated in Cancer
genetic and epigenetic alterations that cause cancer occur within the We now understand that a handful of genetic hits are required for the
somatic tissues during the lifetime of the individual. As previously evolution of full-blown cancer. There also are a small number of spe-
discussed, the frequency of genetic changes can be increased by expo- cific pathways that must be altered in order for cancer to develop. There
sure to mutagens, that is, agents causing mutations, and by defects may be more than one way to alter a pathway, but for each tumor only
in DNA repair. Because these genetic events occur in somatic cells a single mutation in each pathway is needed. These pathways regulate
as opposed to germ cells, they are not transmitted to future genera- immortality, cell cycle progression, and apoptosis (Figure 9-12) and
tions. Even though they are genetic events they are not inherited! will now be described in more detail.6,25
It is possible, however, for cancer-predisposing mutations to occur
in germline cells (cells that produce gametes). Mutations present Alterations in Progrowth and Antigrowth Signals
in germline cells result in the transmission of cancer-causing genes Cancer cells must have mutations that enable them to attain self-suf-
from one generation to the next, producing families with a high inci- ficiency and proliferate in the absence of external growth signals, the
dence of specific cancers23 (Figure 9-11). These inherited mutations phenomenon seen in the laboratory as growth factor independence.
that predispose to cancer are almost invariably in tumor-suppressor To achieve this, some cancers acquire the ability to secrete their own
genes (see Table 9-4). growth factors (for example, platelet-derived growth factor [PDGF])
Although rare, such “cancer families” demonstrate that inheri- to stimulate their own growth, a process known as autocrine stimula-
tance of a mutated gene can cause cancer. Inheritance of one mutant tion (also see Chapter 1). Other cancers have an increase in growth fac-
allele in these families predisposes a person to a specific form of can- tor receptors, which are often receptor tyrosine kinases. For example,
cer. Individuals who inherit the germline mutant allele will inevita- in some breast cancers the epidermal growth factor (EGF) receptor
bly suffer loss of the normal allele by loss of heterozygosity (LOH) 2 (ERBB2), also known as HER2/neu, is up-regulated and this sends
or epigenetic silencing (see Figure 9-10) in some cells and eventually growth signals into the cell even when growth factors are at very low
develop the tumor. Examples of human cancers that can be inherited levels. Inhibitors of HER2 and other EGF receptor tyrosine kinases
are retinoblastoma, a childhood cancer of the eye that can be caused can block this pathway and are effective in treating selected breast and
by germline mutations in one allele of the RB gene; Wilms tumor, lung cancers.13 Alternatively, the signal cascade from the cell-surface
a childhood cancer of the kidney (WT1); neurofibromatosis (NF1); receptor to the nucleus may be mutated in the “on” position. Up to

II

III

IV

V
FIGURE 9-11  A Familial Colon Cancer Pedigree. Darkened symbols represent individuals diagnosed
with colon cancer. One of the individuals in the first generation must have carried a mutation in the
APC gene. Squares, Males; circles, females; filled circles, diagnosed with colon cancer. (From Jorde LB
et al: Medical genetics, ed 3, St Louis, 2003, Mosby.)
 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer 235

Self-sufficiency in
Evading
growth signal
apoptosis

Tissue invasion Insensitivity to

and metastasis anti-growth signals

Limitless
Sustained
Survival/proliferation replicative
angiogenesis
in foreign environments potential

Hypoxia Senescence

Evading Low
pH DNA damage
immune ROS stress
surveillance
Aneuploidy
AT
P

Metabolic Oxidative
stress stress

Proteotoxic Mitotic
stress stress
FIGURE 9-12  The Hallmarks of Cancer. Cancers acquire alterations in specific pathways during their evo-
lution. The six key pathways that must be altered are shown at the top of the circle, and supporting pathways
are shown at the bottom of the circle. Mutation in key genes often alters several pathways; for example,
p53 mutations alter both angiogenesis and evasion of apoptosis. = Inhibits. (From Luo J, Solimini NL,
Elledge SJ: Principles of cancer therapy: oncogene and non-oncogene addiction, Cell 136:823–837,
2009.)

one third of all cancers have an activating mutation in the gene for Tiny cancers lack the ability to grow new blood vessels and may never
an intracellular signaling protein called RAS. This mutant RAS stim- grow larger than a grain of sand. More advanced cancers can, however,
ulates cell growth even when external growth factors are absent (see secrete multiple factors that stimulate new blood vessel growth (called
Figure 9-7).26 neovascularization or angiogenesis). These angiogenic factors, such
Cells also usually receive diverse “antigrowth” signals from their as vascular endothelial growth factor (VEGF), platelet-derived growth fac-
normal milieu. Contact with other cells, with basement membranes, tor (PDGF), and basic fibroblast growth factor (bFGF), recruit new vascu-
and with soluble factors all normally signal cells to stop proliferating. lar endothelial cells and initiate the proliferation of existing blood vessel
These mechanisms can halt unregulated cell growth. In addition, this cells, allowing small cancers to become large cancers. Therapies directed
normal antigrowth signal must be inactivated or ignored. Common against new vessel growth are in clinical use; these agents include bevaci-
mutations that subvert the antigrowth signal include inactivation of zumab, a monoclonal antibody that inhibits VEGF; erlotinib, sorafenib,
the tumor-suppressor retinoblastoma (RB) or, conversely, activation of and sunitinib, inhibitors of the VEGF and PDGF receptor tyrosine
the protein kinases that drive the cell cycle, the cyclin-dependent kinases kinases; and thalidomide, which decreases vascular proliferation
(CDKs) (see Chapter 1). Next, cells normally have a mechanism that (Figure 9-13).27
causes self-destruction when growth is excessive and cell cycle check-
points have been ignored. This self-destruct mechanism, called apop-
tosis, is triggered by diverse stimuli, including normal development 4 QUICK CHECK 9-5
and excessive growth (see Chapter 3). Advanced cancers develop ways 1. Distinguish between mutations in somatic cells versus in germ cells.
to evade apoptosis. The most common mutations conferring resis- 2. What type of cell pathways are altered to cause cancer?
tance to apoptosis occur in the p53 tumor-suppressor gene (TP53). 3. Why is angiogenesis important to cancer development?

Angiogenesis
If cancers are to grow larger than a millimeter in diameter, they need their Telomeres and Unlimited Replicative Potential
own blood supply to deliver oxygen and nutrients. However, new blood A hallmark of cancer cells is their immortality. Usually the only cells in
vessel growth in adults is normally limited to areas of wound healing the body that are “immortal” are germ cells (those that generate sperm
and to the uterus during the proliferative phase of the menstrual cycle. and eggs) and stem cells. Other cells in the body are not immortal and
236 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer

Circulating precursor
endothelial cells

VEGF
Tumor
VEGFR

PDGF
PDGFR

bFGF
bFGFR

MMPs
Platelet VEGF
bFGF
PDGF
Alpha granules
Endostatin
Angiostatin
Blood vessel Platelet factor 4
FIGURE 9-13  Tumor-Induced Angiogenesis. Malignant tumors secrete angiogenic factors and tis-
sue-remodeling matrix metalloproteinases (MMPs) that actively induce formation of new blood vessels.
New blood vessels are formed from both local endothelial cells and circulating precursor cells recruited
from the bone marrow. Circulating platelets can also release regulatory proteins into the tumor. bFGF
and bFGFR, Basic fibroblast growth factor and its receptor, respectively; MMPs, matrix metallopro-
teases; PDGF and PDGFR, platelet-derived growth factor and its receptor, respectively; VEGF and
VEGFR, vascular endothelial growth factor and its receptor, respectively. (Adapted from Folkman J:
Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6[4]:273–286, 2007.)

can divide only a limited number of times (known as the Hayflick Cancer Metabolism
limit) before they either cease dividing or die. One major block to Cancer cells live in a distinct milieu from normal cells and have differ-
unlimited cell division (i.e., immortality) is the size of a specialized ent nutritional requirements from nonproliferating cells. The success-
structure called the telomere. Telomeres are protective ends, or caps, ful cancer cell divides rapidly, with the consequent requirement for
on each chromosome and are placed and maintained by a specialized the building blocks of new cells. Cancers often must grow in a hypoxic
enzyme called telomerase (Figure 9-14). As one might expect, telom- and acidic environment. Cancers also are parasites, able to selectively
erase is usually active only in germ cells (in ovaries and testes) and extract nutrients from the bloodstream without any evolutionary pres-
in stem cells. All other cells of the body lack telomerase. Therefore, sure for balanced metabolism. Nonmalignant cells in the presence of
when non–germ cells begin to proliferate abnormally, their telomere adequate oxygen normally generate adenosine triphosphate (ATP) by
caps become smaller and smaller with each cell division. Short telo- mitochondrial oxidative phosphorylation (OXPHOS), generating 36
meres normally signal the cell to cease cell division (senescence). If the ATP molecules from each glucose molecule that is broken down to
telomeres become critically small, the chromosomes become unstable water and carbon dioxide. Only in the absence of sufficient oxygen do
and fragment, and then the cells die. When they reach a critical age, normal cells perform anaerobic glycolysis, generating only two ATP
cancer cells somehow activate telomerase to restore and maintain molecules per molecule of glucose, with lactic acid as a byproduct.
their telomeres, thereby allowing them to continue dividing. Because However, even in the presence of oxygen, cancer cells perform gly-
telomerase is specifically activated in cancer cells, and potentially in colysis, not OXPHOS29 (Figure 9-15). Although this aerobic glycolysis
cancer stem cells, it is an attractive therapeutic target.28 was originally postulated to be caused by some form of cancer-specific
 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer 237

Chromosome mitochondrial dysfunction, it is now apparent that this is instead a

highly regulated and beneficial adaptation for cancer cells. This shift
from OXPHOS to glycolysis allows lactate and its metabolites to be
used for the more efficient production of lipids and other molecu-
lar building blocks needed for rapid cell growth. Furthermore, many
Adult somatic cells cancer genes promote this switch to aerobic glycolysis. Alterations in
a number of cancer genes, including receptor tyrosine kinases, AKT,
Nucleus PTEN, TP53, and MYC, inhibit OXPHOS and promote the activity
of glycolytic and related metabolic pathways that support the rapid
growth of cancers.29,30
Clinically the high glucose utilization of a cancer can be exploited
for its detection. 18F-Fluorodeoxyglucose (FDG) is incorporated into
cells in the same way as glucose, with two key differences. Because it is
Stem, germ, and missing a key hydroxyl group it cannot be broken down by glycolysis
Telomere
cancer cells and, thus, FDG accumulates in cells. Because it is tagged with 18F, it
can be imaged by positron emission tomography (a PET scan). Small
metastatic tumor masses that are consuming huge amounts of glucose
can readily be detected with this imaging method (Figure 9-16).

Oncogene Addiction
Telomerase As described earlier in this chapter, there are a number of common
enzyme driver mutations in cancer. Cancers that arise because of these muta-
tions often depend on these mutant genes and proteins for their contin-
FIGURE 9-14  Control of Immortality: Telomeres and Telomerase
Normal adult somatic cells cannot divide indefinitely because the ends
ued growth and survival. If the mutations and abnormal proteins can
of their chromosomes are capped by telomeres. In the absence of the be returned to their normal states, the cancers often stop growing and
telomerase enzyme, telomeres become progressively shorter with even regress. The cancers are addicted to their mutant cancer genes,
each division until, when they are critically short, they signal to the a concept known as oncogene addiction. This also provides a key
cell to stop dividing. In germ cells, adult stem cells, and cancer cells example of how targeted cancer therapy can work—for example, if the
the telomerase gene is “switched on,” producing an enzyme that oncogene is a protein kinase (e.g., BCR-ABL, EGFR, HER2, or BRAF)
rebuilds the telomeres. Thus, like germ cells, the cancer cell becomes that can be inhibited by a drug, then the cancer can be deprived of the
immortal and able to divide indefinitely without losing its telomeres. function of the oncogene. Treating the addiction treats the cancer.31

Differentiated tissue Proliferative Tumor

tissue

or
+O2 –O2
+/–O2
Glucose Glucose Glucose

O2 Pyruvate Pyruvate O2 Pyruvate

5% 85%

Lactate Lactate Lactate

CO2 CO2

Oxidative Anaerobic Aerobic glycolysis

phosphorylation glycolysis (Warburg effect)
–36 mol ATP/ 2 mol ATP/ –4 mol ATP/
mol glucose mol glucose mol glucose

FIGURE 9-15  Cancers Have Altered Metabolism. Normal tissues use oxidative phosphorylation
(OXPHOS) to turn glucose into CO2 and energy (in the form of ATP). Cancers take a different approach;
even in the presence of oxygen, they do not use OXPHOS. Instead, they consume large quantities
of glucose to make cellular building blocks, supporting rapid proliferation. (From Van der Heiden MG,
Cantley LC, Thompson CB: Understanding the Warburg effect: the metabolic requirements of cell pro-
liferation, Science 324:1029–1033, 2009.)
238 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer

Cancer Stem Cells

Many tissues, most notably the skin, intestines, and blood-forming cells,
continuously renew themselves. The human gut sheds and replaces
hundreds of grams of cells each day. This ongoing proliferation of these
tissues with a high turnover rate depends on their regeneration from a
small fraction of cells known as adult stem cells. Adult stem cells have
two essential characteristics: first, they self-renew (that is, some fraction
of the cell divisions creates new stem cells); second, they are multipo-
tent, or have the ability to differentiate into multiple different cell types.
In the bone marrow, it is estimated that only 0.05% (1 in 20,000) of the
blood-forming cells are stem cells, yet this small pool of stem cells can
be stimulated to divide and to repopulate all the mature bone marrow–
derived cells in approximately 2 weeks after bone marrow transplanta-
tion. As few as 10 stem cells are sufficient to entirely repopulate the entire
bone marrow of a mouse in bone marrow transplantation experiments.
Many cancers, like normal tissues, are heterogeneous, with differ-
ences in cell shape, size, behavior, and protein expression. There are
two models to explain this heterogeneity within tumors. In the clonal
evolution model, all the cancer cells divide regularly, and heterogeneity
FIGURE 9-16  The Intense Glucose Requirement of Cancer
Aids in Diagnosis. This 54-year-old woman had a non–small cell arises from proliferation, mutation, epigenetic changes, differences in
lung cancer (NSCLC) surgically removed. Five years later, these local environment, and natural differentiation of cells. In this model,
images were obtained. The positron emission tomography (PET) most of these cells are still robust cancer cells, capable of forming com-
scan using 18F-deoxyglucose shows metastatic lesions in the brain, plex tumors in experimental animals. In contrast, in the cancer stem
right shoulder, and mediastinal and cervical lymph nodes as well cell model, heterogeneity arises because there is a rare cancer stem cell
as the liver, left pelvis, and proximal femur. (Left) PET whole-body whose offspring do not have stem cell properties, but undergo a limited
image. (Right) Representative coronal image from the whole-body number of divisions while generating heterogeneity through epigenetic
FDG-PET/CT–fused image of the same patient. The fused image and environmental alterations. However, similar to the adult tissue stem
consists of the CT image with the metabolic information superim- cells, only the cancer stem cell, if transplanted, is postulated to be capable
posed in color. The pattern of distribution is most likely from the
of forming complex and heterogeneous tumors. The typical cancer stem
primary tumor to the large mediastinal lymph nodes, followed by
lymphatic spread to cervical lymph nodes. Blood-borne dissemina- cell experiment separates cancer cells into different pools depending on
tion produced the bone, brain, and liver metastases. Normally, only some measurable characteristic such as cell-surface proteins, and then
the heart, brain, and bladder show a strong signal on PET scan. assays how many cells must be injected into an experimental mouse to
CT, Computed tomography; FDG, fluorodeoxyglucose. (Images form a cancer. In some cases, these tumor-initiating cells are very rare,
courtesy John Hoffman, MD, Huntsman Cancer Institute, Salt Lake with only 1 in 10,000 human colon cancer cells able to re-form a com-
City, Utah.) plex and heterogeneous colon cancer in mice (Figure 9-17).32 However,

Primary tumor

~100,000 cells to
form one tumor

Hypothetical cancer
Cell sorting stem-cell specific therapy

Primary tumor Tumor regresses

slowly
~10–1000 cells
required to form
one tumor

Conventional cytotoxic
chemotherapy Tumor recurs
B Stem cells remain

A Secondary tumor
FIGURE 9-17  The Concept of Cancer Stem Cells. (A) Only rare cells within a cancer can initiate cancer
regrowth. In laboratory experiments it takes as many as 100,000 breast cancer cells injected into a mouse
mammary fat pad to form a new cancer. If the breast cancer cells are sorted, one rare subtype (shown here
in red) is much more proficient at forming new cancers. (B) Conventional chemotherapy can destroy the
bulk of a cancer. However, if the cancer stem cells (red cells) are not destroyed, the cancer may regrow. If
therapies can be devised that kill the cancer stem cells, then durable long-term responses may be achieved.
 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer 239

these tumor-initiating cells are not always rare; in human melanomas,

one in four cells can initiate a complex tumor in the appropriate mouse
4 QUICK CHECK 9-6
1. Define telomeres, telomerase, and senescence.
model.33 This is an experimentally difficult area of research, because
2. What is meant by the clonal evolution model and the stem cell model?
human cancers are examined in mice where there are multiple barri-
3. Define heterogeneity of tumors.
ers to transplantation, including immune responses, as well as species
differences in the various growth factors, cytokines, and microenviron-
ment that can all influence the results. Therefore most progress is likely
to be made by studying cancer stem cells arising in mouse tumors rather Stroma-Cancer Interactions
than human tumors. Normal tissues contain a complex mixture of cell types, including spe-
Enthusiasm for the cancer stem cell model arises, in part, from cialized cells, fibroblasts, vascular cells, immune cells, and a support-
its therapeutic potential. Most of the drugs now used in treating ing extracellular matrix. Cancers disrupt this environment, and in turn
cancer can kill a large fraction of cancer cells but may not touch recruit local and distant cells to assist in cancer progression. Although
the cancer stem cell. If less than 1 in 100,000 cells in a cancer is the immune cells frequently found in tumors were once thought to
responsible for perpetuating a cancer, then perhaps we should be be futile attempts at an antitumor response, instead it appears that
looking for drugs that target those rare cells instead of using more cancers actively recruit an immune and stromal response to assist in
toxic drugs that initially shrink tumors but do not kill the cancer remodeling of tissues, formation of new blood vessels, and promo-
stem cells. tion of metastasis34 (Figure 9-18). The tumor-associated inflammatory

Blood Lymphatic
BMDC Mast cell Fibroblast vessel endothelial cell

Macrophage MSC Endothelial Normal epithelial

cell cell
Invasive
Neutrophil Lymphocyte Pericyte tumour cell

FIGURE 9-18  Cancers Live in a Complex Microenvironment. Neoplastic cells produce angiogenic
factors (cytokines and chemokines) that are mitogenic or chemoattractants, or both, for numerous
types of stromal cells, including fibroblasts, bone marrow–derived cells (BMDCs), macrophages, mes-
enchymal stem cells (MSCs), and other inflammatory and immune cells. In return, these activated
stroma cells secrete additional proteolytic enzymes and growth factors that stimulate the cancer cells
and promote new blood vessel growth. This stromal reaction, which in the normal situation promotes
wound healing, now stimulates tumor growth and promotes metastatic dissemination. (From Joyce JA,  
Pollard JW: Microenvironmental regulation of metastasis, Nat Rev Cancer 9:239–252, 2009.)
240 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer

cells and fibroblasts are stimulated by the cancer cells and the ensuing
TABLE 9-5 CHRONIC INFLAMMATORY
stromal disruption, and, in turn, these otherwise normal cells secrete
a broad range of factors that promote proliferation, angiogenesis, and
CONDITIONS AND INFECTIOUS
cancer cell motility. The cancers also may release signals that actively AGENTS ASSOCIATED WITH
recruit circulating bone marrow–derived mesenchymal stem cells to NEOPLASMS
populate the tumor stroma, subverting a process that normally func- INFLAMMATORY ASSOCIATED
tions in wound healing. CONDITION NEOPLASM(S)
One of the key cells that promote tumor survival and metastasis is
Asbestosis, silicosis Mesothelioma, lung carcinoma
the tumor-associated macrophage, or TAM. These specialized macro-
Bronchitis Lung carcinoma
phages are recruited to tumors secreting the chemoattractant CSF1.
Cystitis, bladder inflammation Bladder carcinoma
The TAMs in turn secrete factors such as epidermal growth factor
Gingivitis, lichen planus Oral squamous cell carcinoma
(EGF), Wnts, and proteases, further stimulating tumor growth and
Inflammatory bowel disease, Crohn Colorectal carcinoma
facilitating tumor invasion of blood vessels. In both animal models
disease, chronic ulcerative colitis
and humans, TAMs appear critical for tumor growth and metastasis,
Lichen sclerosus Vulvar squamous cell carcinoma
and therapies targeting the nonmalignant TAMs are effective at slow-
Chronic pancreatitis, hereditary Pancreatic carcinoma
ing cancer progression.34,35
­pancreatitis
Inflammation, Immunity, and Cancer Reflux esophagitis, Barrett esophagus Esophageal carcinoma
Sialadenitis Salivary gland carcinoma
Chronic inflammation has been recognized for close to 150 years as
Sjögren syndrome, Hashimoto MALT lymphoma
being an important factor in the development of cancer.36 Epidemio-
thyroiditis
logic studies strongly support the conclusion that the active immune
Skin inflammation Melanoma
response in chronic inflammation predisposes to cancer. Individuals
who have suffered with ulcerative colitis for 10 years or more have up INFECTIOUS AGENT ASSOCIATED
to a 30-fold increase in the risk of developing colon cancer. Chronic (NONVIRAL) NEOPLASM(S)
viral hepatitis caused by hepatitis B virus (HBV) or hepatitis C virus Helicobacter pylori Gastric adenocarcinoma, MALT
(HCV) infection markedly increases the risk of liver cancer. One large Chronic bacterial cholecystitis Gallbladder cancer
study found a 66% increase in risk of lung cancer among women Schistosomiasis Bladder, liver, rectal carcinoma;
with chronic asthma, an inflammatory disease of the airways. Table follicular lymphoma of spleen
9-5 details the various inflammatory conditions and infectious agents Liver flukes Cholangiocarcinoma
associated with cancer.
Inflammation and cancer have much in common.37 In both can- INFECTIOUS AGENT ASSOCIATED
cer and inflammation (e.g., after injury and during infection), inflam- (VIRAL) NEOPLASM(S)
matory cells, including neutrophils, lymphocytes, and macrophages, Human immunodeficiency virus type 1 Non-Hodgkin lymphoma,
migrate to the site of injury and release cytokines and growth and sur- (HIV-1) ­squamous cell carcinomas,
vival factors that stimulate local cell proliferation and new blood vessel Kaposi sarcoma
growth to promote wound healing by tissue remodeling (see Chapter Hepatitis B and hepatitis C Hepatocellular carcinoma
5). These factors combine in chronic inflammation to promote contin- Epstein-Barr virus B cell non-Hodgkin lymphoma,
ued proliferation. In addition, inflammatory cells release compounds Burkitt lymphoma, nasopha-
such as reactive oxygen species (ROS) and other reactive molecules that ryngeal carcinoma
can promote mutations and block the cellular response to DNA dam- KSHV/HHV8 and immunodeficiency Kaposi sarcoma
age. Notably, an increased abundance of the enzyme cyclooxygenase-2 HPV-16, -18, -31, others Cervical, anogenital
(COX-2), which generates prostaglandins during acute inflammation, HTLV-1 Adult T cell leukemia/­
has been associated with colon and some other cancers. Meta-analysis lymphoma
of multiple clinical studies have concluded that long-term high-dose
From Kuper H, Adami HO, Trichopoulos D: Infections as a major pre-
use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspi-
ventable cause of human cancer, J Intern Med 248(3):171–183, 2000.
rin, that inhibit COX-2 can reduce the risk of colon cancer by as much
as 20% (see Chapter 5).38
virus) and up to 1000-fold increased risk of Kaposi sarcoma (caused by
The Immune System Protects Us Against Viral-Associated human herpesvirus 8 [HHV8]) (additional information about viruses
Cancers and cancer is found under Viral Causes of Cancer). The same immu-
There is a popular belief that damage to the immune system predisposes nosuppressed individuals, however, have only a slight increase in the
to common cancers. This idea arose decades ago as our understanding risk of common cancers such as lung and colon cancer (and this could
of the genetic basis of cancer and the details of the immune response well be because of increased inflammation at those sites).4,40,41
against infectious disease developed. Modern data support a more In fact, there are many complex interactions between elements of
nuanced conclusion. Although the immune system is indeed impor- the immune system and tumors (see Figure 9-18). Tumors activate sur-
tant in protecting us against cancers caused by specific viral infections rounding stromal and inflammatory cells, including tumor-­infiltrating
(detailed later), it has mixed results when faced with the most common lymphocytes and macrophages, to secrete multiple cytokines that sup-
cancers.39 Individuals taking chronic powerful immunosuppressive port tumor growth and dissemination. In parallel, various cells of
drugs, such as those given for kidney, heart, or liver transplant, have a the immune system can exert antitumor effects through factors such
much higher risk of developing viral-associated cancers, with a 10-fold as tumor necrosis factor (TNF)-related apoptosis-inducing ligand
increased risk of non-Hodgkin lymphoma (caused by Epstein-Barr (TRAIL), interleukin-10 (IL-10), and IL-12. The double-edged effects
 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer 241

of the immune cells, both promoting and inhibiting proliferation, Human T cell leukemia-lymphoma virus (HTLV) is an oncogenic
may explain why it has been so difficult to harness the immune system retrovirus linked to the development of adult T cell leukemia and lym-
to fight cancer. phoma (ATLL).43 HTLV is transmitted vertically (that is, inherited by
children from infected parents) and horizontally (e.g., by breast-feed-
Viral Causes of Cancer ing, sexual intercourse, blood transfusions, and exposure to infected
As noted, a number of viruses have been associated with human needles). Infection with HTLV may be asymptomatic, and only a small
­cancer.42,43 An even broader spectrum of viruses have been associated fraction of infected individuals develop ATLL, often many years after
with cancer in animals. In humans, hepatitis B and C viruses (HBV, acquiring the virus.
HCV), Epstein-Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV) In all of these cases, it is clear that infection by an oncogenic virus is
(also known as HHV8), and human papillomavirus (HPV) are associ- far from sufficient to cause cancer. For example, in some industrialized
ated with about 15% of all human cancers worldwide. Cancer of the regions, Epstein-Barr virus can infect 90% of the adolescent and young
cervix and hepatocellular carcinoma account for approximately 80% adult population, yet only a very small percentage of these individuals
of the cases of virus-linked cancer. The initial infection with hepati- develop EBV-related cancer. For each of these infections, important
tis B or C is not associated with cancer; instead, it is acquisition of cofactors (immunosuppression, cirrhosis, toxins) increase the risk that
a chronic viral hepatitis that markedly increases cancer risk (also see an infection will develop into cancer.
Inflammation, Immunity, and Cancer). Chronic hepatitis B infections
are common in parts of Asia and Sub-Saharan Africa and confer up to Bacterial Cause of Cancer
a 200-fold increased risk of developing liver cancer. Chronic hepatitis Helicobacter pylori (H. pylori) is a bacterium that infects more than
C infections have become increasingly recognized in Western coun- half of the world’s population. Chronic infection with H. pylori is an
tries. Up to 80% of liver cancer cases worldwide are associated with important cause of peptic ulcer disease and is strongly associated with
chronic hepatitis caused either by HBV or by HCV. In both cases, it gastric carcinoma, a leading cause of cancer deaths worldwide. It is also
appears that a lifetime of chronic liver inflammation predisposes to the associated with a less common cancer, gastric mucosa–associated lym-
development of hepatocellular carcinoma. Widespread use of the HBV phoid tissue (MALT) lymphomas. H. pylori infection is often acquired
vaccine is expected to significantly decrease the incidence of chronic in childhood and disproportionately affects lower socioeconomic
hepatitis B and hence hepatocellular carcinoma. Unfortunately, a vac- classes. Although most infections are asymptomatic, prolonged chronic
cine for HCV is not yet available. inflammation can lead to atrophic gastritis that can, in a small fraction
Virtually all cervical cancer is caused by infection with spe- of individuals, progress to dysplastic changes and finally frank gastric
cific subtypes of HPV, which infects basal skin cells and commonly adenocarcinoma. H. pylori infection can both directly and indirectly
causes warts. There are more than 100 HPV subtypes, but only a few produce genetic and epigenetic changes in infected stomachs, including
(HPV16, -18, -31, -45, and a few others) are associated with cervical, mutations in p53 and alterations in the methylation of specific genes.47,48
anogenital, and penile cancer (see Chapters 10 and 32). The initial Eradication of H. pylori from infected individuals before the develop-
HPV infection does not cause cancer. HPV only causes cancer when ment of dysplasia may prevent the development of cancer.49 However,
the viral DNA becomes accidentally integrated into the genomic there is no expert consensus on the value of population screening and
DNA of the infected basal cell of the cervix and directs the persis- treatment strategies. The MALT lymphomas associated with chronic H.
tent production of viral oncogenes. Early oncogenic HPV infection pylori infections may depend on chronic inflammation and antigenic
is readily detected by the Papanicolaou (Pap) test, an examination of stimulation associated with infections, and therefore treatment with
cervical epithelial scrapings. Early detection of cellular atypia in a Pap antibiotics may be useful even in cases of early lymphoma.
test alerts healthcare providers to the possibility of cervical carcinoma
in situ, which can be effectively treated. Vaccines protecting against
the common oncogenic HPV subtypes were approved for clinical
4 QUICK CHECK 9-7
1. Why is the stroma important for cancer growth and invasion?
use beginning in 2006; if these vaccines are administered to young 2. Identify cancers that are the result of chronic inflammation.
women before an initial HPV infection, this is likely to prevent many 3. Why does inflammation fuel cancer development/invasion?
cases of cervical cancer.44 4. Identify common viruses that can cause cancer.
EBV and HHV8 are members of the Herpesviridae family.42 EBV,
the cause of infectious mononucleosis, infects B lymphocytes and
stimulates their proliferation. In individuals who are immunosup-
CANCER INVASION AND METASTASIS
pressed because of HIV infection or because of drugs given for an
organ transplant, persistent EBV infection can lead to the development Metastasis is the spread of cancer cells from the site of the original
of B cell lymphomas. Development of B cell lymphomas in persons tumor to distant tissues and organs through the body. Metastasis is a
with organ transplants is known as post-transplant lymphoprolifera- defining characteristic of cancer, contributes significantly to the pain
tive disorder (PTLD).45 One effective therapy for PTLD is, if possible, and suffering from cancer, and is the major cause of death from cancer.
to decrease or stop the administration of immunosuppressant drugs Cancer that has not metastasized can often be cured by a combina-
and allow the immune system to attack the virus. EBV infection also tion of surgery, chemotherapy, and radiation. These same therapies
is associated with Burkitt lymphoma in areas of endemic malaria and are frequently ineffective against cancer that has metastasized. For
with nasopharyngeal carcinoma, a cancer endemic in Chinese pop- example, in appropriately treated women with low-stage breast can-
ulations in Southeast Asia.46 HHV8 is linked to the development of cer, the 5-year survival rate is often greater than 90%. Tragically, less
Kaposi sarcoma, a cancer that was once seen primarily in older men than 30% of women with metastatic breast cancer are alive 5 years after
but now occurs in a markedly more virulent form in immunocom- diagnosis. A growing body of basic and clinical research is defining the
promised individuals, especially those with acquired immunodefi- biologic principles of metastasis, with the hope that this improved
ciency syndrome (AIDS). HHV8 also has been linked to several rare understanding will lead to novel diagnostic approaches and better
lymphomas. therapies to prevent and treat metastatic cancers.50
242 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer

The Sequential Process of Metastasis

Transformation Angiogenesis Motility and invasion

Capillaries, venules,
lymphatic vessels

Arrest in
capillary beds Embolism and circulation

Adherence Transport

Extravasation
into organ
parenchyma

Response to
microenvironment

Metastasis of
metastases
Tumor cell proliferation
and angiogenesis
FIGURE 9-19  Cancer Metastasis Requires a Complex Series of Events. Cancer cells must gain
access to blood and lymphatic vessels, survive the trip to distant locations, move back into the tissues,
and initiate a new tumor. Because each of these steps is required, the successful metastatic cell is rare
compared with the huge numbers of cancer cells at the primary site. Consequently, metastasis usually
only occurs late in cancer evolution. (From Talmadge JE, Fidler IJ: AACR centennial series: the biology
of cancer metastasis: historical perspective, Cancer Res 70:5649–5669, 2010.)

Invasion, or local spread, is a prerequisite for metastasis and is then to distant organs through the bloodstream. A cancer’s ability to
the first step in the metastatic process. In its earliest stages local inva- establish a metastatic lesion in a new location requires that the cancer
sion may occur by direct tumor extension. Eventually, however, cells both attach to specific receptors and survive in the specific environ-
migrate away from the primary tumor and invade the surrounding tis- ment. Because metastasis requires successful completion of each and
sues. Mechanisms important in local invasion include recruitment of every step, there may be many opportunities to interrupt this poten-
macrophages and other cell types to the primary tumor, where they tially lethal pathway.
promote digestion of connective tissue capsules and other structural
barriers by secreted proteases; changes in cell-to-cell adhesion, often Very Few Cells in a Cancer Have the Ability
by changes in the expression of cell adhesion molecules such as cadher- to Metastasize
ins and integrins, making the cancer cells more slippery and mobile; Metastasis is a highly inefficient process. A landmark clinical review
and increased motility of individual tumor cells51 (Figure 9-19). To examined a group of women with advanced ovarian cancer.52 These
transition from local to distant metastasis, the cancer cells must also unfortunate women had accumulated a large amount of peritoneal
be able to invade local blood and lymphatic vessels, a task facilitated fluid filled with malignant ovarian cancer cells (malignant ascites).
by stimulation of neoangiogenesis and lymphangiogenesis by factors To relieve the pressure caused by the ascites, the fluid was surgi-
such as VEGF. Finally, a successful metastatic cell must be able to sur- cally shunted into the venous circulation. This palliative procedure
vive in the circulation, attach in an appropriate new microenviron- relieved the abdominal pressure but had the side effect of moving
ment, and multiply to produce an entire new tumor, similar to the billions of ovarian cancer cells an hour directly into the bloodstream.
characteristics of a cancer stem cell. Different cancers have different Despite this direct injection of billions of cancer cells into the circula-
patterns of spread, determined by a combination of factors. Cancers tion, these women unexpectedly had no increased number of metas-
often spread first to regional lymph nodes through the lymphatics and tases when they died. The conclusion from this clinical study is that
 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer 243

most cancer cells cannot successfully cause metastases, a conclusion increases the number of cells in the cancer mass with new abilities that
that has been supported by many other clinical and laboratory stud- can facilitate metastasis.
ies. The reason lies both in the seed and in the soil. Cancer cells (the
seeds) must surmount multiple physical and physiologic barriers in CLINICAL MANIFESTATIONS AND TREATMENT
order to spread, survive, and proliferate in distant locations, and the OF CANCER
destination (the soil) must be receptive to the growth of the cancer.
It has been suggested that the metastatic cell must, like a decathlon Clinical Manifestations of Cancer
champion, be successful in every event to allow a cancer to spread. Diagnosis and Staging
How do cancer cells develop the ability to metastasize? The same Cancer can be discovered in many ways: after screening tests, from
heritable changes that occur to cause the primary cancer, including routine exams, and after investigation of symptoms (see Health Alert:
gene mutations, deletions, translocations, epigenetic silencing, and Screening Mammograms: Far from Perfect). The symptoms a cancer
changes in miRNA expression, all work to provide genetic heterogene- produces are as diverse as the types of cancer. The location of the can-
ity in the tumor cells as they proliferate. As this diversity increases, this cer can determine symptoms by physical pressure, obstruction, and

HEALTH ALERT
Screening Mammograms: Far From Perfect
Screening mammograms illustrate many of the difficulties faced by population- itself, increases the risk of breast cancer, especially if screening starts at younger
based screening tests. The goal of screening tests is early and accurate detection ages. In addition, screening mammograms lead to significant overdiagnosis and
of a treatable disease. We want screening tests not to miss disease (to have a overtreatment—they detect DCIS (ductal carcinoma in situ), a condition that
low false-negative rate), but we do not want a lot of false alarms (we want a low might, but often does not, become a malignant disease. The problem with finding
false-positive rate). We also do not want to detect as abnormal, conditions that DCIS is that because some women with DCIS progress to cancer, once it is found
do not need treatment (overdiagnosis). Several large studies suggest that screen- it is usually treated with lumpectomy and radiation therapy. The added unneces-
ing mammograms can prevent 15% to 20% of deaths from breast cancer when sary radiation therapy may cause additional health problems. This accumulation
they are routinely performed in women ages 50 and older. However, these data of findings, summarized in a recent Cochrane meta-analysis, found that screening
are confounded by parallel advances in medical care and self-examination and so 2000 women over 10 years can prevent 1 breast cancer fatality but at the same
other studies question how much of the improvement is due to mammography (for time unnecessarily turn 10 healthy women with DCIS into cancer patients. The
example see Autier). Screening mammograms may be valuable in younger women same authors have generated a fair amount of controversy by concluding: “It is
with higher than average risk of breast cancer, for example, those with positive thus not clear whether screening does more good than harm.” Women considering
family histories. However, current screening methods remain controversial. screening mammography should be aware that the experts disagree on its value.
The mammogram is not an ideal screening test. Screening women 50 and older What should be recommended? Because the more common the disease the
by routine mammography might reduce the relative risk of dying from breast can- more effective the screening becomes, it makes sense to recommend screening
cer by 15% to 20%, but because most women die of other diseases, the absolute to women 50 and older, especially those with risk factors such as strong fam-
reduction in risk of death from all causes is much lower, as low as 0.05% (i.e., 1 ily histories of breast and ovarian cancer. Screening has the least benefit and
in 2000). Even this calculated benefit from screening mammograms is not reli- the greatest risks among women younger than age 50 with a negative family
able. In the combined Canadian National Breast Cancer studies following almost history. Based on these data, the United States Preventive Services Task Force
90,000 women ages 40 to 59, mammography did not decrease deaths from breast recommends that routine screening mammograms should begin at age 50 rather
cancer when added to routine physical and breast exams. Recent studies con- than age 40. Good life-style choices, careful regular breast exams by experi-
tinue to provide conflicting data. Screening mammograms also can miss 25% enced healthcare providers, and improved analysis of targeted mammograms to
or more of breast cancers (the false-negative rate). In a subset of the same Cana- reduce false-positive rates might do more to reduce breast cancer deaths than
dian studies, screening of approximately 32,000 women identified 45 cancers, but routine screening of the general population. From a public health perspective,
missed another 39 that were found clinically within the next 12 months. Screen- the resources allocated to screening mammography might be better spent teach-
ing mammograms also have a remarkably high false-positive rate: in the United ing primary prevention strategies, delivering proven therapies to women without
States, 9 out of 10 suspicious mammograms interpreted as abnormal (sometimes insurance, and performing more research on the root causes and early detection
with computer-aided diagnosis) are eventually determined to be noncancerous. of breast cancer. Women need to understand the limited benefits and the often
Screening tens of thousands of healthy women annually delivers radiation that, understated harms of screening mammography to make truly informed choices.

Data from Tabár L, et al: Swedish Two-County Trial: Impact of mammographic screening on breast cancer mortality during 3 decades, Radiology
(2011). Epub ahead of print; Autier P, et al: Breast cancer mortality in neighbouring European countries with different levels of screening but similar
access to treatment: trend analysis of WHO mortality database. BMJ 343:d4411, 2011; Miller AB et al: Canadian National Breast Screening Study-
2: 13-year results of a randomized trial in women aged 50-59 years, J Natl Cancer Inst 92:1490–1499, 2000; Miller AB et al: The Canadian National
Breast Screening Study-1: breast cancer mortality after 11 to 16 years of follow-up. A randomized screening trial of mammography in women age
40 to 49 years, Ann Intern Med 137:305–312, 2002; Fenton JJ, et al for the Breast Cancer Surveillance Consortium: Effectiveness of computer-aided
detection in community mammography practice, Journal of the National Cancer Institute pp. 10.1093/jnci/djr206, 2011; Baines CJ, et al: Impact of
menstrual phase on false-negative mammograms in the Canadian National Breast Screening Study, Cancer 80:720–724, 1997; Elmore JG et al: Inter-
national variation in screening mammography interpretations in community-based programs, JNCI, J Natl Cancer Inst 95:1384, 2003; Berrington
de González A, Reeves G: Mammographic screening before age 50 years in the UK: comparison of the radiation risks with the mortality benefits,
Br J Cancer 93:590–596, 2005; Gøtzsche PC, Nielsen M: Screening for breast cancer with mammography, Cochrane Database Syst Rev (Online),
CD001877:2006; Fletcher SW, Elmore JG: Clinical practice. Mammographic screening for breast cancer, N Engl J Med 348:1672–1680, 2003;
Qaseem A, et al: Screening mammography for women 40 to 49 years of age: a clinical practice guideline from the American College of Physicians,
Ann Intern Med 146:511–515, 2007.
244 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer

loss of normal function, or a cancer can cause problems far away from initially involves determining the size of the tumor, the degree to which
its source by pressing on nerves or secreting bioactive compounds. it has locally invaded, and the extent to which it has spread (metasta-
Whatever the initial complaint, once the diagnosis is suspected and a sized) (Figure 9-20). Specific molecular tests are increasingly used in
tumor has been identified, it is essential that tumor tissue be obtained staging as well. Diverse schemes are used for staging different tumors.
to establish a definitive diagnosis and correctly classify the disease. In general, a four-stage system is used, with carcinoma in situ regarded
Various methods of obtaining tissue are described in Table 9-6. as a special case. Cancer confined to the organ of origin is stage 1; can-
Once tissue is obtained, it is examined microscopically by the patholo- cer that is locally invasive is stage 2; cancer that has spread to regional
gist for the histologic hallmarks of cancer detailed in the beginning of structures, such as lymph nodes, is stage 3; and cancer that has spread
this chapter. The classification of the cancer can be further facilitated to distant sites, such as a liver cancer spreading to lung or a prostate
by a variety of clinically available tests, including immunohistochemi- cancer spreading to bone, is stage 4. One common scheme for stan-
cal stains, flow cytometry, electron microscopy, chromosome analysis, dardizing staging is the World Health Organization’s TNM system:
and nucleic acid–based molecular studies. T indicates tumor spread, N indicates node involvement, and M indi-
If the diagnosis of cancer is established, it is critical to determine cates the presence of distant metastasis (see Figure 9-20). The prognosis
if the cancer has spread, known as the stage of the cancer. Staging generally worsens with increasing tumor size, lymph node involve-
ment, and metastasis. Staging also may alter the choice of therapy, with
more aggressive therapy being delivered to more invasive disease.
TABLE 9-6 OBTAINING TISSUE—
THE BIOPSY Paraneoplastic Syndromes
PROCEDURE PURPOSE EXAMPLE Paraneoplastic syndromes are symptom complexes that are triggered
Excisional biopsy Complete removal, usually Full resection (e.g., by a cancer but are not caused by direct local effects of the tumor mass.
with margin of normal tissue mastectomy, partial They are most commonly caused by biologic substances released from
colectomy) the tumor (e.g., hormones) or by an immune response triggered by the
Incisional biopsy Removal of portion of lesion Lymph node biopsy, tumor.53 For example, a small fraction of carcinoid tumors release hor-
muscle mass biopsy mones, including serotonin, into the bloodstream that cause flushing,
Core needle Often performed with direct Needle biopsy of diarrhea, wheezing, and rapid heartbeat. A number of cancers trigger
biopsy vision, or guided with ultra- prostate or liver an antibody response that attacks the nervous system, causing a variety
sound or CT mass of neurologic disorders that can precede other symptoms of cancer by
Fine needle Obtains dissociated cells for Thyroid, breast mass months.54
aspirate cytologic study but does not Although infrequent, paraneoplastic syndromes are significant
preserve tissue structure because they may be the earliest symptom of an unknown cancer and,
Exfoliative Cells shed from surface (e.g., from Brushings from lung in affected individuals, can be serious, often irreversible, and some-
­cytology cervix, sputum [lung], or urine) or colon endoscopy times life-threatening. Table 9-7 presents the classifications of para-
neoplastic syndromes.

Local tissues T = Primary tumor; the number equals

size of tumor and its local extent.
The number can vary according to site.
T0 = Breast free of tumor

T Organ T1 = Lesion <2 cm in size

T2 = Lesion 2-5 cm
Tumor T3 = Skin and/or chest wall involved
by invasion

0 1 2 3

N = Lymph node involvement; a higher

number means more nodes are

N involved.
N0 = No axillary nodes involved
Nodes N1 = Mobile nodes involved
N2 = Fixed nodes involved

0 1 2
Bone Example
is breast ? M = Extent of distant metastases
cancer M0 = No metastases

M Lung ? M1 = Demonstrable metastases

M2 = Suspected metastases
Metastases ?
Liver

0 1 2
FIGURE 9-20  Tumor Staging by the TNM System. Example of staging for breast cancer. (See figure
for explanation of the abbreviations.)
 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer 245

TABLE 9-7 PARANEOPLASTIC SYNDROMES

MAJOR FORMS
CLINICAL SYNDROMES OF UNDERLYING CANCER CAUSAL MECHANISM
Endocrinopathies
Cushing syndrome Small cell carcinoma of lung ACTH or ACTH-like substance
Pancreatic carcinoma
Neural tumors
Syndrome of inappropriate antidiuretic Small cell carcinoma of lung; intracranial Antidiuretic hormone or atrial natriuretic
hormone (SIAH) secretion neoplasms hormones
Hypercalcemia Squamous cell carcinoma of lung PTHRP, TGF-α, TNF, IL-1
Breast carcinoma
Renal carcinoma
Adult T cell leukemia/lymphoma
Ovarian carcinoma
Hypoglycemia Fibrosarcoma Insulin or insulin-like substance
Other mesenchymal sarcomas
Hepatocellular carcinoma
Carcinoid syndrome Bronchial adenoma (carcinoid) Serotonin, bradykinin
Pancreatic carcinoma
Gastric carcinoma
Polycythemia Renal carcinoma Erythropoietin
Cerebellar hemangioma
Hepatocellular carcinoma

Nerve and Muscle Syndromes

Myasthenia Bronchogenic carcinoma Immunologic
Disorders of central and peripheral nervous systems Breast carcinoma

Dermatologic Disorders
Acanthosis nigricans Gastric carcinoma Immunologic; secretion of epidermal growth
factor
Lung carcinoma
Uterine carcinoma
Dermatomyositis Bronchogenic, breast carcinoma Immunologic

Osseous, Articular, and Soft Tissue Changes

Hypertrophic osteoarthropathy and clubbing of fingers Bronchogenic carcinoma Unknown

Vascular and Hematologic Changes

Venous thrombosis (Trousseau phenomenon) Pancreatic carcinoma Tumor products (mucins that activate clotting)
Bronchogenic carcinoma
Other cancers
Nonbacterial thrombotic endocarditis Advanced cancers Hypercoagulability
Anemia Thymic neoplasms Unknown

Others
Nephrotic syndrome Various cancers Tumor antigens, immune complexes

From Kumar V, Abbas AK, Fausto N: Pathologic basis of disease, ed 7, Philadelphia, 2005, Saunders.
ACTH, Adrenocorticotropic hormone; IL, interleukin; PTHRP, parathyroid hormone–related protein TGF, transforming growth factor; TNF, tumor
necrosis factor.

Pain Cancer-associated pain can arise from a variety of direct and indi-
Pain is one of the most feared complications of advanced cancer. Although rect mechanisms. Direct pressure, obstruction, invasion of a sensitive
pain can be one of the presenting symptoms of cancer, most commonly structure, stretching of visceral surfaces, tissue destruction, infection,
there is little or no pain during the early stages of malignant disease. Sig- and inflammation all can cause pain. Pain can occur at the site of the
nificant pain, however, occurs in a large fraction of those individuals who primary tumor or can result from a distant metastatic lesion. Further-
are terminally ill with cancer. Pain is strongly influenced by fear, anxiety, more, pain may be referred away from the involved site and manifest,
sleep loss, fatigue, and overall physical deterioration. It occurs through an for example, as back pain.
interaction among physiologic, cultural, and psychologic components. Specific sites are more prone to cancer-associated pain. Bone
(The neurophysiology of pain is discussed in Chapter 13.) metastases, common in advanced breast and prostate cancer, can cause
246 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer

significant pain because of periosteal irritation, medullary pressure,

vertebral collapse, and pathologic fractures. Brain tumors (primary or
metastatic) can, depending on the location, cause headache, seizures,
or neurologic deficits. Pain in the abdomen may be caused by bowel
obstruction, or inflammation and infection. Hepatic malignancies can
stretch the liver, resulting in a dull pain or a feeling of fullness over the
right upper abdominal quadrant. Mucosal surfaces can develop pain-
ful ulcerative lesions from the cancer, chemotherapy, and radiation or
leukopenia (or both).
The diagnosis and treatment of pain is one of the primary
responsibilities of the medical team. The individual’s perception
and, hence, reporting of pain can vary widely and be affected by
such factors as age and cultural background. The first priority of
treatment is to control pain rapidly and completely as judged by
the individual. The second priority is to prevent recurrence of pain.
Objective measurements of pain are increasingly being included
along with the reporting of more traditional vital signs. Many
FIGURE 9-21  Cachexia. This severe form of malnutrition results
institutions are using specialized pain management teams that are in wasting and extensive loss of adipose tissue. (From Kamal A,
trained to recognize different types of acute and chronic pain, as Brockelhurst JC: Color atlas of geriatric medicine, ed 2, St Louis,
well as the individual’s response to that pain. Many modalities are 1991, Mosby.)
available to treat pain, ranging from combinations of NSAIDs and
narcotics to palliative surgery and radiation therapy. Individual-
controlled analgesia provides many benefits, not the least of which including insulin resistance, hypertriglyceridemia, muscle wasting,
is regaining some control over one’s own body. Although cancer and general increased derangement of metabolism, lead to significant
pain is a complex problem arising from multiple sources, individu- inefficiency of energy usage. Anorexia, or loss of appetite, frequently
als should be assured that suffering is not inevitable and that relief worsens the weight loss associated with this abnormal metabolic state.
is attainable.55 Anorexia itself can be caused by pain, depression, chemotherapy, and/
or radiotherapy. Alterations in taste, making foods seem bland or dis-
Fatigue tasteful, by these same causes also can account for the anorexia present
Fatigue is the most frequently reported symptom of cancer and can- in individuals with cancer.
cer treatment. The exact mechanisms that produce fatigue are poorly Altered carbohydrate metabolism causes a syndrome resembling
understood.56 Suggested causes include sleep disturbances, various diabetes mellitus. Individuals show hyperinsulinemia, insulin resis-
biochemical changes secondary to disease and treatment, numerous tance, hyperglycemia, and abnormal glucose tolerance test results.
psychosocial factors, level of activity, nutritional status, and other envi- These disturbances cause increased gluconeogenesis, which produces
ronmental and physical factors.57 glucose from amino acids. In starvation, protein usually is spared to
The physiologic understanding of fatigue probably includes mech- protect vital structures; however, in cancer, protein and fatty acids are
anisms for decreased muscle contractility. Overall, studies of muscle used to meet energy needs.
function suggest that some individuals with cancer may lose por- An unusual and frustrating component of cancer care is the per-
tions of muscle function needed to perform normal physical activi- son’s early satiety, or a sense of being full after only a few mouthfuls
ties. Other areas of research include muscle function consequences of food. Cytokines, including TNF-α, IL-6, and interferon-γ, appear
from metabolic products of cancer treatment and associated muscle to cause the metabolic alterations associated with tissue loss in cancer
loss from circulating cytokines (e.g., tumor necrosis factor [TNF] wasting. Tumor metabolites may also contribute to a cachectic state.
and interleukin-1 [IL-1]). Similar to pain, fatigue is a subjective clini- For example, a factor found in the urine of some individuals with
cal manifestation. Fatigue is described by individuals with cancer as cancer induces the catabolism of muscle. This factor, originally called
tiredness, weakness, lack of energy, exhaustion, lethargy, inability to proteolysis-inducing factor, is a partial fragment of an antimicrobial
concentrate, depression, sleepiness, boredom, lack of motivation, and peptide, dermcidin, normally expressed in the skin.60 (Cytokines are
decreased mental status. Some of these symptoms have been termed discussed in detail in Chapter 6.)
“chemo brain,” or mild cognitive impairment. The changes in cogni-
tive function can be caused by the cancer itself or by the stress associ- Anemia
ated with the diagnosis of cancer, however, because symptoms similar Anemia is commonly associated with malignancy, with 20% of per-
to “chemo brain” also occur in individuals who have not received sons diagnosed with cancer having hemoglobin concentrations less
chemotherapy.58 than 9 g/dl (normal value = 15 g/dl). Mechanisms that cause anemia
in persons with cancer include chronic bleeding (resulting in iron defi-
Cachexia ciency), severe malnutrition, cytotoxic chemotherapy, and malignancy
The syndrome of cachexia includes a constellation of symptoms in blood-forming organs. Chronic bleeding and iron deficiency can
including anorexia, early satiety (filling), weight loss, anemia, asthenia accompany colorectal or genitourinary malignancy. Iron also is mal-
(marked weakness), taste alterations, and altered protein, lipid, and absorbed in persons with gastric, pancreatic, or upper intestinal can-
carbohydrate metabolism (Figure 9-21). Cachexia is the most severe cer. Often there is a defect in the reutilization of iron because of lack
form of malnutrition associated with cancer and results in wasting, of transfer of iron from the storage pool to blood cell precursors. This
emaciation, and decreased quality of life.59 Cachexia occurs even with defect may be caused by increased secretion of IL-6 and hepcidin.61
seemingly adequate caloric intake because metabolic disturbances, Defects in erythropoietin production and shortened duration of red
 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer 247

cell survival have also been documented. In addition, anorexia can proliferate and differentiate rapidly. Thrombocytopenia is a major
cause both iron and folate deficiency. Megaloblastic (large red cell) cause of hemorrhage in persons with cancer and is often treated with
anemias also may develop after methotrexate treatment. platelet ­transfusions. Thrombocytopenia also is an accompanying
Administration of erythropoietin, which stimulates production of disorder of disseminated intravascular coagulation that occurs in per-
erythrocytes, has been effective in correcting anemia in persons with sons with acute promyelocytic leukemia (see Chapter 20) and severe
cancer; fewer red blood cell transfusions were required in most of the infections.
studied subjects. In addition, anemias occurring after chemotherapy or
radiotherapy have been treated successfully with erythropoietin. How- Infection
ever, recent studies have shown that aggressive use of erythropoietin Infection is the most significant cause of complications and death
increases the risk of blood clots and can decrease cancer survival.62,63 in persons with malignant disease. When the absolute granulocyte
count falls below 500 cells per microliter, the risk of serious micro-
Leukopenia and Thrombocytopenia bial (bacterial and fungal) infection increases. Persons with cancer
Direct tumor invasion of the bone marrow causes both leukopenia also have debility with advanced disease, and immunosuppression
(a decreased total white blood cell count) and thrombocytopenia (a from the underlying cancer and the radiotherapy and chemotherapy
decreased number of platelets). More commonly, many chemother- used to treat it. (Factors that predispose persons with cancer to infec-
apeutic drugs are toxic to the bone marrow, often causing granulo- tion are summarized in Table 9-8.) Surgery also can lower resistance
cytopenia and thrombocytopenia. Granulocytopenia also can result to ­infection because removal of large quantities of tissue, together
from radiation therapy if it encompasses significant areas of the with hemorrhage, dead spaces, and poor tissue perfusion, can create
bone marrow. The duration of granulocytopenia and hence the risk favorable sites for infection. Hospital-related (nosocomial) infections
of serious infection can be lessened by treatment with recombinant increase because of indwelling medical devices, inadequate wound
human granulocyte colony-stimulating factor (rhG-CSF, filgrastim).64 care, and the introduction of microorganisms from visitors and other
rhG-CSF stimulates white blood cell precursors in the marrow to individuals.

TABLE 9-8 FACTORS PREDISPOSING INDIVIDUALS WITH CANCER TO INFECTION

FACTOR BASIS
Age Many common malignancies occur mostly in older age.
Immunologic functions decline with age.
General debility reduces immunocompetence.
Immobility predisposes to infection.
Far-advanced cancer often results in immobility and general debility that worsens with age.
Elderly persons are predisposed to nutritional inadequacies.
Malnutrition impairs immunocompetence.
Tumor Nutritional derangements can result.
Sites and circumstances favorable to growth of microorganisms (obstruction, serous or blood effusion, ulceration) can be
created.
Far-advanced disease predisposes individuals to debility and immobility.
Humoral or cellular immune defects may result.
Metastasis to bone marrow may cause leukopenia or other defects in immunity.
Leukemias Inadequate granulocyte production (impaired phagocytosis) results.
Thrombocytopenia (bleeding, breaks in skin integrity) can occur.
Late effect: Chronic lung disease from Pneumocystis carinii pneumonia can develop during therapy.
Lymphomas and other mononuclear Humoral and cellular immune defects (anergy, altered immunoglobulin production) result.
phagocyte malignancies Late effect: Splenectomy in children can cause increased susceptibility to infection.
Surgical treatment Invasive procedure interrupts first lines of defense.
Radical nature of surgery (removal of large blocks of tissue in lengthy procedures) causes hemorrhage, decreased tissue
perfusion, creation of dead spaces, devitalization of tissues.
Procedure may be “dirty” surgery (bowel, infected or contaminated areas).
Surgery patients are often older and at poor risk.
Long preoperative hospitalization often precedes surgery.
Patients may have received previous adrenocorticosteroid therapy.
Patients may have infections at sites remote from operative area.
Nutritional derangements (especially important in head and neck surgery) may result.
Lymph node dissection may predispose patient to local infection and impair containment to area.
Gynecologic surgery may result in fistulae.
Lung surgery may cause bronchopleural fistulae.
Debility and immobility may result.

Data from Donovan MI, Girton SF: Cancer care nursing, ed 2, New York, 1984, Appleton-Century-Crofts; Murphy GP, Lawrence W, Lenhard RE:
Clinical oncology, ed 2, New York, 1994, American Cancer Society.
248 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer

Gastrointestinal Tract Chemotherapy

The entire gastrointestinal (GI) tract relies on rapidly growing cells to The era of modern chemotherapy began with the observation in World
produce an effective barrier to trauma and infection and to provide War II that mustard gas exposure caused suppression of the bone mar-
an absorptive surface for nutrients. Both chemotherapy and radiation row. Related compounds, such as nitrogen mustard and cyclophospha-
therapy may cause a decreased cell turnover, thereby leading to oral mide, were then tested and produced clinical responses in hematologic
ulcers (stomatitis), malabsorption, and diarrhea. The disruption of malignancies, including lymphomas. Also in the late 1940s, based on
barrier defenses also increases the risk for infection, especially invasion the remarkable clinical observation that the vitamin folic acid could
by a person’s own GI flora. Therapy-induced nausea, thought to be increase leukemia growth, antifolate drugs were developed (leading
caused by an agent’s direct action upon the central nervous system’s ultimately to methotrexate) that produced remissions in previously
vomiting centers, historically has been a major obstacle in therapy. untreatable leukemias.65
Aggressive antinausea (antiemetic) therapy, including the centrally All chemotherapeutic agents take advantage of specific vulnerabilities
acting serotonin 5-hydroxytryptamine (5-HT3) antagonists (such as in target cancer cells. Antimetabolites, such as methotrexate and l-aspar-
ondansetron or dolasetron), has allowed better tolerance of highly aginase, block normal growth pathways in all cells, but leukemia and
emetogenic protocols. Other popular antiemetics include steroids other cancer cells are exquisitely sensitive to folic acid and asparagine
and phenothiazines. Synthetic cannabinoids, the active ingredients in deprivation, whereas nonmalignant cells are far less sensitive. Similarly,
marijuana, increase appetite in addition to having antinausea prop- some cancer cells are highly sensitive to DNA-damaging agents, such as
erties. Analgesia often includes opiate agents, vital in treating severe cyclophosphamide and anthracyclines, because of the oncogenic muta-
cases of mucosal lesions. Supplemental nutrition through enteral or tions that accelerate the cell cycle and DNA synthesis. Cellular check-
parenteral routes may be needed to combat malnutrition. Good oral points prevent normal cells treated with microtubule-directed drugs,
hygiene may help prevent complications arising from mucosal mem- such as vincristine and the taxanes, from undergoing mitosis, whereas
brane breakdown. cancer cells treated with these agents lack normal checkpoints, continue
through mitosis, and undergo mitotic catastrophe (see Chapter 1).
Hair and Skin Single chemotherapeutic agents often shrink cancers, but these
Alopecia (hair loss) results from chemotherapy effects on hair follicles. drugs given alone rarely, if ever, provide a cure. Hence, chemotherapy
Alopecia is usually temporary, although hair may regrow with a differ- drugs are usually given in combinations designed to attack a cancer
ent texture initially. Not all chemotherapeutic agents cause alopecia. from many different weaknesses at the same time and to limit the dose
Decreased renewal rates of the epidermal layers in the skin may lead and therefore the toxicity of any single agent. Cancers contain a very
to skin breakdown and dryness, altering the normal barrier protection large number of cells, and commonly a small fraction of those cells
against infection. Radiation therapy may cause skin erythema (red- may be resistant to a particular drug. However, those cells are likely
ness) and contribute to breakdown. to be sensitive to the second or third drug in a chemotherapy cocktail.
Scheduling of drug administration is also very important, with many
Treatment of Cancer studies showing cancers are more likely to develop drug resistance if
The diagnosis of cancer has a profound effect on individuals and their there are significant delays between planned courses of chemotherapy.
families. Responses range from depression to resigned fatalism to an The newest highly targeted agents used to treat cancer exploit spe-
aggressive no-holds-barred pursuit of therapy. The choice of therapy cific vulnerabilities uncovered by molecular analysis in specific dis-
should be based on full consideration by the individual, the family, and eases (Table 9-9). These new drugs are still used in combination with
the medical team of the individual’s diagnosis, prognosis, and therapeu- conventional chemotherapy and to be effective they must be used in
tic options. Many types of cancer can be effectively treated with chemo- diseases in which the molecular target is present. For example, ima-
therapy, radiotherapy, surgery, and combinations of these modalities. tinib is highly effect in treating CML and gastrointestinal stromal
Caregivers must recognize that many individuals seek additional non- tumor (GIST) but ineffective in virtually all other cancers. Fortunately,
science-based explanations and therapies and often use alternative because these drugs are so tightly targeted they have much less toxicity
therapies, either concurrently or sequentially. Alternative therapies can than conventional chemotherapies that have targets in virtually all cells.
be biologically harmless or harmful; rarely is there any evidence these Chemotherapy can be used for several distinct purposes. Induction
approaches are medically effective and in the worst cases they can be chemotherapy seeks to cause shrinkage or disappearance of tumors.
expensive, delay the use of effective therapies, and produce toxic side In Hodgkin disease, for example, chemotherapy alone can be used in
effects. A challenge for the medical team is to provide the same level of some cases to cure the disease. In other settings, chemotherapy may
psychosocial comfort and support that alternative therapies can provide, shrink the tumor and improve symptoms without ultimately provid-
while also providing scientifically rational evidence-based therapies. ing a cure. Adjuvant chemotherapy is given after surgical excision of

TABLE 9-9 EXAMPLES OF MOLECULAR-ERA ANTICANCER DRUGS

DRUG (TRADE NAME) TYPE OF DRUG MOLECULAR TARGET DISEASE
Imatinib (Gleevec) Small molecule TKI BCR-ABL tyrosine kinase, FGF receptor Chronic myeloid leukemia (CML),
tyrosine kinase ­gastrointestinal stromal tumor (GIST)
Erlotinib (Tarceva) Small molecule TKI EGF receptor tyrosine kinase Subset of lung cancer
Trastuzumab (Herceptin) Monoclonal antibody HER2 receptor tyrosine kinase HER2-positive breast cancer
Bevacizumab (Avastin) Monoclonal antibody VEGF receptor Advanced colorectal cancer
Rituximab Monoclonal antibody CD20 antigen on B lymphocytes B cell malignancies

EGF, Endothelial growth factor; FGF, fibroblast growth factor; HER2, human epidermal growth factor receptor 2; TKI, tyrosine kinase inhibitor;
VEGF, vascular endothelial growth factor.
 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer 249

a cancer with the goal of eliminating micrometastases. Neoadjuvant Surgery

chemotherapy is given before localized (surgical or radiation) treat- Surgery plays many roles in the care of individuals with cancer. The
ment of a cancer. As with induction chemotherapy, the effectiveness, multiple approaches to obtaining tissue for diagnosis have been dis-
or lack thereof, of neoadjuvant therapy can be measured (for example, cussed. Surgery is often the definitive treatment of cancers that do not
with follow-up scans). Neoadjuvant therapy can shrink a cancer so spread beyond the limits of surgical excision. It is also indicated for the
that surgery may spare more normal tissue. For example, in the bone relief of symptoms, for instance, those caused by tumor mass obstruc-
cancer osteogenic sarcoma, neoadjuvant therapy often converts a large tion. In selected high-risk diseases, surgery plays a role in the preven-
tumor mass into a much smaller mass, allowing the surgeon to per- tion of cancer. For example, individuals with familial adenomatous
form a limb-sparing excision rather than an amputation. polyposis because of germline mutations of the APC gene have close
to a 100% lifetime risk of colon cancer, so a prophylactic colectomy
Radiation Therapy is indicated. Similarly, women with BRCA1/2 mutations have a mark-
Radiation therapy is used to kill cancer cells while minimizing damage to edly increased risk of breast and ovarian cancer, and often choose pro-
normal structures. Ionizing radiation damages cells by imparting enough phylactic mastectomy or bilateral salpingo-oophorectomy (removal of
energy to cause molecular damage, especially to DNA. The damage may ovaries and fallopian tubes), or both.66
be lethal, in which the cell is killed by radiation; potentially lethal, in Key principles apply specifically to cancer surgery, including
which the cell is so severely affected by radiation that modifications in its obtaining adequate surgical margins during a resection to prevent local
environment will cause it to die; or sublethal, in which the cell can subse- recurrences, placing needle tracks and biopsy incision scars (that may
quently repair itself. Cellular compartments with rapidly renewing cells be contaminated with cancer cells) carefully so they can be removed in
are, in general, more radiosensitive. Effective cell killing by radiation also subsequent incisions, avoiding the spread of cancer cells during surgical
requires good local delivery of oxygen, something not always present procedures through careful technique, and paying attention to obtain-
in large cancers. Radiation produces slow changes in most cancers and ing adequate tissue specimens during biopsies so that the pathologist
irreversible changes in normal tissues as well. Because of these irrevers- can be confident of the diagnosis. Additionally, the surgeon provides
ible changes, each tissue has a maximum lifetime dose of radiation it can critical staging information by inspection, sampling, and removal of
tolerate. Radiation is well suited to treat localized disease in areas that are local and region lymph nodes during procedures.
hard to reach surgically, for example, in the brain and pelvis. A number
of radiation delivery methods are available, with external beam being
the most common. Radiation sources, such as small 125I-labeled capsules
4 QUICK CHECK 9-8
1. Define local spread and metastasis.
(also called seeds), can also be temporarily placed into body cavities, a 2. Describe the major clinical manifestations of cancer.
delivery method termed brachytherapy. Brachytherapy is useful in the 3. What are the most common treatments of cancer?
treatment of cervical, prostate, and head and neck cancers.

DID YOU UNDERSTAND?

Cancer Terminology and Characteristics 2. Cancer cells are immortal.
1. Benign tumors are usually encapsulated and well differentiated and do not 3. Genetic events are the primary basis of carcinogenesis. The stepwise accu-
spread to distant locations. mulation of a small set of changes in the deoxyribonucleic acid (DNA) and
2. Malignant tumors, compared with benign tumors, have more rapid growth chromosomes of the cancer cell cause it to become cancerous.
rates, specific microscopic alterations (anaplasia, loss of differentiation), 4. Heritable changes in cells can contribute to cancer. These changes include
absence of normal tissue organization, and no capsule; they invade blood small and large DNA mutations that alter genes, chromosomes, and non–
vessels and lymphatics and have distant metastases. coding RNAs, as well as epigenetic changes because of altered chemical
3. Carcinomas arise from epithelial tissue, and leukemias are cancers of modifications of DNA and histones.
blood-forming cells. CIS refers to noninvasive epithelial tumors of glandular 5. The incidence of cancer increases with age. An explanation for this increase
or squamous cell origin. Localized cancer is considered low stage, whereas is the individual acquires a number of genetic hits or mutations with time.
cancers that have spread regionally or distantly are termed stage 3 and Mutations activate growth-promotion pathways, block antigrowth signals,
stage 4, respectively. prevent apoptosis, stimulate telomerase and new blood vessel growth, and
4. The classification, and hence the treatment decisions, of cancers was allow tissue invasion and distant metastasis.
originally based on gross and light microscopic appearance, and is now 6. From sophisticated molecular analyses it has been determined that some
commonly accompanied by immunohistochemical analysis of protein mutations are more important for cancer progression. These mutations can
expression. Increasingly, this is supplemented by a more extensive molecu- be called driver mutations. Passenger mutations are random mutations that
lar analysis of the tumors. presumably do not contribute to cancer progression.
5. Tumor markers are substances (i.e., hormones, enzymes, genes, antigens, 7. Key genetic mechanisms have a role in human carcinogenesis: (a) activa-
antibodies) found in cancer cells and in blood, spinal fluid, or urine. They are tion of proto-oncogenes, resulting in hyperactivity of growth-related gene
used to screen and identify individuals at high risk for cancer, to help diag- products (such genes are called oncogenes); (b) mutation of genes, result-
nose specific types of tumors, and to follow the clinical course of cancer. ing in loss or inactivity of gene products that normally would inhibit growth
(such genes are called tumor-suppressor genes); and (c) mutation of care-
The Biology of Cancer Cells taker genes that normally prevent mutations.
1. Cancer cell behavior is a major topic of laboratory study. Based on these 8. Caretaker genes are responsible for maintaining genomic integrity.
studies cancer cells are identified as transformed cells and lack contact Inherited mutations can disrupt caretaker genes and cause chromosome
inhibition. Cancer cells are described as anchorage independent; that is, instability.
they continue to divide even when suspended in a petri dish.
250 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer

DID YOU UNDERSTAND?—cont’d

9. Because each person has two chromosomes, one from each parent, a per- 2. Tumor staging involves the size of the tumor, the degree to which it has locally
son is always heterozygous for nearby multiple genetic markers; loss of one invaded, and the extent to which it has spread. A standard scheme for staging
copy (allele) of a specific chromosome region in a tumor is referred to as is the T (tumor spread), N (node involvement), and M (metastasis) system.
loss of heterozygosity, or LOH. 3. Paraneoplastic syndromes are rare symptom complexes, often caused by
10. Abnormal gene silencing is emerging as a major factor in cancer progres- biologically active substances released from a tumor or by an immune
sion. Gene expression can be regulated in a heritable manner (i.e., passed response triggered by a tumor, that manifest as symptoms not directly
from a parent to a child or from a single cell to its progeny) by an “epigen- caused by the local effects of the cancer.
etic” mechanism called silencing. Inheritance occurs during cell division 4. Clinical manifestations of cancer include pain, cachexia, anemia, leukope-
and does not require mutations or changes in DNA sequence. nia, thrombocytopenia, and infection.
11. Changes in gene regulation can affect not just single genes, but entire net- 5. Pain is generally associated with the late stages of cancer. It can be caused
works of signaling. Gene expression networks can be regulated by changes by pressure, obstruction, invasion of a structure sensitive to pain, stretch-
in microRNAs (miRNAs or miRs) and other non–coding RNAs (ncRNAs). ing, tissue destruction, and inflammation.
12. Most of the genetic and epigenetic alterations that cause cancer occur 6. Fatigue is the most frequently reported symptom of cancer and cancer
within the somatic tissues during the lifetime of the individual. treatment.
13. In rare families, cancer is inherited in an autosomal dominant fashion as a 7. Cachexia (loss of appetite, early satiety, weakness, inability to maintain
result of mutations in tumor-suppressor genes such as p53, RB, and BRCA1. weight, taste alterations, altered metabolism) leads to protein-calorie mal-
14. Like many normal adult tissues, cancers can contain rare stem cells. To fully nutrition and progressive wasting.
eradicate a cancer, it may be necessary to target the cancer stem cell. 8. Anemia associated with cancer usually occurs because of malnutrition,
15. Advanced cancers can secrete multiple factors that stimulate new blood chronic bleeding and resultant iron deficiency, chemotherapy, radiation,
vessel growth (called neovascularization or angiogenesis). Active inflam- and malignancies in the blood-forming organs.
mation predisposes to cancer by stimulating a wound-healing response 9. Leukopenia is usually a result of chemotherapy (which is toxic to bone mar-
that includes proliferation and new blood vessel growth. row) or radiation (which kills circulating leukocytes).
16. When they reach a critical age, cancer cells somehow activate telomerase 10. Thrombocytopenia is usually the result of chemotherapy or malignancy in
to restore and maintain their telomeres, thereby allowing cancer cells to the bone marrow.
divide repeatedly or become immortal. 11. Infection may be caused by leukopenia, immunosuppression, or debility
17. The successful cancer cell divides rapidly, with the consequent requirement associated with advanced disease. It is the most significant cause of com-
for the building blocks of new cells; cancer cell division often occurs in a plications and death.
hypoxic and acidic environment. Many cancer genes also encourage aero- 12. The gastrointestinal tract relies on rapidly growing cells to provide an
bic glycolysis and promote high glucose utilization of a cancer. absorptive surface for nutrients. Both chemotherapy and radiation therapy
18. Stroma-cancer interactions actively recruit an immune and stromal may cause decreased cell turnover, thereby leading to oral ulcers (stomati-
response to assist in remodeling of tissues, formation of new blood ves- tis), malabsorption, and diarrhea.
sels, and promotion of metastasis. 13. Alopecia (hair loss) results from chemotherapy effects on hair follicles.
19. In both cancer and inflammation (e.g., after injury and during infection), Alopecia is usually temporary, although hair may initially regrow with a dif-
inflammatory cells, including neutrophils, lymphocytes, and macrophages, ferent texture. Not all chemotherapeutic agents cause alopecia. Decreased
migrate to the site of injury and release cytokines and growth and survival renewal rates of the epidermal layers in the skin may lead to skin break-
factors that stimulate local cell proliferation and new blood vessel growth down and dryness, altering the normal barrier protection against infection.
to promote wound healing by tissue remodeling. These factors combine in 14. Cancer is treated with surgery, radiation therapy, chemotherapy, and com-
chronic inflammation to promote continued proliferation. binations of these modalities.
20. Defects in the immune system increase the risk of viral-associated cancers 15. The theoretic basis of chemotherapy is the vulnerability of tumor cells in
but have a minimal effect on the risk of other cancers. various stages of the cell cycle.
16. Modern chemotherapy uses combinations of drugs with different targets
Cancer Invasion and Metastasis and different toxicities.
1. Metastasis is the major cause of death from cancer. 17. A new generation of specific targeted drugs attacks targets identified by
2. Metastasis is a complex process that requires cells to have many new the molecular analysis of cancers.
abilities, including the ability to invade, survive, and proliferate in a new 18. Ionizing radiation causes cell damage; therefore the goal of radiation ther-
environment. apy is to damage the tumor without causing excessive toxicity or damage
to nondiseased structures.
Clinical Manifestations and Treatment of Cancer 19. Surgical therapy is used for nonmetastatic disease (in which cure is pos-
1. The diagnosis of cancer requires a biopsy and examination of tumor tis- sible by removing the tumor) and as a palliative measure to alleviate
sue by a pathologist. Cancer classification is established by a variety of symptoms.
tests.
 CHAPTER 9  Biology, Clinical Manifestations, and Treatment of Cancer 251

 KEY TERMS
•  denocarcinoma  223
A •  pigenetic change  228
E •  ncomir  233
O
• Adjuvant chemotherapy  248 • Epigenetics  228 • p53 tumor-suppressor gene (TP53)  235
• Adult stem cell  238 • Epigenetic silencing  233 • Paraneoplastic syndrome  225
• Anaplasia  223 • Gene amplification  231 • Personalized medicine  223
• Anchorage independent  227 • Human T cell leukemia-lymphoma virus • Pleomorphic  223
• Angiogenesis  235 (HTLV)  241 • Point mutation  229
• Angiogenic factor  235 • Immortal  227 • Post-transplant lymphoproliferative disor-
• Apoptosis  235 • Induction chemotherapy  248 der (PTLD)  241
• Autocrine stimulation  234 • Inheritance  233 • Proto-oncogene  229
• Benign tumor  223 • Leukemia  223 • RAS  235
• Brachytherapy  249 • Loss of heterozygosity (LOH)  233 • Receptor tyrosine kinase  234
• Cachexia  246 • Lymphoma  223 • Retinoblastoma gene (RB)  231
• Cancer  222 • Malignant tumor  223 • Sarcoma  223
• Carcinoma  223 • Metastasis  241 • Silencing  233
• Carcinoma in situ (CIS)  223 • MicroRNA (miRNA, miR)  233 • Stage of cancer  244
• Caretaker gene  233 • Multipotent  238 • Stroma  223
• Chromosome instability  233 • Mutagen  234 • Telomerase  236
• Chromosome translocation  229 • Neoadjuvant chemotherapy  249 • Telomere  236
• Clonal expansion  228 • Neoplasm  222 • Transformed cell  227
• Clonal proliferation  228 • Neovascularization  235 • Tumor  222
• Contact inhibition  227 • Non–coding RNA  228 • Tumor marker  225
• Copy number variation (CNV)  231 • Oncogene  229 • Tumor-suppressor gene  229
• DNA methylation  233 • Oncogene addiction  237

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high-risk nasopharyngeal carcinoma families in Taiwan, Cancer Epidemiol chemotherapy-induced neutropenia: evidence based review, Curr Opin
Biomarkers Prev 14(4):900–905, 2005. Oncol 19(4):328–335, 2007.
47. Matsumoto Y, et al: Helicobacter pylori infection triggers aberrant 65. DeVita VT Jr, Chu E: Principles of medical oncology. In DeVita VT,
­expression of activation-induced cytidine deaminase in gastric epithelium, ­Lawrence TS, Rosenberg SA, editors: Cancer: principles and practice of
Nat Med 13:470–476, 2007. oncology, ed 8, Philadelphia, 2008, Lippincott Williams & Wilkins, p 337.
48. Niwa T, et al: Inflammatory processes triggered by Helicobacter pylori 66. Rebbeck TR, Kauff ND, Domchek SD: Meta-analysis of risk reduction
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49. Wong BC, et al: Helicobacter pylori eradication to prevent gastric cancer in
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291(2):187–194, 2004.
 CHAPTER

10
Cancer Epidemiology
Kathryn L. McCance

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Genes, Environmental-Lifestyle Factors, and Risk Factors, 253 Electromagnetic Radiation, 276
Epigenetics and Genetics, 257 Sexual and Reproductive Behavior: Human Papillomaviruses, 277
Tobacco Use, 261 Other Viruses and Microorganisms, 278
Diet, 261 Physical Activity, 278
Alcohol Consumption, 266 Chemicals and Occupational Hazards as Carcinogens, 278
Ionizing Radiation, 267 Air Pollution, 278
Ultraviolet Radiation, 274

Although cancer arises from a complicated and interacting web of mul- include cigarette smoking, excessive alcohol consumption, poor diet,
tiple causes, avoiding exposure to individual carcinogens, or cancer- lack of exercise, excessive sunlight exposure, and sexual behavior that
causing substances, may prevent many cancers. Research has shown increases exposure to certain viruses. Additional factors include expo-
that environmental-lifestyle factors and occupational exposure are sure to radiation, hormones, medical drugs, viruses, bacteria, pesti-
responsible for the majority of cancer cases and deaths.1-7 Widespread cides, and other environmental chemicals present in air, water, food,
general exposure to pollutants from water, air, and the work environ- soil, and the workplace. Investigations of occupational groups with
ment; personal lifestyle choices (such as smoking, excessive alcohol high exposure to chemicals have identified numerous chemicals as car-
use, and poor diet); and involuntary or unknown exposures to car- cinogens (Table 10-1).
cinogens in the air, water, and occupational environments are major Studies of gene-environmental interactions, whereby individuals
contributors to cancer development. The National Cancer Institute with particular genetic predispositions may be more susceptible to
(NCI) and the National Institute for Environmental Health Sciences the biologic effects of environmental exposures, do not explain the
(NIEHS) note in the document titled Cancer and the Environment that increased cancer risk found in most individuals exposed to carcino-
two thirds of all cancers are caused by environmental-lifestyle factors.2 gens. Thus it appears that the majority of cancers are caused by car-
cinogen exposure rather than by rare genetic conditions.2 For example,
GENES, ENVIRONMENTAL-LIFESTYLE FACTORS, for women who have mutated cancer susceptibility genes, BRCA1 or
BRCA2, the risk of having breast cancer at age 50 is 24% for those born
AND RISK FACTORS before 1940 but 67% for those born later.8 The implication here is
Cancers are caused by environmental-lifestyle and genetic factors. At related to lifestyle factors that have changed since 1940 (e.g., hormone
the cellular level, cancer is a genetic process. Because relationships therapy, later age at first pregnancy, increased nulliparity). Investiga-
are unclear investigators are challenged to connect the complex web tions of more complex gene-gene environment interactions and pro-
between genotype, phenotype, and the environment to understand a teins expressed by the genome (proteomics) may or may not alter these
person’s chances of developing cancer. Environmental-lifestyle factors conclusions.

253
254 CHAPTER 10  Cancer Epidemiology

TABLE 10-1 SUMMARY OF ENVIRONMENTAL AND OCCUPATIONAL LINKS WITH

CANCER
CARCINOGENIC
CATEGORY AGENT SOURCE/USES STRONG* SUSPECTED†
Aromatic amines Benzidine, Antioxidants in production of rubber and cutting oils, intermedi- Bladder: benzidine, Prostate
1-­naphthylamine, ates in azo dye manufacturing, and as pesticides. Contaminant 2-­naphthylamine, (­heterocyclic
4,4′-methylenebis in chemical and mechanic industries and aluminum transforma- 4,4′-methylenebis aromatic amines)
(2-chloroaniline) tion and air contaminant from tobacco smoking. Used widely in (2-choloraniline) (MOCA),
(MOCA), chloronaph- textile industry and as hair dyes. and chloronaphthalene
thalene, heterocyclic
aromatic amines
Chlorination Trihalomethanes Chloroform, bromodichloromethane, chlorodibromomethane, and Bladder, rectal
byproducts bromoform. Result from interaction of chlorine with organic
chemicals. Several halogenated compounds may form from
these reactions although trihalomethanes are most common.
Brominated byproducts are also formed from reaction of
chlorinated byproducts with low levels of bromide in drinking
water.
Environmental Contains more than 50 Environmental tobacco smoke (ETS, also known as passive Lung, breast
tobacco smoke known carcinogens smoke) is combination of smoke emitted from burning end of
cigarette, cigar, or pipe and smoke exhaled by smoker.
Metals Arsenic Byproduct of nonferrous metal production, mostly from copper Bladder, lung, skin, Brain/CNS,
production, comprising >10% of dust content in some smelter soft tissue sarcoma kidney, liver and
operations. Inorganic arsenic is commonly used to preserve (­angiosarcoma of liver) biliary, prostate,
wood but also as pesticide on cotton plants. soft tissue
sarcoma
Beryllium Nuclear, aircraft, and medical devices industry. Alloy or in Lung
­specialty ceramics for electric and electronic applications.
Found as contaminant in combustion of coal and fuel oil.
Cadmium Occurs naturally in ores together with zinc, lead, and copper. Lung Pancreatic, kidney,
Used as stabilizers in PVC products, color pigment, several prostate
­alloys, and now most commonly in rechargeable nickel-­
cadmium batteries. Also present as pollutant in phosphate
fertilizers.
Chromium Chromium is used in steel and other alloy production. Chromium Lung, nasal and
III and chromium VI are used in chrome plating, manufacture of ­nasopharynx
dyes and pigments, leather tanning, and wood preserving.
Lead Used primarily in production of batteries, ammunition, metal Brain/CNS, kidney,
products such as solder and pipes, and devices to shield stomach
x-rays. Lead is also found in gasoline, paints, ceramic products,
caulking, and pipe solder, but has been reduced dramatically in
United States.
Nickel Used primarily as alloy in stainless steel. Also used in nickel Lung, nasal and Laryngeal,
plating and battery production. ­nasopharynx ­pancreatic,
stomach
Metal-working Straight oils, soluble Used in variety of industries including metal machining, print Bladder, laryngeal, lung, Esophageal,
fluids and/or oils, synthetic and press operating, and cotton and jute spinning. nasal and nasopharynx ­pancreatic,
mineral oils semisynthetic fluids (mineral oils), rectal, skin, prostate
stomach
Natural fibers/ Asbestos Inorganic naturally occurring fibrous silicate particle used primar- Laryngeal, lung,
dust ily in acoustical and thermal insulation. Asbestos fibers can ­mesothelioma
be divided into two groups: chrysolite (most widely used) and
amphibole, which includes amosite, crocidolite, anthophyllite,
actinolite, and tremolite fibers.
Silica Inorganic particle used in foundries, brick-making, and Lung
­sand-blasting.
Talc containing Mineral used in manufacture of pottery, paper, paint, and Lung
­asbestiform fibers cosmetics.
Wood dust Used primarily in carpentry, joinery, and furniture and cabinetry Lung, nasal and nasoparynx Laryngeal
making.
 CHAPTER 10  Cancer Epidemiology 255

TABLE 10-1 SUMMARY OF ENVIRONMENTAL AND OCCUPATIONAL LINKS WITH

CANCER—cont’d
CARCINOGENIC
CATEGORY AGENT SOURCE/USES STRONG* SUSPECTED†
Pesticides Herbicides, fungicides, Used for preventing, destroying, repelling, or mitigating any pest Brain/CNS, breast,
and insecticides or in use as plant regulator, defoliant, or desiccant. Majority of colon, Hodgkin
pesticides as registered with U.S. EPA are used in agricultural lymphoma,
applications, although residential application is also important ­leukemia, lung,
source. multiple myeloma,
non-Hodgkin lym-
phoma, ovarian,
pancreatic, kid-
ney, soft tissue
sarcoma, stom-
ach, testicular
Petrochemicals Petroleum products, Petrochemicals are derived from natural gas or petroleum and Lung (PAHs, air ­pollution Bladder (PAHs),
and combustion motor vehicle exhaust used to produce variety of other chemicals and materials including diesel exhaust, breast (di-
byproducts (including diesel), including pesticides, plastics, medicines, and dyes. Substances soot, dioxin), NHL oxin), esophageal
polycyclic aromatic can be produced as building blocks for other products, but ­(dioxin), soft tissue (soot), laryngeal
hydrocarbons (PAHs), mainly result from incomplete combustion of burning coal, ­sarcoma (dioxin), (PAHs), multiple
soot, and dioxins oil, gas (diesel exhaust), household waste, tobacco, and other skin (PAHs) myeloma (­dioxin),
organic substances. Dioxins are a class of chemicals that are prostate (dioxin
byproducts of combustion processes containing chlorine and and PAHs)
chemicals such as PVC plastics. Dioxins are also created during
chlorine-bleaching processes for whitening paper and wood
pulp.
Radiation Ionizing radiation Any of several types of particles and rays emitted by radioac- Bone, brain and CNS, Bladder, colon,
tive material, high-voltage equipment, nuclear reactions, and breast, leukemia, liver nasal and
stars. Alpha and beta particles, x-rays, and γ-rays are radiation and biliary, lung, multiple ­nasopharynx,
particles of concern to human health. myelomas, soft tissue ovarian, stomach
sarcoma, skin, thyroid
Nonionizing radiation Composed of microwaves and electromagnetic f­ requencies Brain, breast,
including radio waves and extremely low-frequency leukemia
­electromagnetic fields.
Ultraviolet radiation Ultraviolet radiation is part of solar radiation emitted by sun. Skin
Reactive Butadiene Used in production of polymers for manufacture of styrene-­ Leukemia
­chemicals butadiene rubber for tires; nitrile rubber for hoses, gaskets,
adhesives, and footwear; acrylonitrile-butadiene-styrene
polymers for parts, pipes, and various appliances; and
­styrene-butadiene latexes for paints and carpet backing.
Ethylene oxide Used as sterilant, disinfectant, and pesticide. Also used as raw Leukemia Breast
ingredient in making resins, films, and antifreeze.
Formaldehyde Primary use is in production of urea, phenol, or melamine resins Nasal and
for molded products such as appliances, electric controls, and ­nasopharynx
telephones; in particle-board, plywood, and surface coatings.
Mustard gas Produced and used primarily in World War I as chemical warfare Lung Laryngeal
agent.
Vinyl chloride Vinyl chloride is used in polyvinyl resins for production of plastic Liver and biliary, soft tissue
pipes and floor coverings and in electric and transportation sarcoma (angiosarcoma
applications. of liver)
Sulfuric acid Used widely in industry for production of isopropyl alcohol, Laryngeal Lung
ethanol; treatment of metals; and manufacture of soaps,
detergents, and batteries.
Solvents Benzene Used as intermediate in production of plastics, resins, and some Leukemia, NHL Brain/CNS, lung,
synthetic and nylon fibers. Also used to make some types of nasal and
rubbers, lubricants, dyes, detergents, drugs, and pesticides. ­nasopharynx,
Also found in crude oil, gasoline, and cigarette smoke. multiple
­myeloma

Continued
256 CHAPTER 10  Cancer Epidemiology

TABLE 10-1 SUMMARY OF ENVIRONMENTAL AND OCCUPATIONAL LINKS WITH

CANCER—cont’d
CARCINOGENIC
CATEGORY AGENT SOURCE/USES STRONG* SUSPECTED†
Carbon tetrachloride Used primarily in various industrial applications. Before being Leukemia
banned, it also was used in production of refrigeration fluid
and propellants for aerosol cans, as pesticide, as cleaning
fluid and degreasing agent, in fire extinguishers, and in spot
removers.
Methylene chloride Used primarily as solvent in industrial applications and as paint Brain/CNS, liver
stripper. May also be found in some aerosol and pesticide and biliary
products and in production of photographic film.
Styrene Used in production of rubber, plastic, insulation, fiberglass, NHL
pipes, automobile parts, food containers, and carpet backing.
Toluene Used in production of paints, paint thinners, fingernail polish, Brain/CNS, lung,
lacquers, adhesives, and rubber. Also used in some printing rectal
and leather-tanning processes.
Trichloroethylene (TCE) Mainly used for degreasing metal parts. Precious use as dry Liver and biliary, kidney Cervical, Hodgkin
cleaning agent. TCE may be found in printing inks, varnishes, lymphoma,
adhesives, paints, and lacquers. Important contaminant in leukemia, NHL,
general environment as a result of emissions and leakage from kidney
industrial settings.
Tetrachloroethylene Used to degrease metal parts and as solvent in variety of Bladder, cervical,
(PCE) ­industrial applications. Since the 1930s it was used by an esophageal,
increasingly large percentage of U.S. dry-cleaning operations. NHL, kidney
Xylene(s) Used as cleaning agent, thinner for paint, and in paint and Brain/CNS, rectal
varnishes; in printing, rubber, and leather industries; found in
small amounts in gasoline and airplane fuel.
Other Creosotes Includes coal tar and coal-tar pitch formed by high-temperature Bladder (coal tars), lung,
treatment of wood or coal or from resin of the creosote bush. skin
Wood creosote was historically used as disinfectant, laxative,
and cough treatment. Coal-tar products are used in medicine,
animal and bird repellants, and pesticides. Coal-tar, coal-tar
pitch, and coal-tar pitch volatiles are used in roofing, road
­paving, aluminum smelting, and coking.
Endocrine disruptors A number of chemicals capable of mimicking body’s natural Breast (DES), cervical (DES) Breast, prostate,
hormones. See www.ourstolenfuture.org/Basics/chemlist.htm. testicular
Hair dyes Coloring products used on hair. Hair dyes usually fall into one Bladder, brain
of four categories: temporary, semipermanent, demi, and (SCNS),
permanent. Chemical agents used in dyes are specific to color ­leukemia,
and degree of permanency. ­multiple
­myeloma, NHL
Nitrosamines and Class of chemicals that forms as result of chemical reaction of Brain/CNS
N-nitroso compounds amines and nitrosating agents. Found in rubber, metal, and
agricultural industries, in cosmetics, and in foods such as fried
bacon and cured meats.
Polychlorinated Used as coolants and lubricants in transformers, capacitors, and Liver and biliary Breast, NHL
­biphenyls (PCBs) other electric equipment. PCBs have been banned in United
States since 1997.

From Clapp RW, Jacobs MM, Loechler EL: Environmental and occupational causes of cancer: new evidence, 2005–2007, Rev Environ Health
23(1):1–37, review, 2008.
*Strong evidence of a causal link is based primarily on a Group 1 designation by the International Agency for Research on Cancer.
†Suspected evidence of a causal link is based on the assessment that results of epidemiologic studies are mixed, yet positive findings from well-

designed and conducted studies warrant precautionary action and additional scientific investigation.
CNS, Central nervous system; DES, diethylstilbestrol; EPA, Environmental Protection Agency; NHL, non-Hodgkin lymphoma; PVC, polyvinyl chlo-
ride; SCNS, subcutaneous nerve stimulation.
 CHAPTER 10  Cancer Epidemiology 257

Strong evidence suggests that certain environmental-lifestyle and

BOX 10-1 ESTABLISHED
occupational exposures are associated with cancers of the bladder,
bone, brain, central nervous system (CNS), breast, liver, larynx, scro-
ENVIRONMENTAL-LIFESTYLE
tum, kidney, skin, and thyroid as well as Ewing sarcoma, melanoma, FACTORS AND RISK OF CANCER
mesothelioma, non-Hodgkin lymphoma (NHL), and soft tissue sar- Tobacco use
coma (see Table 10-1). Dietary choices (inadequate fruits, vegetables, and fiber; consumption of fat
Although tobacco smoke remains the single most preventable and alcohol)
cause of cancer, it is not linked to the majority of cancers that have Obesity
increased substantially in the United States. These cancers include mel- Reproductive/menstrual traits (age at menarche, age at menopause, parity,
anoma, non-Hodgkin lymphoma, testicular, brain, and thyroid.2 For age at first birth, lactation)
example, testicular cancer, which affects men mostly in their 20s and Sun exposure
30s, increased about 75% from the 1970s to the 1980s; incidence rates Ionizing radiation
remain about 11 to 12/100,000 in the United States. This increase is Viruses (hepatitis B and viruses, human papillomaviruses, Epstein-Barr virus)
not attributed to improved diagnostic methods and cancer registration Bacteria (Helicobacter pylori)
rates.9 Among all population groups, brain and nervous system can- Occupational exposures (asbestos, rubber, others [see Table 10-1])
cers increased from 10/100,000 in 1973 to 20.9/100,000 in 1992—an Population-wide screening activities (prostate-specific antigen [PSA]), mam-
astounding 109% increase.3,7,10 mography, Pap smears*
Lung cancer rates have risen and fallen, paralleling the prevalence of
smoking. Meanwhile, the prevalence of stomach cancer in the United Data from Kolonel LN, Altshuler D, Henderson BE: Nat Rev Cancer
4(7):519–527, 2004.
States dropped dramatically over the past century.2 The decrease may
*Not a risk factor per se but increases the rates of cancer in the short
be caused by the adoption of healthier lifestyles or by the reduction of
term and in the long term can actually increase the number of cancer
bacterial infection from Helicobacter pylori, or both. cases diagnosed by detecting latent, potentially noninvasive, but histo-
Studies comparing the relationship between environmental-­ pathologically apparent cancer.
lifestyle factors and cancer risk for different populations around the
world are compelling. Breast cancer, for example, is prevalent among
northern Europeans and Americans but is relatively rare among these factors affect our individual resistance to cancer-causing agents.
women in developing countries. If ethnicity played a major role, then Research needed for shaping public policy concerning environmen-
immigrants should retain the cancer incidence rates of their country tal exposures should focus on (1) the relationship between the timing
of origin. Instead, within one or two generations immigrants acquire of exposures (periods of vulnerability), multiple exposures, and chronic
the cancer rates of their geographic relocation.11,12 A particularly exposures; (2) risks among racial groups and gender; (3) human con-
instructive group of studies has been the Multiethnic Cohort (MEC) tamination (biomonitoring); and (4) scrutinization of unexplained
study. These studies are focused on ethnic and migrant populations in patterns of risk. Table 10-2 summarizes the estimated new cases and
Hawaii. The large populations of ethnic groups in Hawaii assist with deaths caused by cancer, by gender, for specified sites.
establishing interethnic comparisons and disentangling the effects of
genes, environment, and lifestyle on cancer rates. These results and
others support the claim that cancer risk is substantially influenced by 4 QUICK CHECK 10-1
environmental factors (Box 10-1). 1. Discuss what is meant by “environment is the main cause of cancer.”
Elevated cancer rates are more common in cities, in farming loca- 2. What are the types of cancers that have increased in the United States
tions, near hazardous waste sites, downwind of industrial and radia- substantially?
tion activities, and near contaminated water wells. In addition, cancers 3. What is the single most preventable cause of cancer?
are associated with areas of high pesticide use, toxic work exposures, 4. For cancer prevalence, why is it important to study immigrant populations?
waste incinerators, and other sources of pollution.13,14
Farmers have increased death rates from brain, multiple myeloma,
prostate, Hodgkin lymphoma, leukemia, non-Hodgkin lymphoma, Epigenetics and Genetics
and lip and stomach cancers.15 Migrant farmers also experience ele- The idea that increased risk of disease originates from interactions
vated rates of some of these cancers.2 Public health advocates have among genes and environmental-lifestyle factors may not be directed
argued that the manufacturers of environmental hazards (e.g., chemi- by the genetic code. A source of heated debate has been the relative
cals, tobacco, drugs, radiologic products) should be required to assess importance of genetic versus epigenetic processes. As discussed in
the health, safety, and environmental effects of their products before Chapter 9, epigenetics is a change in the expression of the gene or
they are introduced to the marketplace; in addition, information phenotype that is heritable but does not involve deoxyribonucleic
regarding these products should be publicly available. acid (DNA) mutation. The epigenome is sometimes called the code
A new paradigm shift suggests that susceptibility to disease is estab- over the DNA code. Although it is clear that inherited variation in
lished in utero or neonatally as the result of nutrition and exposures DNA sequence influences individual risk of cancer, this occurs in
to environmental toxins or stressors, or both.16 Children also may be only a small percentage of the population.18 In addition, the mech-
affected by prenatal exposures, by parental exposures before concep- anism by which structural variation of the genome increases can-
tion, and by contaminated breast milk. Some epidemiologic studies cer risk is unknown. An explosion of recent data now indicates the
have linked higher risks of childhood leukemia and brain and CNS can- importance of epigenetic processes, especially those with resultant
cers with parental and childhood exposure to particular solvents, pesti- gene silencing (not broken, but mute) of key regulatory genes (see
cides, petrochemicals, dioxins, and polycyclic aromatic hydrocarbons.17 Chapter 9). Epigenetic changes collaborate with genetic changes
Environmental-lifestyle factors play important roles in cancer and environmental-lifestyle factors to cause the development of
development, but there are major gaps in our knowledge of how cancer (Figure 10-1). These changes are mitotically and meiotically
258 CHAPTER 10  Cancer Epidemiology

TABLE 10-2 ESTIMATED NEW U.S. CANCER CASES AND DEATHS BY GENDER, 2010*

ESTIMATED NEW CASES ESTIMATED DEATHS

BOTH GENDERS MALE FEMALE BOTH GENDERS MALE FEMALE
All sites 1,529,560 789,620 739,940 569,490 299,200 270,290
Oral cavity and pharynx 36,540 25,420 11,120 7,880 5,430 2,450
Tongue 10,990 7,690 3,300 1,990 1,300 690
Mouth 10,840 6,430 4,410 1,830 1,140 690
Pharynx 12,660 9,880 2,780 2,410 1,730 680
Other oral cavity 2,050 1,420 630 1,650 1,260 390
Digestive system 274,330 148,540 125,790 139,580 79,010 60,570
Esophagus 16,640 13,130 3,510 14,500 11,650 2,850
Stomach 21,000 12,730 8,270 10,570 6,350 4,220
Small intestine 6,960 3,680 3,280 1,100 610 490
Colon† 102,900 49,470 53,430 51,370 26,580 24,790
Rectum 39,670 22,620 17,050
Anus, anal canal, and anorectum 5,260 2,000 3,260 720 280 440
Liver and intrahepatic bile duct 24,120 17,430 6,690 18,910 12,720 6,190
Gallbladder and other biliary 9,760 4,560 5,310 3,320 1,240 2,080
Pancreas 43,140 21,370 21,770 36,800 18,770 18,030
Other digestive organs 4,880 1,660 3,220 2,290 810 1,480
Respiratory system 240,610 130,600 110,010 161,670 89,550 72,120
Larynx 12,720 10,110 2,610 3,600 2,870 730
Lung and bronchus 222,520 116,750 105,770 157,300 86,220 71,080
Other respiratory organs 5,370 3,740 1,630 770 460 310
Bones and joints 2,650 1,530 1,120 1,460 830 630
Soft tissue (including heart) 10,520 5,680 4,840 3,920 2,020 1,900
Skin (excluding basal and squamous) 74,010 42,610 31,400 11,790 7,910 3,880
Melanoma-skin 68,130 38,870 29,260 8,700 5,670 3,030
Other nonepithelial skin 5,880 3,740 2,140 3,090 2,240 850
Breast 209,060 1,970 207,090 40,230 390- 39,840
Genital system 311,210 227,460 83,750 60,420 32,710 27,710
Uterine cervix 12,200 12,200 4,210 4,210
Uterine corpus 43,470 43,470 7,950 7,950
Ovary 21,880 21,880 13,850 13,850
Vulva 3,900 3,900 920 912
Vagina and other genitalia, female 2,300 2,300 780 780
Prostate 217,730 217,730 32,050 32,050
Testis 8,480 8,480 350 350
Penis and other genitalia, male 1,250 1,250 310 310
Urinary system 131,260 89,620 41,640 28,550 19,110 9,440
Urinary bladder 70,530 52,760 17,770 14,680 10,410 4,270
Kidney and renal pelvis 58,240 35,370 22,870 13,040 8,210 4,830
Ureter and other urinary organs 2,490 1,490 1,000 830 490 340
Eye and orbit 2,480 1,240 1,240 230 120 110
Brain and other nervous system 22,020 11,980 10,040 13,140 7,420 5,720
Endocrine system 46,930 11,890 35,040 2,570 1,140 1,430
Thyroid 44,670 10,740 33,930 1,690 730 960
Other endocrine 2,260 1,150 1,110 880 410 470
Lymphoma 74,030 40,050 33,980 21,530 11,450 10,080
Hodgkin lymphoma 8,490 4,670 3,820 1,320 740 580
Non-Hodgkin lymphoma 65,540 35,380 30,160 20,210 10,710 9,500
Myeloma 20,180 11,170 9,010 10,650 5,760 4,890
Leukemia 43,050 24,690 18,360 21,840 12,660 9,180
Acute lymphocytic leukemia 5,330 3,150 2,180 1,420 790 630
Chronic lymphocytic leukemia 14,990 8,870 6,120 4,390 2,650 1,740
Acute myeloid leukemia 12,330 6,590 5,740 8,950 5,280 3,670
Chronic myeloid leukemia 4,870 2,800 2,070 440 190 250
Other leukemias‡ 5,530 3,280 2,250 6,640 3,750 2,890
Other and unspecified primary sites‡ 30,580 15,170 15,510 44,030 23,690 20,340
 CHAPTER 10  Cancer Epidemiology 259

Epigenetic Mechanisms
are affected by these factors and processes:
• Development (in utero, childhood)
• Environmental chemicals
Chromosome • Radiation
• Drugs/pharmaceuticals
• Aging
• Diet

Chromation

Health Endpoints
• Cancer
• Autoimmune disease
• Mental disorders
Methyl group • Diabetes
Epigenetic
factor
DNA methylation
Methyl group (an epigenetic factor found
in some dietary sources) can tag DNA
and activate or repress genes.

Histone tail
Histone
Gene
DNA

DNA accessible, gene inactive

Histone modification
DNA inaccessible, gene inactive The binding of epigenetic factors
to histone “tails” alters the extent
Histones are proteins around which
to which DNA is wrapped around
DNA can wind for compaction and
histones and the availability of
gene regulation.
genes in the DNA to be activated.
FIGURE 10-1  Epigenetics, Genetics, Environment, and Cancer. Epigenetic mechanisms are
affected by many factors and processes including development in utero and during childhood, diet,
environmental chemicals, radiation, drugs/pharmaceuticals, and aging. DNA methylation occurs when
methyl groups, an epigenetic factor found in some dietary sources, for example, can tag DNA and
activate or repress genes. Histones are proteins around which DNA can wind for compaction and gene
regulation. Histone modification occurs when the binding of epigenetic factors to histone “tails” alters
the extent to which DNA is wrapped around histones and the availability of genes in the DNA to be acti-
vated. All of these factors and processes can have an effect on and influence people’s health, possibly
resulting in cancer, autoimmune disease, mental disorders, diabetes, and other diseases. (Division of
Program Coordination, Planning, and Strategic Initiatives. From National Institutes of Health Common
Fund, National Institutes of Health, Washington, DC, U.S. Department of Health and Human Services.)

TABLE 10-2
Estimated new cases are based on 1995-2006 incidence rates from 44 states and the District of Columbia as reported by the North American
Association of Central Cancer Registries (NAACCR), representing about 89% of the U.S. population. Estimated deaths are based on data from
U.S. Mortality Data, 1969-2007, National Center for Health Statistics, Centers for Disease Control and Prevention, 2010. © 2010, American Cancer
Society. Cancer Facts and Figures 2010. Atlanta: American Cancer Society, Inc.
*Rounded to the nearest 10; estimated new cases exclude basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
About 54,010 cases of female carcinoma in situ of the breast and 46,770 cases of melanoma in situ will be newly diagnosed in 2010.
†Estimated deaths for colon and rectal cancers are combined.
‡More deaths than cases may reflect lack of specificity in recording underlying causes of death on death certificates of an undercount in the base

estimate.
260 CHAPTER 10  Cancer Epidemiology

TABLE 10-3 DIFFERENCES BETWEEN TABLE 10-4 SOMATIC VERSUS GERM

MULTIGENERATIONAL CELL INHERITANCE
AND TRANSGENERATIONAL CELL TYPE BIOLOGIC RESPONSE
PHENOTYPES Somatic cells Critical for adult-onset disease in exposed
PHENOTYPE EXPOSURE DEFINITION ­individual; not transmitted to future generations as
Multigenerational Direct Simutaneous exposure of ­transgenerational effect
multiple generations to an Germ cells Allows transmission between generations; promotes
environmental factor transgenerational phenotype
Transgenerational Initial germline Transgenerational phenotype is
­exposure transmitted to future genera-
­(ancestral) tions via germline inheritance Ecosystem
Society
Population
heritable.19,20 The following are the three major types of epigenetic Behavior
processes:
1. Methylation (the addition of a methyl group [CH3] to the cytosine
ring) (see Figure 9-10); aberrant methylation can lead to silencing
of tumor-suppressor genes.
2. Histone modifications (e.g., histone acetylation, alterations in
­chromatin) can result in gene silencing (see Figure 10-1). Internal External
3. Micro–ribonucleic acids (miRNAs) are small RNA molecules that environment Epigenetics environment
can target gene expression post-transcriptionally. MicroRNAs act
like a volume control lever to modulate the production of defined
proteins in cells. The expression of miRNAs has been linked to
carcinogenesis because they can act as either oncogenes or tumor-
suppressor genes.21
An important feature of epigenetic mechanisms and their role in Genes
development and disease is that epigenetic processes can be modi- Cells
fied by lifestyle, particularly diet and the environment, pharmacologic Organs
interventions, or both.22 Data have also shown that aging affects DNA Physiology
methylation in many cell types in various organisms.23-25 The majority
of environmental factors apparently do not promote genetic mutations FIGURE 10-2  Fetal Vulnerability to External and Internal Envi-
or alterations in DNA sequence; however, environmental factors can ronments. The fetus is particularly vulnerable to changes in the
alter the epigenome.26 Significant evidence for environment-lifestyle external and internal environments, which can have immediate and
as the major contributor to age-related effects on the “epigenome” was lifelong consequences. Such environmentally induced changes
can occur at multiple levels, including molecular and behavioral.
demonstrated in a recent study of monozygotic (MZ) twins. Cell types
Ultimately these alterations may be epigenetic, inducing mitoti-
and patterns of DNA methylation across the genome were similar in cally heritable alterations in gene expression without changing the
young MZ twins, but diverged in older twins.27 These data suggest DNA. (Adapted from Crews E, McLachlan JA: Endocrinology 147
that environmental-lifestyle factors act on individuals throughout life, [6 suppl]:S4–S10, 2006.)
changing gene expression through epigenetic mechanisms with sub-
sequent implications for health. The heritable transmission to future
generations of environmentally-caused phenotypes is called transgen- In Utero and Early Life Conditions
erational inheritance. Most epigenetic changes from environmental From studies of the etiology of certain cancers, it is widely accepted
causes involve somatic cells and will not promote transgenerational that a long latency period precedes the onset of adult cancers. Accu-
phenotypes. These somatic effects, however, are critical for the indi- mulating data suggest early life events influence later susceptibility to
vidual exposed because it can lead to adult-onset disease or other phe- certain chronic diseases (Figure 10-2).30 Developmental plasticity is
notype alterations.26 An epigenetic alteration in germline cells (sex the degree to which an organism’s development is contingent on its
gametes) can lead to transgenerational effects independent of contin- environment. It requires stable gene expression that in part appears to
ued environmental exposure. Tables 10-3 and 10-4 include important be modulated by epigenetic processes such as DNA methylation and
explanations of these new findings.26 histone modification.30 Sensitivity to environmental-lifestyle factors
Nutrition has become a major focus because it influences DNA influences the mature phenotype and is dependent on the interactions
methylation in several ways (see p. 262). Biologically active food com- of both the genome and the epigenome.
ponents modify DNA methylation directly. Nutrition influences meta- Perhaps one of the best examples of early life events and future
bolic effects associated with energy balance. Because adipose tissue cancer is the chemical exposure to diethylstilbestrol (DES), a synthetic
is endocrine tissue, obese individuals accumulate macrophages that estrogen. This medication was prescribed between 1938 and 1971 in an
secrete various proinflammatory signaling molecules and cytokines attempt to prevent multiple pregnancy-related problems, such as mis-
(see p. 264). Inflammation is strongly associated with cancer develop- carriage, premature birth, and abnormal bleeding.31 In 1953 a clinical
ment, and inflammatory bowel disease is related to methylation in the study found that DES did not reduce the risk of miscarriage, and by
colon.28,29 The role of nutrition and diet is discussed on p. 261. the 1950s it became clear that DES interfered with the development of
 CHAPTER 10  Cancer Epidemiology 261

the reproductive system in the fetus. Recent data suggest that a DES- regular smokers are killed by this habit. On average, smokers die 13
associated increase in cancer of the female genital tract is elevated to 14 years earlier than nonsmokers;42 about 25% will die prematurely
throughout a woman’s reproductive years.32 More recent studies have during middle age (35 to 69 years).43
revealed that daughters of women who took DES during pregnancy Cigarette smoking accounts for 1 of every 5 deaths each year in the
may have a slight increased risk of breast cancer before age 40 (i.e., 1.9 United States.44 About 21% of all U.S. adults smoke cigarettes. Esti-
times the risk compared with unexposed women at age 40).33 For every mates of cigarette smoking by age are as follows: 23.6% ages 18 to 24;
1000 DES-exposed women ages 45 to 49 it is estimated that 4 will be 23.8% ages 25 to 44; 22.4% ages 45 to 64; and 8.8% ages 65 and older.45
diagnosed with breast cancer. Cigarette smoking is more common among men (23.9%) than women
Research from animal studies has demonstrated a relationship (18.5%), and the prevalence of cigarette smoking is higher among
between DES exposure and an increased rate of a rare type of tes- Native Americans/Native Alaskans (36.4%) than whites (21.4%),
ticular cancer (rete testis) and prostate cancer.34,35 In terms of in blacks (19.8%), Hispanics (13.3%), and Asians (9.6%).45 It is more
utero exposures, testicular cancer has been linked to exposure to common among adults living below the poverty level (30.6%) than
abnormal levels of estrogen,36 and testicular cancer is a risk factor those at or above the poverty level (20.4%).45,46
for men with undescended testicles, a factor in some studies cor- Overall, cigarette smoking in developed countries is responsible for
related with DES exposure. However, studies comparing the risk of 30% of all cancer deaths, and an epidemic of cancer deaths is expected
testicular or prostate cancer in men and DES exposure are unclear in developing countries.42 Tobacco use is associated primarily with
and continuing.37 squamous and small cell adenocarcinomas. In addition, smoking
In summary, epidemiologic and animal studies reveal that small causes even more deaths from vascular, respiratory, and other diseases
changes in the developmental environment can alter phenotypic than from cancer. Smoking tobacco is linked to cancers of the lower
changes, resulting in individual responses in adulthood. Continu- urinary tract (renal, penis, and bladder), upper aerodigestive tract (oral
ing evidence indicates that epigenetic mechanisms are responsible for cavity, pharynx, larynx, nasal cavity, paranasal sinuses, esophagus, and
tissue-specific gene expression during cellular differentiation and that stomach), liver, kidney, pancreas, cervix, and uterus, as well as myeloid
these mechanisms modulate developmental phenotypic changes.30 The leukemia.47 Evidence is lacking that smoking causes breast, prostate, or
phenotypic effects of epigenetic modifications during development may endometrial cancer of the uterus.43 However, tobacco smoke is known
need long latency periods, such as in cancer, thus manifesting later in to cause mammary tumors in animals. Smoking during the prepartum
life. In addition, epigenetic effects may help explain transgeneration period of pregnancy, when breast tissue is less differentiated, appears
effects (see Tables 10-3 and 10-4). For example, Newbold and col- to be relevant for breast cancer risk.48-51 Japanese researchers reported
leagues35 demonstrated that DES-related reproductive cancers in mice that both active and passive smoking (secondhand smoke) increased
also occurred in the grandsons and granddaughters of mothers treated the risk of breast cancer in premenopausal women.52
with DES. Secondhand smoke, also called environmental tobacco smoke
In addition to altering some cancer risks, investigators are studying (ETS), is the combination of sidestream smoke (burning end of a ciga-
diet during pregnancy. Recently, a striking experiment in mice dem- rette, cigar, or pipe) and mainstream smoke (exhaled by the smoker).
onstrated how extra vitamin doses during pregnancy in the mother’s More than 4000 chemicals have been identified in mainstream tobacco
diet changed the fur color of pups.38 This was the first study to show smoke (250 chemicals as toxic) of which 60 are considered carcino-
maternal nutrition and subsequent phenotype changes. The nutrients genic.53 Measuring secondhand smoke is difficult. Nonsmokers who
(B12, folic acid, choline, and betaine) silenced the gene that rendered live with smokers are at greatest risk for lung cancer as well as numer-
mice fat and yellow but did not alter its DNA sequence. Silencing, or ous noncancerous conditions.53
switching the gene off, linked prenatal diet to such diseases as dia- Cigar or pipe smoking, or both, is strongly and causally related to
betes, obesity, and cancer. These concepts, called the developmental cancers of the oral cavity, oropharynx, hypopharynx, larynx, esopha-
basis of health and disease, are defining the hypothesis of disease onset. gus, and lung. Cigar smokers who inhale deeply may be at increased
Subsequently, the focus of disease prevention and intervention needs risk for developing coronary heart disease and chronic obstructive
to include the decades before onset—that is, in utero and neonatal pulmonary disease.54 Pipe smokers have a lower risk of dying from
periods. tobacco than cigarette smokers, but it is as harmful as and perhaps
more harmful than cigar smoking.55 Bidi smoking, a small amount

4 QUICK CHECK 10-2

of tobacco wrapped in the leaf of another plant (used in South Asia),
delivers higher amounts of nicotine per gram of tobacco and com-
1. Define epigenetics. parable or greater amounts of tar compared with cigarettes.47 Case-
2. Discuss how epigenetic processes can be modified by environmental controlled studies indicate bidi smoking can cause cancers of the
factors. respiratory and digestive sites. Epidemiologic data from the United
3. Define developmental plasticity. States and Asia show an increased risk of oral cancer with smokeless
4. Define the developmental basis of health and disease. tobacco products.56 These data, however, are not confirmed in north-
ern European studies.56
Measures that prevent young adults from starting smoking would
Tobacco Use substantially avoid future disease burden. A public health approach
Cigarette smoking is carcinogenic and remains the most important is therefore needed that prevents young people from starting smoking
cause of cancer. The risk is greatest in those who begin to smoke when and helps others stop smoking.
young and continue throughout life.39 Globally, tobacco use is great-
est in developing countries, where 84% of 1.3 billion current smokers Diet
live.40 The World Health Organization (WHO) reports tobacco use Understanding dietary factors that increase the risk for cancer can be
causes more than 5 million deaths per year from cancer, chronic lung difficult. The ways in which diet affects one’s likelihood of developing
disease, cardiovascular disease, and stroke.41 Approximately 50% of cancer are complicated by the variety of foods consumed, the many
262 CHAPTER 10  Cancer Epidemiology

constituents of foods, the metabolic consequences of eating, and the Bioactive Food Substances in Epigenetics
temporal changes in the patterns of food use. Cancer risks in older
adults may depend as much on diet in early life as on current eating
practices.39,57 In addition, studies in humans targeting diet and disease Nutrients
associations face a variety of challenges including measurements of
specific nutrients, food types, and dietary patterns. Genetic
Humans are constantly exposed to a variety of compounds termed differences
xenobiotics (the Greek word xenos means “foreign;” bios means “life”)
that include toxic, mutagenic, and carcinogenic chemicals. Many of SAM SAH
these chemicals are found in the human diet. Most xenobiotics are
transported in the blood by lipoproteins and penetrate lipid mem-
branes (see Chapter 3).
Dietary sources of carcinogenic substances include compounds Methyltransferase
CpG (DNMT) CH3– – CpG
produced in the cooking of fat, meat, or protein, and naturally occur-
ring carcinogens associated with plant food substances, such as alka-
loids or mold byproducts.58 The most studied and most relevant Demethylation
carcinogens produced by cooking are the polycyclic aromatic hydro-
carbon benzo[a]pyrene and the heterocyclic aromatic amines gen-
erated by meat protein. The greatest levels are found in well-done Nutrients
charbroiled beef. People, likewise, ingest xenobiotics that are found in
environmental or industrial contaminants (e.g., particulate matter of
diesel exhaust, contaminating pesticides in food and water supplies)
and in certain prescribed and over-the-counter medicines. Dietary
Tumor
components can act directly as mutagens or interfere with mutagen
elimination. Nutritional factors may alter cellular environments by
FIGURE 10-3  Dietary Factors, DNA Methylation, and Cancer.
modulating hormonal axes or influencing cellular proliferation, or
Certain dietary factors (see Table 10-5) may supply methyl groups
both.59
(+CH3) that can be donated through S-adenosylmethonine (SAM) to
Nutrition may directly influence epigenetic factors that silence many acceptors in the cell (DNA, proteins, lipids, and metabolites).
genes that should be active or activate genes that should be silent.59 Donation and removal (demethylation) are affected by numerous
Importantly, specific nutrients may directly affect the phenotype or enzymes, including DNA methyltransferase (DNMT). Increased
expression of key genes, for example, epigenetically through abnor- DNMT activity occurs in many tumor cells. Hypermethylation can
malities of methylation of the promoter regions of genes or histones. inhibit or silence tumor-suppressor genes (see Chapter 9) and DNA
Epigenetic signals appear to act through remodeling of chromatin methylation inhibitors as anticancer agents and can block DNMT,
structure.60 These alterations can affect DNA structure and mRNA for thus reactivating tumor-suppressor genes. DNA hypomethylation
transcription.59 Clearly, epigenetic events are susceptible to change, can reactivate and mutate genes, including cancer-causing onco-
genes. SAH, S-Adenosylhomocysteine.
thus offering potential explanations of how environmental factors
(e.g., diet) may modify cancer risk and tumor behavior. DNA methyla-
tion—the attachment of a methyl group to the 5-position of cytosine
within cytosine guanine dinucleotides (CpGs)—is one of several epi- sulforaphane (SFN). SFN is an isothiocyanate found in cruciferous
genetic changes important in gene regulation and expression (Figure vegetables, such as broccoli and broccoli sprouts. A growing body of
10-3). DNA is also susceptible to hypomethylation, which can cause evidence suggests that SFN acts through epigenetic mechanisms to
overexpression of transcription of proto-oncogenes, increased recom- inhibit HDAC activity in human colon and prostate cancer lines.65 In
bination and mutation (i.e., oncogenes), and failure to imprint. These human subjects, a single ingestion of 68 g (1 cup) of broccoli sprouts
alterations can all promote cancer.61 Aberrant DNA methylation pat- inhibited HDAC activity in circulating white blood cells 3 to 6 hours
terns occur in several cancers (colon, lung, prostate, and breast). after eating.66
Specific nutritional factors seem to influence susceptibility to can- In summary, epidemiologic and laboratory evidence suggests
cer (see Nutrition & Disease: Components of a Cancer Risk Reduction that diet is a significant factor in the cause, progression, and pre-
Diet). Continuing studies are determining whether certain deficien- vention of cancer (Box 10-2 and Health Alert: Snapshot of Foods
cies, such as vitamin D and compounds found in fruits and vegetables, as Therapeutic Nutrients). Diet affects many pathways to can-
can increase cancer incidence (Table 10-5).61,62 Excess intake of alco- cer including cell cycle control, differentiation, DNA repair, gene
hol can promote cancer (see p. 266). Aflatoxin (produced by mold), silencing, inflammation, apoptosis, and carcinogen metabolism.
which can contaminate corn, peanuts, and rice stored in hot, humid Many of these processes are likely influenced, if not regulated, by
­environments, and Chinese-style salted fish are known to cause can- DNA methylation, an epigenetic mechanism that affects gene func-
cer. With emphasis on epigenetic and aberrant methylation (Figure tion. Imbalances of nutrients can lead to global hypomethylation,
10-4) the role of folic acid in cancer is prominent and it is also com- and there is reason to believe that diet can affect gene-specific hypo-
plicated.63 For example, low intake of folic acid is correlated with an methylation or hypermethylation, or both.67 Much more research is
increased risk of colorectal cancer. However, it is important to note needed to identify how specific nutrients can alter DNA methylation
that once a cancerous lesion is present folate intake may increase and restore gene function as well as other pathways (e.g., apoptosis)
tumor growth.64 that can prevent tumor development. Studies on diet and cancer
Selective dietary agents that inhibit histone deacetylase (HDAC), need testing in a variety of settings and among different population
and thereby abnormal patterns of histone modification, include groups.
 TABLE 10-5 RELATIONSHIP OF DIETARY FACTORS TO RISK OF MAJOR CANCERS*
COLO- ESOPHA-
DIET RECTAL BREAST PROSTATE LUNG STOMACH GEAL ORAL PANCREATIC BLADDER KIDNEY ENDOMETRIAL CERVICAL
Micronutrients/Energy Balance
Obesity ↑↑ ↑↑ ↑† ↑† ↑ ↑ ↑↑
GI/GL,‡ IGF, height, or ↑↑ ↑ ↑ ↑ ↑ ↑
metabolic syndrome
Animal fat ↑ ↑
Nutrients
Folic acid ↓↓a ↓¶ ↓
Defects methionine ↑ ↑ ↑ ↑ ↑ ↑
pathway (folic
acid, vitamin B12
deficiency)
Alcohol ↑↑ ↑↑¶ ↑↑ ↑
Calcium ↓ ↑

β-Carotene ↑↑∥ ↓
­supplements
Lycopene-containing ↓ ↓ ↓
foods
Vitamin C ↓??
Vitamin E ↓?
Selenium ↓? ↓

CHAPTER 10  Cancer Epidemiology

Foods
Red or processed meat ↑ ↑
Fruits§ ↓ ↓ ↓ ↓ ↓ ↓ ↓
Vegetables§ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓
Other
Grilled meat ↑ ↑
Western diet pattern ↑
High-fiber diet ↓
Salt, preserved foods ↑
Hot beverages ↑ ↑

From Koushik A et al: J Natl Cancer Inst 99(19):1471–1483, 2007; McCullough ML, Giovannucci EL: Oncogene 23(38):6349–6364, 2004; Zhang SM et al: Cancer Epidemiol Biomarkers Prev
14(8):2004–2008, 2005.
*Two arrows indicate more consistent evidence.
†Cancers of the gastric cardia.
‡GI/GL signifies glycemic index/glycemic load.
§Evidence for a potential benefit from some components of fruits and vegetables (not necessarily blanket effect).
∥Increased risk limited to smokers.
¶Data support hypothesis that higher folate intake reduces estrogen receptor–breast cancer, particularly important with alcohol consumption.

IGF, Insulin-like growth factor; ?, select trial; ??, vital trial.

aOnce colon cancer is present, folic acid may increase tumor growth.

263
264 CHAPTER 10  Cancer Epidemiology

(a) +

(b) +

A (c) +

(d) +

(e) +

Promoter
region

DNMT Gene expression

Genomic homeostasis

(1)
Cytosine 5-Methylcytosine

NH2 NH2

CH3
N 4 DNMT N 4
3 5 3 5
B 2 6 methylation 2 6
1 1
O N O N
H H

DNMT Gene silencing

Tumorigenesis

(2)
Promoter
region
FIGURE 10-4  Methylation of a Gene Region and Its Effect on Gene Transcription. (A) (Green circles)
Unmethylated cytosine guanine dinuceotide (CpG) sites (a) and (black circles) methylated CpG sites.
Methylation of exons (b, c) does not block gene transcription. Mosaic methylation of promoter CpG
island also does not block transcription (d). However, dense methylation of promoter CpG islands com-
pletely blocks transcription, and is often associated with hypomethylation of downstream regions (e).
(B) DNA methylation in normal and cancer cells. DNA methylation in normal cells (1). A hypomethylated
promoter is related to gene expression. DNA methylation in cancer cells (2). Aberrant DNA hypermeth-
ylation in the promoter leads to gene silencing (muting) and tumor development. The DNA methyla-
tion process is catalyzed by the enymes DNA methyltransferases (DNMTs) by adding a methyl group
(CH3) to the 5-position of the cystosine ring of CpG dinucleotides. (Green circles) Unmethylated cyto-
sine guanine dinucleotide (CpG) sites; (black circles) hypermethylated CpG sites. (A from Ushijima T:
J Biochem Mol Biol 40[2]:143, 2007; B adapted from Li Y, Tollefsbol TO: Impact on DNA methylation
in cancer prevention and therapy by bioactive dietary components, Curr Medicin Chem 17[1]:2, 2010.
[Epub ahead of print.])

Obesity recommended by the WHO64 (Table 10-6) and supported by other

Obesity in most developed countries (and in urban areas of many panels and federal agencies.
developing countries) has been increasing rapidly over the past 20 years Excess body weight, expressed in studies as increased BMI, is asso-
(Figure 10-5). The only globally accepted criteria for overweightness ciated with the increased risk of some common cancers in men and
and obesity are based on the body mass index (BMI). Widely accepted women.68-70 A recent hypothesis states that the observed increased
standards based on BMI criteria for overweightness and obesity are incidence of such cancers as breast, endometrium, colon, liver, kidney,
 CHAPTER 10  Cancer Epidemiology 265

NUTRITION & DISEASE

Components of a Cancer Risk Reduction Diet
Some foods increase the risk of cancer, whereas other foods decrease the risk. Spices (curcumin [turmeric], garlic, cloves, capsaicin, ginger, coriander, fennel,
Observing the following dietary guidelines might reduce the risk of cancer. fenugreek)
Whole grains instead of refined grains (wheat, rice, maize)
Increase Lycopene (tomatoes, tomato paste, watermelon)†
Fruits and vegetables (especially broccoli, cauliflower, cabbage, spinach, Legumes (lentils, peas)
onions, garlic, bok choy, brussels sprouts, kale, chard, collard greens, chicory, Nuts
romaine, blueberries, and grapes)
Fiber (limiting glycemic index) Decrease
Foods containing vitamins A, C, D, and E; mineral selenium (not to exceed Fat (especially large amounts of omega-6 fatty acids)
200 mcg/day) High-glycemic-index carbohydrates, sugar
Vitamin B6 (grains, beans, liver, avocados) Foods with high amounts of preservatives
Vitamin D (see Chapter 2) Alcohol
Vitamin C? Grilled, blackened foods
Foods containing folate (fruits, vegetables [asparagus, broccoli], legumes, Fried foods
grains*) High levels of calcium (≥2000 mg)
Epigallocatechin gallate (found in green tea) Refined grain products

Data from Ingraham BA et al: Curr Med Res Opin 24:139–149, 2008; Lee KW et al: Am J Clin Nutr 78:1074–1078, 2003.
*Whole grains.
†Recent data of inhibition of AK-signaling pathway.

BOX 10-2 DIET AND CANCER KEY POINTS HEALTH ALERT

Cancer is not evenly distributed throughout the world. Snapshot of Foods as Therapeutic Nutrients
Study of migrant populations shows extreme variations in incidence of cancers Investigators are studying food as a source of anticancer agents. Important
are linked to lifestyle differences. is the understanding that some molecules in food have the ability to interfere
Eating habits by some estimates account for 30% of the overall risk factors with certain processes that occur in the development of cancer. Cancer devel-
for cancer. opment can be partially conceptualized as a malfunction in certain specialized
Adoption of the Western diet and habits has increased the rate of certain proteins or enzymes. Molecules that block enzyme activity can be obtained
cancers. both from pharmaceutical drugs and from foods that are eaten daily. A well-
Major research is needed on the effects of industrialization on food quality. known example is genistein, a molecule that is abundant in soy. Genistein
Nutrition is an important and a complementary approach in the treatment of structurally resembles the estrogen hormone estradiol and is therefore known
cancer. as a phytoestrogen. The genistein molecule can occupy the estrogen receptor,
Continuing research is needed to refine the dietary origins of promoters and preventing or reducing estradiol’s attachment to the receptor. Thus genistein
inhibitors of cancer in macronutrients and micronutrients. reduces the biologic effects caused by estradiol. Molecules of dietary origin
Eat a balanced diet rich in fruits and vegetables; avoid obesity/weight gain. can interact with receptors, illustrating that molecules in food can affect
Important areas of study are geographic latitude, ultraviolet/vitamin D related selective downstream metabolic processes. Examples of particular foods that
cancer research, and micronutrients/macronutrients. seem to provide phytochemicals important for risk reduction of cancer include
tumeric (curcumin), blueberries (delpinidin), strawberries (ellagic acid), green
Diet Composition: Macro and Micronutrients tea (epigallocatechin 3-gallate), soybeans (genistein), grapes (reservatrol),
citrus (limonene), garlic (diallyl sulfide), cabbage (especially Chinese, indole-
3-carbinol), broccoli (sprouts; sulforaphane), and tomatoes (lycopene).
Lipids

Phytochemicals and esophagus (adenocarcinoma) may be associated with obesity.71-73

Proteins Newer studies have added leukemia, multiple myeloma, pancreatic
cancer, non-Hodgkin lymphoma, ovarian cancer,69 gallbladder cancer,
Fibers and thyroid cancer70 to the list. Statistical associations were generally
Vitamins similar in studies from North America, Europe, Australia, and the
Carbohydrates
Asia-Pacific region.70
A large prospective study of 900,000 American adults (mean age 57)
showed obesity is linked to cancer. Individuals were followed for 16 years
and cancer mortality data were collected during that interval.74 Com-
pared with individuals whose BMI was in the normal range (18.5 to 24.9),
men and women with substantial obesity (BMI ≥40) showed significant
increases in cancer mortality. Although significant, people with lesser
266 CHAPTER 10  Cancer Epidemiology

Men
2.0
1.9  Colorectal
1.8  Kidney
 Esophageal
Relative risk of dying
1.7
1.6
1.5
1.4
1.3
1.2
1.1
1.0

A 18.5–24.9 25.0–29.9 30.0–34.9 35.0–39.9

Women
 Uterine
6  Kidney
 Breast
5

1
B 18.5–24.9 25.0–29.0 30.0–34.9 35.0–39.9 40.0
FIGURE 10-5  Weight and Risk of Dying from Cancer. A, As a man’s body mass index (BMI) rises
above the normal range (18.5 to 24.9), his risk of dying of colorectal, esophageal, kidney, and other
cancers also rises. For example, the risk of dying from colorectal cancer is 10% higher for men who are
overweight (BMI 25 to 29.9) than for men of normal or lower BMI. For the most obese men (BMI 35
or higher) the risk is almost double (84%). B, As a woman’s BMI rises above the normal range (18.5 to
24.9), her risk of dying of breast, kidney, uterine, and other cancers rises. For example, the risk of dying of
breast cancer is 34% higher for women who are overweight. For the most obese women (BMI >40), the
risk of dying from breast cancer is double. The risk of kidney cancer is almost five times higher, and the
risk of uterine cancer is six times higher. (Data from Calle EE et al: N Engl J Med 348:1625–1638, 2003.)

degrees of obesity had lower increases in cancer mortality. In men with

TABLE 10-6 WHO CLASSIFICATION OF higher BMI, there were higher rates of death from esophageal, stomach,
BODY MASS INDEX (BMI) colorectal, liver, gallbladder, pancreatic, prostate, and kidney cancers and
WHO OTHER non-Hodgkin lymphoma, multiple myeloma, and leukemia.74 Among
BMI (kg/m2)* CLASSIFICATION DESCRIPTIONS women, high BMI correlated to greater morbidity from colorectal, liver,
gallbladder, pancreatic, breast, uterine, cervical, ovarian, and kidney can-
<18.5 Underweight Thin
cers and from non-Hodgkin lymphoma, and multiple myeloma.
18.5-24.9 Normal range “Healthy,” “normal,” or
The mechanisms of obesity-associated cancer risks are unclear and
“­acceptable” weight
may vary by type of tumor and distribution of body fat. Abdominal
25-29.9 Preobese Overweight
obesity, as defined by waist circumference or waist/hip ratio, has been
30-34.9 Obese class I Obesity
shown to be more strongly related to some tumor types than obesity
35-39.9 Obese class II —*
as defined by BMI.72 Possible associated mechanisms include insulin
>40 Obese class III Morbidly overweight
resistance and resultant chronic hyperinsulinemia and increased levels
Data available at http://apps.who.int/bmi/index.jsp?introPage=intro_3.html. of any of the following: insulin-like growth factors (IGFs), steroid hor-
*The cutoffs are somewhat arbitrary, although they are derived from mones, tissue-derived hormones, cytokines (adipokines), or inflam-
epidemiologic studies of BMI and overall mortality. It is important to matory mediators (Figure 10-6).72,75-77
understand that within each category of BMI there can be substantial
individual variation in total and visceral adiposity and in related meta- Alcohol Consumption
bolic factors. These variations are also true for the normal range BMI. Chronic alcohol consumption is a strong risk factor for cancer of the
WHO, World Health Organization.
oral cavity, pharynx, hypopharynx, larynx, esophagus, and liver.78
Although evidence is inconsistent, alcohol consumption is less strongly
 CHAPTER 10  Cancer Epidemiology 267

Increased weight/adiposity

Target cell
IR
↓ Apoptosis ↑ Free fatty acids, ↑ TNF-
↑ Cell proliferation IGFIR ↑ Resistin?, ↓ Adiponectin

↑ Insulin Insulin resistance

Tumor development ↓ Liver synthesis,

blood, and tissue
↓ IGFBP1
↓ IGFBP2

↑ IGF-1 Bioavailability
FIGURE 10-6  Energy Balance, Lipid Metabolism, and Insulin Sensitivity and Tumor Develop-
ment. In obesity, increased release from adipose tissue of free fatty acids (FFAs), tumor necrosis
factor-alpha (TNF-α), and resistin and decreased release of adiponectin lead to insulin resistance and
compensatory chronic hyperinsulinemia. Increased insulin levels ultimately lead to decreased liver syn-
thesis and blood levels of insulin-like growth factor binding protein-1 (IGFBP1) and, theoretically, also
decreased IGFBP1 synthesis locally in other tissues. Increased fasting levels of insulin in plasma are
also correlated with decreased levels of IGFBP2 in the blood, leading to increased levels of bioavailable
IGF-1. Insulin and IGF-1 signal through the insulin receptor (IR) and IGF-1 receptor (IGF1R) to stimulate
cellular proliferation and inhibit apoptosis in many tissue types. These effects could promote tumor
development. (Adapted from Calle EE, Kaaks R: Nat Rev Cancer 4[8]:579–591, 2004.)

related to breast cancer and colorectal cancer; however, it is known to from 20 to 250 cGy for low linear energy transfer (LET) radiation,
increase cell growth of human breast cancer cells in vitro.79 In addi- such as x-rays or γ-rays. Other data are derived from groups exposed
tion, although the risk is lower, breast carcinogenesis can be enhanced for medical reasons, underground miners exposed to radon gas, and
with relatively low daily amounts of alcohol.78 A meta-analysis showed workers exposed to high doses while in the nuclear weapons program
no consistent relationship between alcohol and cancers of the pan- of the former USSR. The atomic bomb exposures in Japan caused
creas, lung, prostate, or bladder.80 However, alcohol and pancreatic acute leukemias in adults and children and increased frequencies of
cancer studies have produced conflicting findings. Alcohol interacts thyroid and breast carcinomas. Lung, stomach, colon, esophageal, and
with smoke, increasing the risk of malignant tumors, possibly by acting urinary tract cancers and multiple myeloma have been added to the
as a solvent for the carcinogenic chemicals in smoke products. In indi- list. At Nagasaki and Hiroshima, leukemia incidence in individuals
viduals who have never smoked, substantial alcohol consumption (i.e., 15 years or younger reached its peak 6 to 7 years after the explosions
three or more drinks per day) has been associated with head and neck and has steadily declined since 1952. People 45 years and older at the
cancers.81 Inherited factors also put some individuals at increased risk time of exposure had a latent period of 20 years before developing
in DNA repair ability, carcinogen metabolism, and cell cycle ­control.82 acute leukemia.
Individuals having the genes encoding 32-ADH or the dominant nega- Recently, standard models and evaluations of age of exposure to
tive allele for ALDH2 are at reduced risk of alcoholism, despite being at radiation and radiation-induced cancer risks have been questioned.84-87
much higher risk for oropharyngeal cancer.83 Epidemiologic data from Japanese atomic bomb survivors and from
Mechanisms involved in alcohol-related carcinogenesis include the children exposed to radiation for medical intervention suggest that
effect of acetaldehyde, the first metabolite of ethanol oxidation; the excess relative risks (ERRs) for radiation-induced cancers at a given
induction of cytochrome P-450 2E1 (genetic variant CYP2E1), lead- age are exceptionally higher for individuals exposed during childhood
ing to the generation of reactive oxygen species (ROS); increased pro- than for those exposed at older ages.88 These data also are published
carcinogen activation (e.g., nitrosamines) and modulation of cellular by the International Commission on Radiological Protection (ICRP)
regeneration (cell cycle); and nutritional deficiencies (retinol, retinyl and the National Academy of Sciences Committee on the Biological
esters, folic acid, other vitamins). Nutritional deficiencies may predis- Effects of Ionizing Radiation (BEIR Committee).89 What is at question
pose to altered mucosal integrity, enzyme and metabolic dysfunction, is the ERRs of radiation exposure in adulthood and radiation-induced
and other structural abnormalities. The median age for diagnosis is the cancer risk. Recent analyses of Japanese bomb survivors suggest that
early 60s, with a male predominance, especially in laryngeal cancer.81 the ERR for cancer induction decreases with increasing age at exposure
only until exposure ages of 30 to 40 years; with radiation exposure at
Ionizing Radiation older ages, the ERR does not decrease further and for many individual
Much of the knowledge of the effects of ionizing radiation on human cancer sites (liver, colon, lung, stomach, and bladder) the EER may
cancer has stemmed from observations of the Hiroshima and Nagasaki actually increase in all solid cancers combined.85,87,88,90 These new data
atomic bomb exposures, particularly the Life Span Study. These data pre­sent a challenge to our conceptual understanding of the mecha-
provide the best estimate of human cancer risk over the dose range nisms of cancer induction.87 Biologic models of cancer development
268 CHAPTER 10  Cancer Epidemiology

All Categories S and EUS

Space
Internal (background)
(background) (5%)
(5%)
Terrestrial
(background)
(3%)

Radon and thoron

(background)
(37%)
Computed tomography
(medical) (24%)

Industrial (<0.1%)
Occupational (<0.1%)
Consumer (2%)
Nuclear medicine
(medical) (12%) Conventional radiography/
fluoroscopy (medical) (5%)
Interventional fluoroscopy
(medical) (7%)
FIGURE 10-7  Pie Chart Showing Sources of Exposure to Ionizing Radiation. Percent contribution
of various sources of exposure to the total collective effective dose (1,870,000 person-Sv) and the
total effective dose per individual in the U.S. population (6.2 mSv) for 2006. Percent values have been
rounded to the nearest 1%, except those <1%. Sv, Sievert. (From NCRP: 2009 Ionizing radiation expo-
sure of the population of the United States, NCRP Report no. 160. Bethesda, Maryland.)

all predict that ERRs should decrease continuously with increasing age 2009 the National Council on Radiation Protection and Measurements
of radiation exposure. Recent models, however, of radiation carcino- (NCRP)94 reported Americans were exposed to more than seven times
genesis show ionizing radiation acts not only as an initiator of prema- as much ionizing radiation from medical procedures as compared to
lignant cell clones but also as a promoter of preexisting premalignant the 1980s (Figure 10-8). The increased exposure is mostly because of
cell alterations.85,87,90 Promotion is used here to mean the process by the rapid increase in the use of CT imaging.95
which an initiated cell clonally expands. Therefore promotional pro- The risks of low-dose radiation are being debated among radio-
cesses from radiation can result in increasing excess lifetime cancer biologists, geneticists, physicists, and others because of the potential
risks with increasing age at exposure. From these new data investi- effect on the health of current and future generations.96 Limiting is
gators propose that radiation-induced cancer risks after exposure in that general findings on the health risks of low-dose radiation are made
middle age may be almost twice as high as previously estimated.87 by analyses of data on the risk of cancer alone.93 The expression of
Human exposure to ionizing radiation includes emissions from the radiation-induced damage depends not only on dose, fractionation,
environment (e.g., radon), x-rays, radioisotopes, and other radioac- and protraction but also on repair mechanisms, bystander effects,
tive sources (Figure 10-7). Health risks involve not only neoplastic dis- radioprotective substances such as antioxidants, and the mechanism
eases but also cardiovascular disease and stroke following high doses of radiation delivery.93
in therapeutic medicine and lower doses in A-bomb survivors (BEIR
VII).89,91 Late effects of radiation in A-bomb survivors show persis- Radiation-Induced Cancer
tent elevations of inflammatory markers (e.g., interleukin-6 [IL-6], Ionizing radiation (IR) is a mutagen and carcinogen and can penetrate
C-reactive protein [CRP], tumor necrosis factor-alpha [TNF-α]), cells and tissues and deposit energy in tissues at random in the form of
implying immunologic damage may be the cause of later cardiovascu- ionizations (e.g., excitation or removal of an electron from the target
lar effects.92 Other risks include somatic mutations that may contrib- atom). These ionizations can lead to irreversible or indirect damage
ute to other diseases (e.g., birth defects and eye maladies) and, from from formation and attack by water-based free radicals (radiolysis).96
animal studies, inherited mutations that may affect the incidence of IR affects many cell processes, including gene expression, disrup-
diseases in future generations (see Health Alert: Radiation and Vulner- tion of mitochondrial function, cell cycle arrest, and cell death. IR is
able Populations). Heritable mutations are of particular concern for a potent DNA damaging agent causing cross-linking, nucleotide base
women because the number of oocytes is presumably fixed at birth and damage, and single- and double-strand breaks (Figure 10-9).97 Dam-
mutations, if not repaired, are cumulative (see p. 272).93 An important age to DNA and disrupted cellular regulation processes can lead to
summary point in BEIR VII89 is the concern from high-dose medical carcinogenesis.97-99 The double-strand break (DSB) (see Figure 10-9)
exposure, for example, computed tomography (CT) scans (see Health is considered the characteristic lesion observed for the effects of IR.
Alert: Increasing Use of Computed Tomography Scans and Risks). In In certain experimental systems, a single DSB may lead to cell cycle
 CHAPTER 10  Cancer Epidemiology 269

2006

Early 1980s
Background (50%)

Background (83%)
Occupational / Occupational / industrial (0.1%)
industrial (0.3%)
Consumer (2%)
Consumer
Medical (2%)
(15%)
Medical (48%)

Early 1980s 2006

Collective effective dose
(person-Sv) 835,000 1,870,000
Effective dose per individual
in the U.S. population (mSv) 3.6 6.2
FIGURE 10-8  NCRP estimates that 67 million CT scans (compared to 3 million in 1980), 18 million
nuclear medicine procedures, and 17 million interventional fluoroscopy procedures, and 18 million
nuclear medicine procedures were performed in the U.S. in 2006. (From NCRP: 2009 Ionizing radiation
exposure of the population of the United States, NCRP Report no. 160. Bethesda, Md.)

HEALTH ALERT
Radiation and Vulnerable Populations: Pregnant Women, Embryos, Fetus, and Children
Protection of pregnant females against ionizing radiation is unique because of the Children have a number of vulnerabilities that place them at greater risk of
high fetal radiosensitivity during various gestational stages. The main adverse harm after radiation exposure. Because they have a relatively greater minute
effects to the embryo and fetus include malformations, mental retardation, ventilation compared with adults, children are likely to have greater exposure
induced cancer, hereditary effects, and death. These effects differ by absorbed to radioactive gases (e.g., those emitted from a nuclear power plant disaster).
dose, gestational period and exposure, and type of radiation. All of these con- Nuclear fallout quickly settles to the ground, resulting in a higher concentra-
cerns have demanded better radiation dosimetry (e.g., standards) for pregnant tion of radioactive material in the space where children most commonly live and
women. Although setting standards is extremely complex, models of pregnant breathe. Studies of airborne pollutants are needed to test the long-held belief
women have, until very recently, been based on the same methodology devel- that the short stature of children brings them into greater contact than adults
oped 40 years ago. These models were developed by the Oak Ridge National with fallout as it settles to earth. Radioactive iodine is transmitted to human
Laboratory (ORNL) for the Medical Internal Radiation Dose (MIRD) Committee of breast milk, contaminating this valuable source of nutrition to infants. Cow milk,
the Society of Nuclear Medicine. Today published data on fetal doses for external a staple in the diet of most children, can also be quickly contaminated if radioac-
neutron exposure are those by Chen and by Taranenko and Xu. The 2008 report by tive material settles onto grazing areas.
Taranenko and Xu noted that comparison with previously published data showed In utero exposure to radiation also has important clinical effects, depending
large deviations for the fetal doses at 50 keV. Previous data available of coef- on the dose and form of the radiation; transmission of radionuclides across the
ficients for photons were based on stylized models of simplified anatomy. To placenta may occur, depending on the agent.
improve these earlier models, a new set of models, called RPI-P series, represent Radiation-induced cancers occur more often in children than in adults
a pregnant female with the fetus at 3, 6, and 9 months’ gestation. The deviations exposed to the same dose. Finally, children also have mental health vulner-
in data points are attributed to the differences in anatomic models. abilities after any type of disaster, with a greater risk of long-term behavioral
In 2003 the American Academic of Pediatrics Committee on Environmental disturbances.
Health brought attention to the issue of radiation and children with the policy Radiation risks to infants and children per unit of exposure are far greater than
statement Radiation Disasters and Children. The following statements summa- they are to adults. In addition, a higher cancer risk is noted in females for most
rize the risks of radiation to children: cancers.

Data from American Academic of Pediatrics Committee on Environmental Health: Radiation disasters and children, Pediatrics 111(6 Pt 1):
1455–1466, 2003; Chen J: Health Phys 86:285–295, 2004; Chen J: Health Phys 90:223–231, 2006; Chen J: Radiat Prot Dosimetry 126(1–4):
567–671, 2007; International Commission on Radiological Protection: Ann ICRP 30(1):iii–viii, 1–43, 2000; International Commission on Radiological
Protection: Ann ICRP 31(1–3):19–515, 2001; International Commission on Radiological Protection: Ann ICRP 33(1–2):5–206, 2003; Suárez RC et al:
Radiat Prot Dosimetry 127(1–4):19–22, 2007; Taranenko V, Xu XG: Phys Med Biol 53:1425–1445, 2008.
270 CHAPTER 10  Cancer Epidemiology

HEALTH ALERT
Increasing Use of Computed Tomography Scans and Risks
A review article in the New England Journal of Medicine on computed tomog- MEDIAN EFFECTIVE RADIATION DOSE FOR EACH TYPE
raphy (CT) and radiation exposure has received much media attention. The arti- OF CT STUDY
cle was written by radiology researchers at Columbia University. In short, the
numbers of CT scans have greatly increased in the United States. This increase DOSE EQUIVALENT
has occurred both as a diagnostic treatment for individuals with symptoms and ANATOMIC AREA, MEDIAN RANGE (NO. OF CHEST
as a diagnostic modality for individuals without symptoms (heart, lung, colon, STUDY TYPE (mSv) (mSv) X-RAYS)
and whole-body screening). Faster scanning times are partly responsible for Head and Neck
increased CT use in pediatric populations. Typical doses are larger from CT scans Routine head 2 0.3-6 30
than a conventional examination (e.g., 50 times more radiation to stomach than Routine neck 4 0.7-9 55
an x-ray). Based on data correlations from Japanese survivors of atomic bombs, Suspected stroke 14 4-56 199
the authors estimated that 1.5% to 2.0% of cancers in the United States might
be attributable to CT radiation. The authors note that CT scans are sometimes Chest
ordered excessively and repeated unnecessarily because of defensive medicine. Chest, no contrast 8 2-24 117
They also include three ways to reduce radiation exposure from CT: (1) reduce Chest, with contrast 8 2-19 119
radiation doses in individual studies (i.e., use modern scanners), (2) substitute Suspected pulmonary 10 2-30 137
ultrasonography with magnetic resonance imaging (MRI) for CT when possible, embolus
and (3) order CT scans only when absolutely necessary. Coronary angiogram 22 7-39 309

Abdomen-Pelvis
CT scans in the United States Routine abdomen-pelvis, 15 3-43 220
no contrast
1980 3 million
Routine abdomen-pelvis, 16 4-45 234
with contrast
2006 67 million
Multiphase abdomen- 31 6-90 442
0 10 20 30 40 50 60 70 pelvis
NCRP estimates that 67 million CT scans (compared to 3 million Suspected aneurysm or 24 4-68 347
in 1980), 18 million nuclear medicine procedures, and 17 million dissection
interventional fluoroscopy procedures, and 18 million nuclear
medicine procedures were performed in the U.S. in 2006.

Data from Brenner DJ, Hall EJ: N Engl J Med 357:2277, 2007; Brett AS: J Watch 28(1):3, 2008.
Food and Drug Administration Public Health Notification: Reducing radiation risk from computed tomography for pediatric and small adult patients.

SSB
Single strand
break OH Double strand
RO2 break DSB

RO2
e- OH-
X-ray H
-ray H2O H+
O
H
H OH

FIGURE 10-9  Free Radicals. Free radicals formed by water nearby and around DNA cause indirect
effects. These effects have a short life of single free radicals. Oxygen can modify the reaction, enabling
longer lifetimes of oxidative free radicals.

arrest and possible further repair. Yet many DSBs appear to result can occur. Irradiated human cells unable to execute the NHEJ path-
from clustered damage, a consequence of the pattern of distribution way are supersensitive to the introduction of large-scale mutations and
of ionizations with DNA. These patterns of clustered damage may be chromosomal aberrations.96
more difficult to accurately repair.96 Importantly, DSBs are mostly A long-held assumption is that cellular alterations—mutations
repaired by the nonhomologous end joining (NHEJ) pathway. This and malignant transformation—occur only in cells directly radi-
pathway is efficient for joining the DNA broken ends; however, errors ated. It is now known that radiation may induce a type of genomic
 CHAPTER 10  Cancer Epidemiology 271

Mechanism of radiation-induced bystander effects

TNF
IL-1 Trail

IL-8

TGF3 H2O2
NF-kβ

H2O2

OH–
O2–

Nucleus
COX-2 promoter
Mitochondrial iNOS promoter
damage COX-2
iNOS PG-E2

O2 + NO

Inflammatory
ONOO
response
Gap ROS
ROS, cytokines
junctions
Bystander
response
Bystander signal
FIGURE 10-10  Bystander Response Mechanism. Inflammatory cytokines are strongly increased
after exposure to ionizing radiation or oxidants. Membrane-associated cytokines, such as tumor necro-
sis factor-alpha (TNFα), activate intracellular kinases (messengers), which release nuclear factor κβ
(NF-κβ). NF-κβ enters the nucleus and promotes transcription of cyclooxygenase-2 (COX-2) and induces
nitric oxide synthase (iNOS) genes, which stimulate production of nitric oxide (NO). Mitochondrial dam-
age promotes the production of hydrogen peroxide that easily crosses plasma membranes and is sub-
jected to antioxidant removal. Activation of COX-2 provides a continuous supply of reactive radicals and
cytokines propagating bystander signals through gap junctions or medium. H2O2, Hydrogen peroxide;
IL, interleukin; OH, hydroxyl radical; ONOO, peroxynitrite anion; PG-E2, prostaglandin E2; ROS, reactive
oxygen species; TGF, transforming growth factor; TNF, tumor necrosis factor; Trail, TNF-related apop-
tosis-inducing ligand. (Adapted from Hei-TK et al: Mechanism of radiation-induced bystander effects: a
unifying model, J Pharmacy Pharmacol 60:943–950, 2008.)

instability to the progeny of the directly irradiated cells over many the irradiated cells (the targeted cells) and unirradiated cells (the non-
generations of cell radiation, leading to an increased rate at which targeted or bystander cells). Such communication is thought to occur
the genetic effects (i.e., mutations/chromosomal aberrations) arise in from direct physical connection between cells or gap junctions, called
these distant progeny called transgeneration inheritance or effects (see gap junctional intercellular communication (GJIC, see p. 274). Other
p. 260). The directly irradiated cells also can lead to genetic effects in mechanisms, however, may be involved. The bystander and genomic
so-called bystander cells or innocent cells (called bystander effects) instability effects also have been termed “nontargeted” effects (see pp.
even though they themselves received no direct radiation exposure.96 271-274). Numerous intercellular and intracellular signaling pathways
For example, using an in vivo mouse model, investigators found that are implicated in the bystander response and these effects have been
localized radiation to the head led to induced bystander effects in shown to be transmitted to their descendants (Figure 10-10).
the lead-shielded distant spleen tissue.100 These radiosensitive mice Although most of the reports on the bystander effect have been
showed unexpected enhancement of medulloblastoma in their cerebel- detrimental in nature, protective effects also have been reported (e.g.,
lum. Both double-strand DNA breaks and apoptotic cell death were induction of terminal differentiation, apoptosis of potentially dam-
induced by bystander effects, supporting the role of signaling between aged cells).101,102 Overall, bystander effects include mutations, sister
272 CHAPTER 10  Cancer Epidemiology

chromatid exchanges, chromosomal aberrations, neoplastic transfor- radiation exposure) are not solely responsible for tumor development
mation, genomic instability, cell death, proliferation, and differentia- in normal human cells. Such mutations, however, provide a critical
tion. Although bystander and transgeneration IR effects are associated hit or induce genetic instability that makes cells more susceptible to
with induced genomic instability leading to chromosome aberrations, accumulation of genetic alterations caused by other spontaneous or
gene mutations, late cell death, and aneuploidy (an abnormal chro- induced mutations. The accumulation of mutations leads to full trans-
mosome number), all of these effects may be epigenetically mediated formation and cancer).96
(see p. 257). The epigenetic changes include DNA methylation, his- The majority of evidence on radiation-induced human cancer risk
tone modification, and RNA-associated silencing (see Figure 10-1 and is from epidemiologic studies of exposed populations. For example,
Chapter 9).100 an increase of total cancers after the Chernobyl radioactive fallout
Overall, the bystander effect raises questions about the validity of was reported in Sweden.105 Most direct data are available only at rela-
the linear no-threshold (LNT) model for estimating low-dose radiation tively high doses (greater than 0.1 Gy) from mainly low-LET radiation
risk because nonirradiated neighbor cells (not traversed by a charged (x- and γ-rays). Data, however, from cell-culture systems and in vivo
particle) are still affected by the transfer of biologic “stress” factors. In mouse studies are emerging for low-dose radiation. Radiation-induced
addition, previous findings that mutations in the nuclei of irradiated cancers include some leukemias and lymphomas, thyroid cancers,
hit cells can be induced by targeted cytoplasmic irradiation, which can some sarcomas, skin cancers, and some lung and breast carcinomas.
further result in a bystander effect, suggest that the radiation-sensitive Risk estimates for human exposure at low-dose, low-LET ionizing
target is more than just the nucleus. This larger target is sometimes radiation (0 to 100 mSv or less than 0.1 Gy) are constantly debated.
called abscopal, or effects found in other cells or tissue not directly Accurate measurements of risks from low doses of radiation are sta-
radiated. Therefore bystander effects coordinate a complex interplay tistically difficult because they require such large populations; thus
of radiation effects of organs, tissues, and cells.103 Much more research theoretic models are used to estimate response curves (Box 10-3). In
needs to be done with the bystander effect, including mechanistic- 1990 the Fifth Biological Effects of Ionizing Radiation Panel (BEIR V)
based studies and clinical studies. estimated that the risk of radiation was considerably higher than that
Radiation-induced cancer in humans seems to have long latent estimated by prior official studies.104 It supported the LNT relationship
periods—10 years for leukemia and more than 30 years for solid for solid cancers and included estimates of cancer risk. Recent data, on
tumors.104 This implies that radiation-induced gene mutations or the other hand, show that the LNT model underestimates the risk from
chromosomal alterations that can be detected early (within 24 hours of low-dose radiation.106 Yet, some laboratory studies in experimental

BOX 10-3 THEORETIC MODELS TO UNDERSTAND LOW-DOSE RADIATION

Several models include the linear no-threshold (LNT) relationship, in which any dose, including very low doses, has the potential to cause mutations (see A). Another
model, the linear-quadratic relationship, proposes there is a risk mathematical term that is directly proportional to the dose (linear term) and another term proportional
to the square of the dose (quadratic term) (see B). The threshold model proposes a threshold dose below which radiation may not cause cancer in humans (see C).
Proponents of this model argue that such thresholds are derived, for example, from the ability to repair damage caused by lower doses of radiation. There is some
evidence that low doses may actually produce a higher level of risk per unit of dose, which is called the supralinear hypothesis (see D). Currently, the shape of the
response curve for the low-dose region is really unknown.

Risk Risk Risk Risk

0 0 0 0
0 0 0 0
A. Linear no-threshold B. Linear-quadratic C. Threshold model D. Supralinear model
model dose-response model
Theoretic Models for Estimating Risk of Low-Dose Ionizing Radiation. Collective population dose is expressed as a person-rem (roentgen equiva-
lent, man). Estimating a collective dose then enables an application of a “constant risk factor” to obtain a statistical estimate of the number of additional cancers (above
background radiation) resulting from that exposure. These computations apply to low doses—low-dose rates only (A). Many propose the best fit is the linear no-thresh-
old (LNT) model (B). The most common alternative to the LNT model is the linear-quadratic model. The quadratic term is the square of the dose. The linear term is equal to
zero (C). The threshold model is a threshold below which there is no increase in cancer risk. Proponents of this model argue that because some toxic chemicals/materials
exhibit such thresholds, radiation must also have a threshold. Their arguments are related to repair of the radiation damage caused by lower doses of radiation (D).
Some evidence exists that low levels of radiation produce a higher level of risk per unit dose, which is called the supralinear model. (From Makhijani A, Smith B, Thorne
MC: Science for the vulnerable: setting radiation and multiple exposure environmental health standards to protect those at most risk, Takoma Park, Md, 2006, IEER.)

Data from Hoel DG: Ionizing radiation and cardiovascular disease, Ann N Y Acad Sci 1076:309–317, 2006; Preston DL et al: Studies of mortality of
atomic bomb survivors. Report 13: solid cancer and noncancer disease mortality: 1950–1997, Radiat Res 160:381–407, 2003.
 CHAPTER 10  Cancer Epidemiology 273

TABLE 10-7 CANCER INCIDENCE AND FATALITY (BEIR VII) ESTIMATES OF LOW-LEVEL

RADIATION PER GENDER*
SOLID CANCERS LEUKEMIA ALL CANCERS
MALES FEMALES MALES FEMALES MALES FEMALES
Incidence 800 (400-1600)† 1300 (690-2500) 100 (30-300) 70 (20-250) 900 1370
Fatal cancers only 410 (200-830) 610 (300-1200) 70 (20-220) 50 (10-90) 480 660

*Estimated number of cancer cases and deaths expected to occur in 100,000 persons.
†Estimates correspond to 95% confidence interval in parentheses.

systems, not epidemiological data, indicate that extrapolation from

high dose or dose rate down to very low doses and dose-rates may Radiation
overestimate the cancer risks at low doses.106a
BEIR VII estimates of cancer risk from low-level radiation are dif-
ferent from those of BEIR V and are included in Table 10-7. The risk
to women is now estimated to be considerably higher.107 BEIR VII also
provides estimates of risk of cancer incidence and fatal cancer risk as
well as estimates of cancer risk by age.

Carcinogenesis: Genomic Instability

Genomic instability is an increased tendency of the genome to acquire
mutations when various processes involved in maintaining and repli-
cating the genome are dysfunctional. Chromosome instability (CIN) A
is the inability to maintain a correct chromosome complement after
cell division.108 Biologic consequences of exposure to ionizing radia- Radiation
tion include cell death, gene mutations, and chromosome aberrations.
Conventional dogma attributes these effects to alterations resulting
from the deposition of energy to the DNA of an irradiated cell. Even-
tually the cell is presumed repaired by DNA enzymatic mechanisms
that also can occur during DNA replication. It was widely accepted that
most of these changes took place immediately after exposure. Thus if
the damage was faithfully repaired, the descendants of an irradiated
cell would be normal (Figure 10-11, A). If misrepaired, however, the
descendants would be expected to pass on radiation-induced genetic
change and all cells derived from such a cell would have the identical
genetic alteration; in other words, the effect would be clonal ­(Figure B
10-11, B). Yet many in  vitro studies have demonstrated nonclonal
chromosome aberrations and mutations in the clonal progeny of irra- Radiation
diated cells.109 Furthermore, it has been known for many years that
radiation-induced cellular alterations (cytotoxicity), identified as a loss
of reproductive potential, might be delayed for several generations of
cell replication, with death occurring randomly among the progeny
cells.109
Gene
Now it is known that the progeny of irradiated cells can exhibit mutation
an increased death rate and a loss of reproductive potential that con-
tinue for several generations—perhaps indefinitely. This delayed cell
death phenotype is known as “lethal mutation” and “delayed repro- Cell death Micronucleus
ductive death.” As introduced earlier, various genetic alterations are
demonstrated in cells that are not themselves irradiated, but in so-
Chromosome Mitotic failure
called innocent cells (i.e., bystander effects); (see p. 271) and are con- aberration
C aneuploidy
sidered manifestations of a radiation-induced genomic instability (see
following and Figure 10-11, C). This instability is similar to inherited FIGURE 10-11  Models of the Responses of Clonogenic Cells to
chromosome instability syndromes with spontaneously high levels of Ionizing Radiation. Mutations and/or chromosomal aberrations are
shown as filled circles and apparently normal cells as open circles.
chromosomal alterations and mutations.110 Why is radiation-induced
A, If a cell faithfully repairs DNA damage, then its clonal descen-
genomic instability relevant to low-dose exposure? Little and Lau- dants will appear normal. B, If a cell is directly mutated by radia-
riston111 provide a hypothetical model for multistep carcinogenesis tion, then all of its descendants will express the same mutation.
incorporating radiation-induced genomic instability (RIGI). As part C, Radiation-induced genomic instability is characterized by non-
of this model, it is proposed that a number of mutations in individual clonal effects in descendant cells. (From Lorimore SA, Coates PJ,
genes must accumulate in a given group of cells to develop into an Wright EG: Oncogene 22[45]:7058–7069, 2003.)
274 CHAPTER 10  Cancer Epidemiology

invasive tumor. Thus hypothetically, radiation might act at an initial ultraviolet B [UVB]) and the depth of penetration. UV radiation is
stage of carcinogenesis but could act at any time in later stages after known to cause specific gene mutations; for example, squamous cell
one or more initiating mutations have occurred.111 (A discussion of carcinoma involves mutation in the TP53 gene, basal cell carcinoma
new models incorporating initiation and promotion can be found in the patched gene, and melanoma in the p16 gene.116 In addition, UV
on p. 267.) Radiation may induce or increase genomic instability by light induces the release of TNF-α in the epidermis, which may reduce
facilitating new mutations in later generations. This effect may also be immune surveillance against skin cancer.117
mediated by a nontargeted bystander mechanism. Skin exposure to UVR and ionizing radiation, as well as chemi-
Induction of genetic changes in bystander cells, as well as those cal (xenobiotic) agents/drugs, produces ROS in large quantities that
directly radiated, could lead to a “hyperlinearity” response; that is, a can overwhelm tissue antioxidants and other oxygen-degrading path-
disproportionately higher level of risk per unit dose, also called the ways.118 Uncontrolled release of ROS is an important contributor to
supralinear model of the dose-response curve, for low doses (see Box skin carcinogenesis.118 Imbalances in ROS and antioxidants can lead to
10-3) occurs when only a small number of the cells are irradiated.111 oxidative stress, tissue injury, and direct DNA damage (Figure 10-12).
Direct evidence of the dose-response relationship of a supralinear ROS can induce a number of transcription factors (e.g., activator pro-
model was found with an increase in double-strand breaks (DSBs) (see tein-1 [AP-1] and NF-κβ)119 and increase regulating genes that induce
Figure 10-9) in the dose range of 1.2 to 5 mGy and was largely from inflammation.118,120 Inflammation is a critical component of tumor
bystander effects.112 In addition, Little and Lauriston111 speculate that progression.
individuals with a decreased ability to repair their DNA might be more Healthy genes are needed to coordinate the levels of antioxidants
susceptible to bystander effects. and decrease harmful ROS. Antioxidants decrease ROS and oxidative
The genome is constantly challenged by destabilizing factors, stress and other protective mechanisms including DNA repair and
including normal DNA replication and cell division; intracellular and apoptosis (see Figure 10-12). The genetic alterations in proto-onco-
extracellular environmental stresses, such as oxidative metabolism; genes and tumor-suppressor genes may make epidermal cells resistant
exposure to genotoxic chemical agents; and background radiation. to signals for terminal differentiation.120 With oxidative stress, DNA
Cells have complex mechanisms for trying to maintain genomic sta- damage occurs and calcium-dependent enzymes (endonucleases) are
bility. These processes include proofreading of DNA replication, enzy- activated that produce DNA strand breaks.120 In addition, ROS are
matic repair of DNA damage, and implementation of checkpoints to involved in the activation of procarcinogens, such as polycyclic aro-
monitor progression through the cell cycle. Failure of any of these pro- matic hydrocarbons including 7,12-dimethylbenzene[a]anthracene
cesses can result in destabilization of the genome, deleterious muta- (DMBA). The pathophysiology of skin carcinogenesis is discussed fur-
tions, and alterations in cell proliferation. ther in Chapter 39.
Although similar to alterations to the chromosome instability syn- Basal cell carcinoma commonly occurs on the head and neck. Indi-
dromes, the radiation-induced genomic instability seems to reflect viduals with these tumors generally have light complexions, light eyes,
epigenetic phenomena rather than mutation of genome genes.97 and fair hair. They tend to sunburn rather than tan and live in areas of
Experiments have shown that irradiation can induce growth factors high sunlight exposure. Usually these cancers arise on areas of the body
and extracellular matrix (microenvironment) remodeling. A major that receive the greatest sun exposure, although they are not necessarily
function of the microenvironment is to control cell differentiation and restricted to these skin sites. Squamous cell carcinoma is found more
proliferation, and its disruption is required for the establishment of commonly in men who work outdoors. These tumors are distributed
cancer.113 over the head, neck, and exposed areas of the upper extremities (see
Gap junction intercellular communication. Confluent cell cultures Chapter 39).
respond as an integrated whole rather than as separate individual cells The incidence of melanoma has been increasing annually at rates
that have been irradiated, indicating a critical role for cell-to-cell com- of 2% to 7% for white populations;121 because mortality rates have not
munication in mediating the bystander effect. This mediation could be risen as rapidly, however, controversy exists as to whether the inci-
controlled by gap junctions (see Figure 1-9). Gap junctions consist of a dence increase is a true increase in clinically significant melanoma
cell-to-cell channel spanning two plasma membranes; they result from or is a result of overdiagnosis.122 Sun exposure and the risk of mela-
the bridging of two half channels, or connexons, contributed separately noma, a malignant pigmented mole, remain complex. Melanomas can
by each of the two participating cells.114 Exposure of cells to low levels of appear suddenly without warning and can arise from or near a mole
radiation (≤0.16 cGy) has been shown to induce the expression of con- (melanocytic nevus). When detected in the early stages, melanoma is
nexin 43, suggesting that oxidizing mediators increase the expression of highly curable.123 About 20% of melanomas, however, are diagnosed
proteins involved in gap junction intercellular communication (GJIC).115 at nonlocalized and advanced stages.123 According to Sekulic and col-
In conclusion, some data support a role for oxidative stress and leagues,124 the failure of current diagnostic methods to accurately pre-
GJIC in the radiation-induced bystander effects, and studies of the dict individual risk of disease progression and outcome challenges the
molecular mechanisms underlying bystander cells should increase our ability to diagnose melanoma in early stages. Recent progress in under-
understanding of the overall risk of ionizing radiation. standing the molecular alterations in melanoma will likely advance its
diagnosis, prognosis, and treatment.
Ultraviolet Radiation The pathogenesis of melanoma is very complex, involving genetic
Ultraviolet sunlight causes basal cell carcinoma and squamous cell car- and environmental factors. The genetic factors can be inherited, for
cinoma (i.e., photocarcinogenesis), two common skin cancers found example, in high-susceptibility genes (i.e., cyclin-dependent kinase
in white individuals. Exposure to ultraviolet radiation (UVR) can ema- inhibitor 2A [CDKN2A]) or in low-susceptibility genes (i.e., melano-
nate from natural and artificial sources; however, the principal source cortin-1). The emerging molecular changes associated with melanoma
of exposure for most people is sunlight. With further depletion of the emphasize that melanoma, like many other cancers, is not a single dis-
stratospheric ozone layer, people and the environment will be exposed ease but a diverse group of disorders. Thus, understanding aberrant
to higher intensities of UVR. The degree of damage in skin depends molecular alterations involved in important cellular processes, such as
on the intensity and wavelength content (i.e., ultraviolet A [UVA] or signaling networks, cell cycle regulation, and cell death (e.g., apoptosis,
 CHAPTER 10  Cancer Epidemiology 275

UVR Xenobiotics
(DMBA, phorbol esters, etc)
UVB UVA mutate proto-oncogenes

Inflammation
ROS Anti-inflammatories
(e.g., aspirin)

Direct Oxidative Protein oxidation

DNA damage Stress Lipid peroxidation

Apoptosis
(TP53, Bcl-2, Antioxidants
DNA others)
repair
Multistep carcinogenesis
FIGURE 10-12  Theoretic Scheme of Multistep Skin Carcinogenesis. Ultraviolet radiation (UVR), inflam-
mation, and xenobiotics (see p. 262) lead to oxidative stress, resulting in direct DNA damage, protein
oxidation, lipid peroxidation, and apoptosis. The protective mechanisms shown in red include apoptosis,
DNA repair, and antioxidants. DMBA, Dimethylbenz[a]anthracene; ROS, reactive oxygen species; UVA,
ultraviolet A; UVB, ultraviolet B. (Adapted from Sander CD et al: Intl J Dermatol 43[5]:326–340, 2004.)

autophagy), is essential for diagnosis and treatment. Epidemiologic to show that UVB light and an exogenous carcinogen could result in
and case-control studies suggest that UVR exposure is the most sig- a new malignant melanoma, newborn human foreskin (xenograft)
nificant factor for the development of melanoma. Other evidence, was grafted onto immunodeficient mice.130 Melanocytic hyperplasia
however, reports rates of melanoma are uncommon in persons with occurred in 73% of UVB-treated xenografts. One graft treated with
outdoor occupations. An extensive review from the Nordic countries DMBA (chemical carcinogen) and UVB light developed a human
on occupation and cancer showed melanoma steadily increasing until malignant melanoma.
the early 1990s in both men and women. After that, there was a plateau A similar study using UVB light and overexpression of an endog-
in Norway and Finland but a rapid increase in Iceland.7 The highest enous growth factor, basic fibroblast growth factor (bFGF), also
rates of melanoma in men were observed among dentists, physicians, induced human melanoma.131 Numerous local factors may result in
administrators, journalists, religious workers, and teachers. The high- increased cytokine production, including trauma, infection, diet, obe-
est rates among women were dentists followed by public safety work- sity, hormones, and other causes of inflammation. Sunburn reflects
ers, teachers, physicians, and other non-nurse healthcare workers. an overdose of UV light, triggering inflammation with an increase in
These occupations are all primarily indoor jobs. Dentists are exposed cytokine production.
to lamps that emit no UVB but do emit low levels of UVA.7 A recent In 2002 Davies and colleagues132 stunned the field of melanoma
analysis in Iceland suggests sunbed use as the reason for increased research when they detected an activating point mutation in the B-
melanoma, especially in women.125 Indoor tanning (sunbed use) is raf (BRAF) proto-oncogene (i.e., somatic, not germline, mutation)
a risk factor for melanoma126 (i.e., frequent indoor tanning increases in 60% to 70% of malignant melanomas. This mutation results in a
melanoma risk). Certain skin conditions also are treated with UVA marked increase in BRAF kinase activity, leading to activation of the
and UVB light therapy. mitogen-activated protein kinase (MAPK) pathway. This BRAF muta-
Although nonmelanoma skin cancers are related to cumulative tion and others have been linked to sun exposure.133 The development
exposure to UV radiation, melanoma is related to episodes of intense, of melanoma is associated with the loss of E-­cadherin and the appear-
intermittent exposure (measured as history of sunburn).127 Melano- ance of N-cadherin adhesion molecules. Cadherins are cell-surface
mas more commonly occur in body areas less continually exposed glycoproteins that promote calcium-dependent cell-to-cell adhesion.
to sunlight, such as the trunks in men and the backs of the legs in The major adhesion molecule between keratinocytes and normal mela-
women. Family history (i.e., genetic factors), skin type, and the density nocytes is E-cadherin, which disappears during melanoma progres-
of moles are important in determining the risk of developing mela- sion,134 and thus allows the melanoma cells to survive as they migrate
noma. For example, the incidence of melanoma in white populations through the dermis.135 (For further discussion, see Chapter 39.)
is 10 times greater than that in black, Asian, or Hispanic populations Alterations in apoptotic signaling may be important in melanoma cell
residing in the same area.128 Most importantly, the risk of melanoma survival.
from sunlight is certainly modified by risk factors.128 Traits associated Sunscreens protect against sunburn but individuals use sunscreen
with a high risk of melanoma are light-colored hair, eyes, and skin; to stay in the sun for longer periods. Consequently, individuals can be
an inability to tan; and a tendency to freckle, sunburn, and develop exposed to high doses of sunlight that are intermittent or sporadic.136
nevi.129 Intermittent exposure is the strongest solar risk factor for the develop-
Until 1998 a direct causal relationship between UVB light and mel- ment of melanoma. More data are needed to understand if sunscreen
anoma in humans had not been established. In the first experiment prevents melanoma.
276 CHAPTER 10  Cancer Epidemiology

Increased knowledge of the intricate cellular interactions in mela- to induce certain skin abnormalities and is a positive factor in the
noma will increase our understanding of melanoma etiology and development of melanoma.146,147 Yet another recent study denied an
pathogenesis. This knowledge is essential for early detection and association between EMR exposure and female breast cancer.148 A
treatment. recent population-based study (N = 5400 women), however, linked
residential EMR exposure from high-voltage power lines to a 60%
Electromagnetic Radiation increased risk of breast cancer in Norwegian women of all ages.149
Health risks associated with electromagnetic radiation (EMR) are very The controversy about potential health hazards associated with
controversial. Exposure to electric and magnetic fields is widespread. the exposure to EMFs has been stimulated by the increased use of
EMRs are a type of nonionizing, low-frequency radiation without mobile telecommunication devices and the increased emissions from
enough energy to pull electrons from their orbits around atoms and cell towers. Cell phones emit electromagnetic radiation in the range
ionize (charge) the atoms. Microwaves, radar, mobile and cell phones, of 800 to 2000 MHz, which is in the microwave range (300 MHz to
mobile phone base stations, power frequency radiation associated with 300 GHz). The output power of the phone is usually set to the highest
electricity and radio waves, fluorescent lights, computers, and other level between network base stations as a user moves from one location
electric equipment create EMRs of varying strength. Despite the breadth to another or when signal interference is greatest. In rural areas, base
of literature on microwaves (MW) the impact of EMR on human health station power output is much higher because of the great distances
has not been fully assessed. Scientific evidence is accumulating although requiring coverage between sparsely distributed base stations. Cell
hampered by the scarcity of methods to accurately measure exposure, the phones in rural areas are often kept at their maximal power output
lack of a clear dose-response relationship, and the difficulty in reproduc- during use to maintain better communication.150
ing effects. In addition, with competing priorities such as convenience, EMR from a cell phone can penetrate the skull and deposit energy
financial interest, and health necessity, a consensus of the risk/benefit 4 to 6 cm into the brain (Figure 10-13).151 This energy can result in
ratio of EMR exposure may be difficult to achieve and safety standards thermal heating of the tissue. The debate therefore has been whether
significantly vary, up to a 1000 times among countries.137,137a In 1998 these thermal effects could induce carcinogenesis. One thermal mech-
the National Institute of Environmental Health Sciences Electric and anism proposed is a change in protein phosphorylation.152,153 A lin-
Magnetic Fields Working Group138 recommended that low-frequency ear increase in chromosome 17 aneuploidy was demonstrated from
electromagnetic fields (EMFs) be classified as possible carcinogens. exposure of human peripheral blood lymphocytes to EMR associated
A United Kingdom Childhood Cancer Study published in 1999 and with cell phones.154 Control experiments (without EMR) involving
updated in 2000139,140 did not support a link between EMR exposure temperature changes from 24.5° to 38.5° C (76° to 101.3° F) showed
and childhood cancer. A pooled analysis from Europe showed no risk that elevated temperature is not associated with genetic or epigene-
of childhood cancers with average exposures (less than 0.1 microtesla) tic alterations. Thus these findings indicated a genotoxic effect of the
and no increased risk at intermediate exposures; however, the high- EMRs is not elicited by a thermal pathway.154 There are four lines of
est average exposures (>0.3 microtesla in American studies or >0.4 evidence for the non-thermal MW effects: (1) altered cellular responses
microtesla in European studies) showed increased risk affecting a few in laboratory in vitro studies and results of chronic exposures in vivo
children (1.4%) with a significant relative risk of 2.141 In response to studies; (2) results of medical application of non-thermal MW in the
public concern, the WHO requested further studies in high-exposure former Soviet Union countries; (3) hypersensitivity to electromagnetic
areas such as Japan. A case-control study from Japan (N = 312 chil- fields (EMF); (4) epidemiological studies suggesting increased cancer
dren) found acute lymphocytic leukemia (ALL) cases in the highest risks for mobile phone users.137a Increasing evidence indicates that the
exposure category (>0.4 microtesla).142,143 Another case-control study mechanism of harm from EMR is induction of cell stress and damage
reported a link between childhood leukemia and prenatal proximity to of intracellular components (e.g., free radical formation and altered
high-voltage power lines.144 protein conformation).155 Adverse EMR has been reported to affect
Sweden has officially categorized electrohypersensitivity as a func- DNA synthesis, alter cell division, and change the electric charge of
tional impairment.145 Their data show adverse EMR has the potential ions and the structures of molecules within cells.156,157 Interference

BRAIN SCAN BOTH CELL PHONES OFF RIGHT CELL PHONE ON

Left

Area
of scan

Phone Right

Rate of brain glucose metabolism Low High

Source: JAMA Note: Images are from a single participant THE NEW YORK TIMES; IMAGES BY JAMA
FIGURE 10-13  Electromagnetic radiation from a cell phone can penetrate the skull. EMR from
a cell phone can penetrate the skull and deposit energy 4 to 6 cm into the brain.132 50-minute cell
phone exposure was associated with increased brain glucose metabolism in the region closest to the
antenna. This finding is of unknown clinical significance. (From Volkow ND et al: Effects of cell phone
radiofrequency signal exposure on brain glucose metabolism, JAMA 305(8):808–813, 2011.)
 CHAPTER 10  Cancer Epidemiology 277

with cellular electric charges may modify ionic structures, disturbing to 5% each).176,177 HPV types correlated with genital warts, HPV-6
movement of ions across the membrane, including calcium ions.134,158 and HPV-11, are called low risk because they are rarely associated
Some case-control studies159 suggest a harmful association between with cancer.177 HPV-16 is directly mutagenic by inducing the viral
the use of mobile phones and the risk of tumors (risk is highest on genes E6 and E7 (sometimes called oncoproteins). Persistence of
the same side of the head that the phone is used). Some meta-analyses infection with high-risk HPV is a prerequisite for the development
of mobile phone use and malignant brain tumors showed no asso- of cervical intraepithelial neoplasia (CIN) (see Figure 32-13) lesions
ciation or a slight increased risk.160-162 The recent meta-analysis159 of and invasive cervical cancers.176 Biologic factors that determine per-
low-biased case-control studies included both malignant and benign sistence are not understood; controversial risk factors include long-
conditions. Based on evidence from this study, the investigators report term use of oral contraceptives and smoking.178 Newer risk factors
an increased risk of tumors for mobile phone use of 10 years or longer being studied include drug addiction and reproductive factors (i.e.,
(i.e., gliomas and acoustic neuromas). These investigators also assessed age at menarche and menopause). In fact, it has been shown that a
the methodologic rigor and bias of previous studies. Unfortunately, second peak of high-risk HPV prevalence occurs in postmenopausal
they found poor quality and bias to have been prevalent in some (not women.178 Smoking has been implicated in acquiring high-risk HPV
all) previous studies. Relevant epidemiologic studies relating long- (HR-HPV) but not as an independent risk factor for high-grade
term cell phone use (>10 years) to central nervous system tumors are CIN.179 Earlier reported risk factors, for example, number of sex-
appearing.163-166 These data show an increased risk of acoustic neu- ual partners, are probably indicators of HPV exposure rather than
roma, glioma, and parotid gland tumors. Other studies have reported independent risk factors. HPV can be transmitted by genital contact
decreased human sperm motility and changes in sperm structure after (oral, touching, or sexual intercourse); therefore, condoms are not
exposure to cell phone radiation,167 changes in sperm motility in rats necessarily protective (see Chapter 32). The Health Alert contains
exposed to cell phone radiation,168 and a relationship between cell information on the rising incidence of HPV-associated oropharyn-
phone use and semen quality and fertility in men.169-171 geal cancers.
There are no studies of adults who have used cell phones as chil-
dren or adolescents. Concern is for children in whom the effects may
be compounded because of increased vulnerability to radiation and
their longer use of cell phones into adulthood. A recent review of 10 HEALTH ALERT
epidemiologic studies showed that 8 studies reported an increased Rising Incidence of HPV-Associated
prevalence of adverse neurobehavioral symptoms or cancer in popula- Oropharyngeal Cancers
tions living at distances <500 meters from base stations.172 None of
these studies reported exposure above accepted international guide- The incidence of head and neck cancers has fallen with a decrease in smok-
lines. Ongoing unbiased research is desperately needed. A prospective ing in the United States; however, the incidence of HPV-associated oropha-
cohort study is needed to reduce recall and selection biases. Absolute ryngeal cancers (tonsil and tongue base) appears to be rising—especially in
proof of causation may be hindered because of the ethical questions of young white men. The two classes of oropharyngeal squamous cell carcinoma
exposing individuals to potentially harmful interventions.135 seem to have different causes: HPV-positive oral cancers are possibly associ-
ated with sex-related risk factors whereas HPV-negative cancers are associ-
ated with tobacco and alcohol consumption. Epidemiologic studies support
4 QUICK CHECK 10-3 little interaction between the two sets of risk factors, suggesting that HPV-
positive cancer and HPV-negative cancer have distinct pathogenesis. Tobacco
1. What are the cancers associated with cigarette smoking?
2. How are dietary components related to cancer? use and alcohol use are known etiologic factors in head and neck cancers; it
3. What are the possible pathophysiologic mechanisms of obesity-associated is surprising that most cases of oropharyngeal cancers in non-smokers are
cancer risk? HPV-related. Not yet known is whether this increase is attributed to changes
4. How does ionizing radiation contribute to carcinogenesis? in sexual norms (from past generations), with more oral sex partners or oral
5. Discuss the difficulty in determining cancer risks with electromagnetic sex at an earlier age. Smoking, however, has an adverse effect on both HPV-
radiation. positive and HPV-negative oral cancers. In Sweden the incidence of oropha-
ryngeal cancers caused by HPV increased from 23% in the 1970s to 57% in
the 1990s to 93% in 2007. Emerging data indicate that HPV is now the pri-
Sexual and Reproductive Behavior: mary cause of tonsillar cancer in North America and Europe. The mechanism
Human Papillomaviruses of HPV-oropharyngeal cancer is different than that related to tobacco use:
The past decade has demonstrated that sexually transmitted infection P53 degradation occurs (i.e., P53 helps direct genetic repair and cell death
with carcinogenic types of human papillomavirus (HPV), referred [see Chapter 9]), the retinoblastoma RB pathway is inactivated (cell signal-
to as high-risk types of HPV, is required for the development of most ing pathway), and the risk of HPV-16 (i.e., P16) is increased. Tobacco-related
cervical cancers. HPV can cause other cancers, including vagina, oropharyngeal cancers are characterized by TP53 mutation and a decrease
vulva, penis, and anus, and is a newly identified causal factor for in the CDKN2A mutation (cell cycle gene), and thus a decrease in P16. Indi-
squamous cell carcinoma of the head and neck (SCCHN).81,173 HPV viduals with P16-positive tumors have a better prognosis than those with
infections, however, are very common in sexually active women, and P16-negative tumors.
the majority of these infections will resolve or only cause transient,
Data from Lowy DR, Munger K: Prognostic implications of HPV in
minor problems.174 There are more than 100 subtypes of HPV and
oropharyngeal cancer, N Engl J Med 363(1):82–84, 2010; Marur S et al:
the virus is found in 99.7% of women with cervical cancer.175 Of the HPV-associated head and neck cancer: a virus-related cancer epidemic,
100 subtypes of HPV, 30 infect the female and male genital tracts Lancet Oncol, 2010 May 6 [Epub ahead of print]; Nasman A et al:
and two thirds of these are classified as high-risk types. HPV-16, in Incidence of human papillomavirus (HPV) positive tonsillar carcinoma
most countries, accounts for 50% to 60% of cervical cancer cases, in Stockholm Sweden: an epidemic of viral-induced carcinoma? Int J
followed by HPV-18 (10% to 12%) and HPV-31 and HPV-45 (4% Cancer 125:362–366, 2009.
278 CHAPTER 10  Cancer Epidemiology

Head and neck cancers are the sixth most common cancer world- of 60 minutes per day of moderate to vigorous physical activity for
wide with an annual incidence of about 563,826 and 310,408 deaths.173 decreasing weight, BMI, and percent of body fat and intra-abdominal
About 500,000 new cases of cervical cancer are diagnosed each year fat.191
worldwide—the majority in developing countries, mainly Latin
America, the Caribbean, sub-Saharan Africa, and Southeast Asia. Chemicals and Occupational Hazards as Carcinogens
About 80% of these cases affect women between the ages of 15 and An estimated 80,000 synthetic chemicals are used in the United States.
45 years.175 Although HPV is the most prevalent sexually transmitted Of those, only about 7% have been tested for their health effects.192 It
infection in the United States, less than one third of women and men is disturbing that another 1000 chemicals are added each year. Expo-
in the general population have heard of it, and awareness is low among sure to chemicals occurs every day—they are present in air, soil, food,
women in high school and college settings.180 Cervical cancer mortality water, household products, toys, personal care products, workplaces,
has decreased over the past five decades in the United States by more and homes. Table 10-1 (pp. 254-256) provides a summary of chemi-
than 70%, probably attributable to screening with the Papanicolaou cals according to strong and suspected links to various types of cancer.
(Pap) test. HPV vaccination programs have made it possible to elimi- Box 10-4 identifies known occupational carcinogenic agents classified
nate most invasive cervical cancers worldwide (see Chapter 32).180 The by the International Agency for Research on Cancer (IARC), and Box
World Health Organization (WHO) recommends the vaccine be given 10-5 identifies probable occupational carcinogenic agents classified by
to girls between the ages of 9 and 13 years before their first coitus. U.S. the IARC. A substantial percentage of cancers of the upper respiratory
Food and Drug Administration (FDA) did approve the use of the first passages, lung, bladder, and peritoneum are attributed to occupational
HPV vaccine (marketed as Gardasil®) for boys or men age 9 through factors; however, fewer studies of nonsmokers exist.193 One notable
26 for the prevention of genital warts caused by human papillomavi- occupational factor is asbestos, which increases the risk of mesothe-
rus (HPV) types 6 and 11. HPV may be transmitted by genital con- lioma and lung cancer and possibly others. Asbestos was used in homes
tact (oral, touching, or sexual intercourse); therefore condoms are not and buildings built before the 1970s to insulate ceiling tiles, flooring,
necessarily protective. The incidence of oropharyngeal cancers caused and pipe covers. In Western Europe, the epidemic of mesothelioma in
by HPV is increasing worldwide. Human immunodeficiency virus building workers and other workers born after 1940 did not become
(HIV)–infected individuals have demonstrated an increase in oral and apparent until the 1990s because of long latency. No exposure to asbes-
anogenital pathologic conditions because of HPV infection.181 Con- tos is without risk and a large number of countries still use, export, and
sensus is that newborn babies can be exposed to cervical HPV infec- import asbestos-containing products (see Table 10-1).
tion of the mother. The possible modes of transmission in children, The central hypothesis, based on rat studies, for the mechanisms
however, are controversial.182 related to particle-induced lung carcinogenesis is that insoluble par-
ticles cause pulmonary inflammation (e.g., cytokine release, ROS),
Other Viruses and Microorganisms which leads to genotoxic stress, proliferative response, and tissue
A discussion of the relationship between viruses, bacteria, and cancer remodeling progressing toward fibrosis and tumor development.
is contained in Chapter 9. Other microorganisms involved in carcino- Additional research is needed to understand the surface chemistry and
genesis include parasites such as Opisthorchis viverrini and Schistosoma lung tissue remodeling in relation to insoluble particles, lung carcino-
haematobium. Their specific roles in carcinogenesis are thought to be genesis, and other respiratory problems.194
related to cofactors or carcinogens, or both. Carcinoma of the bladder has been linked with the manufacture of
dyes, rubber, paint, and aromatic amines, especially β-naphthylamine
Physical Activity and benzidine. Benzol inhalation is linked to leukemia in shoemakers
Physical activity reduces the risk of breast and colon cancers and may and in workers in the rubber cement, explosives, and dyeing indus-
reduce the risk of other cancers. Several biologic mechanisms causing tries. Other notable occupational hazards include heavy metals (e.g.,
this effect have been proposed and include decreasing insulin and IGF high-nickel alloy, chromium VI compounds, inorganic arsenic), silica,
levels; decreasing obesity; increasing free radical scavenger systems; polycyclic aromatic hydrocarbons, sulfuric acid, and chloromethyl
altering inflammatory mediators; decreasing levels of circulating sex ether. Studies of occupational exposure to diesel exhaust indicate
hormones and metabolic hormones; improving immune function; an increased risk of lung cancer.195 Other important exposures are
enhancing cytochrome P-450, thus modifying carcinogen activation; included in Table 10-1. Disentangling data related to lung cancer, air
and increasing gut motility.182-186 For colon cancer, physical activity pollution, and occupational risks is complex, especially in combina-
increases gut motility, which reduces the length of time (transit time) tion with active and passive smoking and the interplay of environmen-
that the bowel lining is exposed to potential mutagens.187 For breast tal factors and genetic polymorphisms at multiple loci.
cancer, vigorous physical activity may decrease exposure of breast tis-
sue to ovarian hormones, insulin, and IGF. A randomized trial found Air Pollution
that after 12 months of moderate-intensity exercise, postmenopausal A person inhales about 20,000 L of air every day; thus even modest
women had significantly decreased levels of serum estrogens.188 Physi- contamination of the atmosphere can result in inhalation of appre-
cal activity also helps prevent type 2 diabetes, which has been associ- ciable doses of pollutants. Airborne substances contaminate food, soil,
ated with risk of cancer of the colon and pancreas.187,189 and water. Contaminants include outdoor and indoor air pollutants.
Many questions are unanswered regarding frequency, intensity, Concerns include industrial emissions, including arsenicals, benzene,
and duration of exercise. Much of the literature suggests that between chloroform, formaldehyde, sulfuric acid, mustard gas, vinyl chloride,
3.5 and 4 hours of vigorous activity per week are necessary to optimize and acrylonitrile.196 Notable outdoor pollutants include ozone, carbon
protection for colon cancer.186 There is likely a dose-response relation- dioxide, particulates, and sulfur dioxide (Box 10-6) (see Chapter 3
ship for colon cancer and breast cancer, and 30 to 60 minutes per day for a discussion of the mechanism of action and side effects of carbon
of moderate to vigorous intensity is proposed to decrease breast cancer monoxide poisoning).
risk.190 A randomized controlled trial (12 months) recently supported Living close to certain industries is a recognized cancer risk factor,
the Institute of Medicine and Department of Agriculture guidelines although it is difficult to determine cancer risk from outdoor pollution
 CHAPTER 10  Cancer Epidemiology 279

BOX 10-4 KNOWN CARCINOGENIC AGENTS CLASSIFIED BY THE INTERNATIONAL AGENCY

FOR RESEARCH ON CANCER (IARC)
Agents or Group of Agents Radionuclides, α-particle-emitting, internally deposited
4-Aminobiphenyl Radionuclides, β-particle-emitting, internally deposited
Arsenic and arsenic compounds Radium-224 and its decay products
Asbestos Radium-226 and its decay products
Azathioprine Radium-228 and its decay products
Benzene Radon-222 and its decay products
Benzidine Schistosoma haematobium (infection with)
Benzo[a]pyrene Silica, crystalline (inhaled in the form of quartz or cristobalite from occupational
Beryllium and beryllium compounds sources)
N,N-Bis (2-chloromethyl)-2-naphthylamine ether and chloromethyl methyl ether* Solar radiation
1,3-Butadiene Talc containing asbestiform fibers
1,4-Butanediol dimethanesulfonate (busulfan; Myleran) Tamoxifen
Cadmium and cadmium compounds 2,3,7,8-Tetrachlorodibenzo-para-dioxin
Chlorambucil Thiotepa
1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (methyl-CCNU; semustine) Thorium-232 and its decay products, administered intravenously as a colloidal
Chromium IV compounds dispersion of thorium-232 dioxide
Cyclosporine Treosulfan
Cyclophosphamide Vinyl chloride
Diethylstilbestrol x-ray and gamma (γ) radiation
Dyes metabolized to benzidine
Epstein-Barr virus Mixtures
Eronite Aflatoxins (naturally occurring mixtures of)
Estrogen-progestogen menopausal therapy (combined) Alcoholic beverages
Estrogen-progestogen oral contraceptives (combined) Areca nut
Estrogens, nonsteroidal Betel quid with tobacco
Estrogens, steroidal Betel quid without tobacco
Estrogen therapy, postmenopausal Coal-tar pitches
Ethanol Coal tars
Ethylene oxide Herbal remedies containing plant species of the genus Aristolochia
Etoposide Household combustion of coal, indoor emissions from
Formaldehyde Mineral oils, untreated or mildly treated
Gallium arsenide Phenacetin, analgesic mixtures containing
Gamma radiation: see x-ray and gamma (γ) radiation Salted fish (Chinese-style)
Helicobacter pylori (infection with) Shale-oils
Hepatitis B virus (chronic infection with) Soots
Hepatitis C virus (chronic infection with) Tobacco, smokeless
Human immunodeficiency virus type 1 (infection with) Wood dust
Human papillomavirus types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 66
Human T cell lymphotropic virus type I Exposure Circumstances
Melphalan Aluminum production
8-Methoxypsoralen (methoxsalen) Arsenic in drinking water
4,4′-Methylenebis(chloroaniline) (MBOCA) Auramine production
MOPP and other combined chemotherapy including alkylating agents Boot and shoe manufacture and repair
Mustard gas (sulfur gas) Chimney sweeping
2-Naphthylamine Coal gasification
Nickel compounds Coal-tar distillation
N′-Nitrosonornicotine (NNN) Coke production
Oestrogen: see Estrogen Furniture and cabinet making
Opisthorchis viverrini (infection with) Hematite mining (underground) with exposure to radon
Oral contraceptives, combined estrogen-progestogen: see estrogen-progestogen Involuntary smoking (exposure to secondhand or “environmental” tobacco smoke)
oral contraceptives (combined) Iron and steel founding
Oral contraceptives, sequential Isopropyl alcohol manufacture (strong-acid process)
Ortho-toluidine Magenta production
Phosphorus-32, as phosphate Painter (as occupational exposure)
Plutonium-239 and its decay products (may contain plutonium-240 and other Paving and roofing with coal-tar pitch
isotopes) as aerosols Rubber industry
Radioiodines, short-lived isotopes, including iodine-131, from atomic reactor Strong inorganic acid mists containing sulfuric acid (occupational exposure to)
accidents and nuclear weapons detonation (exposure during childhood) Tobacco smoking and tobacco smoke
280 CHAPTER 10  Cancer Epidemiology

BOX 10-5 PROBABLE CARCINOGENIC AGENTS CLASSIFIED BY THE IARC

Agents and Group of Agents Nitrate or nitrite (ingested) under conditions that result in endogenous nitrosation
Acrylamide Nitrogen mustard
Adriamycin N-Nitrosodiethylamine
Androgenic (anabolic) steroids N-Nitrosodimethylamine
Aristolochic acids (naturally occurring mixtures of) Phenacetin
Azacitidine Procarbazine hydrochloride
Bis(chloroethyl)nitrosourea (BCNU) Styrene-7,8-oxide
Captafol Teniposide
Chloramphenicol Tetrachloroethylene
α-Chlorinated toluenes (benzal chloride, benzotrichloride, benzyl chloride, and Trichloropropane
benzoyl chloride) (combined exposures) 1,2,3-Trichloropropane
1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) Tris(2,3-dibromoprophyl) phosphate
4-Chloro-ortho-toluidine Ultraviolet radiation A
Chlorozotocin Ultraviolet radiation B
Cisplatin Ultraviolet radiation C
Clonorchis sinensis (infection with) (Urethane: see Ethyl carbamate)
Cyclopeneta[c,d ]pyrene Vinyl bromide
Dibenz[a,i]anthracene Vinyl fluoride
Dibenz[a,l]pyrene
Diethyl sulfate Mixtures
Dimethylcarbamoyl chloride Creosotes
1,2-Dimethylhydrazine Diesel engine exhaust
Dimethyl sulfate High-temperature frying, emissions from
Epichlorohydrin Hot mate
Ethyl carbamate (urethane) Household combustion of biomass fuel (primarily wood), indoor emissions from
Ethylene dibromide Nonarsenical insecticides (occupational exposures to spraying and
N-Ethyl-N-nitrosourea application of)
Etoposide Polychlorinated biphenyls
Glycidol
Indium phosphide Exposure Circumstances
IQ (2-amino-3-methylimidazo[4,5-f]quinoline) Art glass, glass container, and pressed ware (manufacture of)
Kaposi sarcoma herpesvirus/human herpesvirus B Carbon electrode manufacture
Lead compounds, inorganic Cobalt metal with tungsten carbide
5-Methoxypsoralen Hairdresser and barber (occupational exposure as)
Methyl methanesulfonate Petroleum refining (occupational exposure as)
N-Methyl-N′-nitro-N-nitrosoguanidine (MNNG) Shiftwork that involves circadian disruption
N-Methyl-N-nitrosourea Sunlamps and sunbeds

IARC, International Agency for Research on Cancer.

BOX 10-6 NOTABLE OUTDOOR POLLUTANTS

Ozone is created from the interaction of ultraviolet (UV) radiation and oxygen (O2) pollutants, such as sulfur dioxide. Sulfur dioxide is produced by power plants
in the stratosphere, leading to the formation of the ozone (O3) layer (good ozone) burning oil and coal, copper smelting, and paper mills.
that accumulates miles above the earth’s surface. This layer protects life on Particulate matter, often called soot, is released by coal-fired and oil-fired
earth by absorbing UV radiation emitted from the sun. The heavy use of propel- power plants, by industries burning these compounds, and by diesel exhaust.
lants, such as aerosols, has decreased the good ozone layer, leading to the ban- Fine or ultrafine particles less than 10 micrometers in diameter are considered
ning of chlorofluorocarbons. The accumulating ozone at the lower atmospheric the most harmful. Fine or ultrafine particles are easily absorbed by the lungs
level or ground level (bad ozone) is a toxic air pollutant. This ground-level ozone and phagocytosed by macrophages and neutrophils that consequently release
is a gas formed by reactions with nitrogen oxides, volatile organic compounds, tissue-damaging inflammatory mediators. Acute exposure to diesel exhaust
and sunlight. This gas mixture is emitted from motor vehicle exhausts and indus- that contains fine particles can cause lung, throat, and eye irritation; asthma
trial emissions. Nasty combinations of mixtures cause damage (i.e., ROS and attacks; and myocardial ischemia. The nose and the epithelium of the airways
inflammation) to lung tissue, especially in people with preexisting lung diseases. trap particles greater than 10 micrometers in diameter, decreasing their toxic
These mixtures can also affect healthy people when combined with other air reactions.

Data from Puett RC et al: Chronic fine and course particulate exposure, mortality, and coronary heart disease in the Nurses’ Health Study, Environ
Health Perspect, 117(11):1697–1701, 2009. [Epub, June 15, 2009.]
 CHAPTER 10  Cancer Epidemiology 281

alone because investigators must accurately control for smoking and In China, some regions report very high levels of lung cancer in
radon. Studies that controlled or stratified for smoking demonstrated women who spend much of their time indoors. Exposures from heat-
associations between excess lung cancer rates and heavy metal and ing and cooking combustion sources (e.g., oil vapors) and asbestos are
aromatic hydrocarbon emissions in polluted air. Evidence for cancers, identified as risk factors for lung cancer.198 In addition, domestic coal
other than lung cancer and childhood cancer, is inconsistent.197 use and ETS increase the risk of lung cancer in women and men.199
Indoor pollution generally is considered worse than outdoor pol- Inorganic arsenic (known as a carcinogen since the late 1960s),
lution, partly because of cigarette smoke. Environmental tobacco found principally in underground water (at levels ranging from 1000
smoke (ETS; passive smoking) can cause the formation of reactive to 4000 mcg/L), is found in many regions of the world. According to
oxygen free radicals and thus DNA damage. The IARC has classified the IARC, strong evidence indicates an increased risk of bladder, skin,
ETS as a human carcinogen. Another significant indoor air pollut- and lung cancers following consumption of water with high levels of
ant is radon gas. Radon is a natural radioactive gas derived from arsenic (generally greater than 200 mcg/L).200 Evidence for cancers of
the radioactive decay of uranium that is ubiquitous in rock and the liver, colon, and kidney is weaker. Other sources of inorganic arse-
soil; it can become trapped in houses and form radioactive decay nic are related to occupational exposures (see Box 10-4).
products known to be carcinogenic to humans. The most hazard-
ous houses can be identified by testing and then by being modified
to prevent further radon contamination. Exposure levels are greater
from underground mines than from houses. Most of the lung can-
4 QUICK CHECK 10-4
1. Identify the high-risk types of HPV that are carcinogenic.
cers associated with radon are bronchogenic; however, small cell 2. Chemicals present a notable challenge to the environment and cancer-why?
carcinoma does occur with greater frequency in underground min- 3. What components of air pollution are considered most important for
ers. Radon increases the risk of lung cancer in underground miners carcinogenesis?
whether they smoke or not.

DID YOU UNDERSTAND?

Genes, Environmental-Lifestyle Factors, and Risk Factors Tobacco Use
1. Environmental-lifestyle factors and occupational exposures are increasing 1. Cigarette smoking is carcinogenic and the most important cause of cancer.
the number of cancer cases and deaths. The risk is greatest in those who begin to smoke when young and continue
2. Cancers are caused by environmental-lifestyle and genetic factors. Investi- throughout life.
gators are connecting the complex web between genotype, phenotype, and 2. Cigarette smoking causes more than 5 million deaths per year from cancer,
the environment and carcinogenesis. chronic lung disease, cardiovascular disease, and stroke.
3. Studies of individuals with particular genetic predispositions who may be 3. Smoking tobacco is linked to cancers of the lung, lower urinary tract, upper
more susceptible to the biologic effects of environmental exposures cannot aerodigestive tract, liver, kidney, pancreas, cervix, uterus, and myeloid
explain the increased cancer risk in exposed groups. leukemia.
4. It appears that the majority of cancers are caused by carcinogen exposure 4. Environmental tobacco smoke (ETS) is the combination of sidestream and
rather than by rare genetic conditions. mainstream smoke.
5. The cancers increasing substantially in the United States include melanoma, 5. More than 60 chemicals in tobacco smoke are considered carcinogenic.
non-Hodgkin lymphoma, testicular, brain, and thyroid. These cancers are not ­Nonsmokers who live with smokers are at greatest risk for lung cancer as
linked to cigarette smoking. well as other noncancerous conditions.
6. Statistics have shown that immigrants acquire the cancer incidence rates of 6. Cigar or pipe smoking is strongly and causally related to cancers of the oral
the country where they relocate within one or two generations; thus ethnic- cavity, esophagus, and lung. Cigar smokers who inhale deeply may have
ity or country of origin may not be as important as immediate environment. other disease risks. Bidi smoking can cause cancers of the respiratory and
7. A new paradigm shift suggests that susceptibility to disease may be estab- digestive sites.
lished in utero or neonatally.
Diet
Epigenetics and Genetics 1. Diet can expose individuals to xenobiotics.
1. An explosion of new data indicate the relative importance of genetic versus 2. Carcinogenic substances from diet can develop from the cooking of fat, meat,
epigenetic processes. or protein (e.g., heterocyclic aromatic amines), and from naturally occurring
2. The importance of epigenetic processes includes gene silencing of key regu- compounds associated with plant foods.
latory genes. 3. Nutrition may directly influence epigenetic factors that silence genes that
3. Epigenetic changes collaborate with the genetic changes and environmen- should be active or activate genes that should be silent.
tal-lifestyle factors to cause the development of cancer. 4. Dietary components can act directly as mutagens or interfere with their
4. Developmental plasticity is the degree to which an organism’s development elimination.
is contingent on its environment. It requires stable gene expression that in 5. Dietary factors may alter hormonal axes, influence cellular proliferation, and
part appears to be modulated by epigenetic processes such as DNA methyla- affect phenotype or expression of key genes, for example, epigenetically.
tion, histone modification, and micro-RNAs. 6. Diet affects pathways to cancer including cell cycle control, differentia-
5. Epidemiologic and animal studies reveal that small changes in the devel- tion, DNA repair, gene silencing, inflammation, apoptosis, and carcinogenic
opmental environment can alter phenotypic changes, resulting in individual metabolism.
responses in adulthood.
282 CHAPTER 10  Cancer Epidemiology

DID YOU UNDERSTAND?—cont’d

Obesity 4. Skin exposure to UVR produces ROS in large quantities that can overwhelm
1. Obesity has been increasing in developed countries and in urban areas of tissue antioxidants and other oxygen-degrading pathways. Imbalances in
developing countries. Studies in the United States have suggested obesity is ROS can lead to oxidative stress, tissue injury, and direct DNA damage.
associated with some cancers, though it may not be a causal factor in cancer 5. UVR can activate the transcription factor NF-κβ and other free radicals
mortality. important in regulating genes that induce inflammation. Inflammation is a
2. A recent hypothesis is obesity may be associated with the incidence of can- critical component of tumor progression.
cers of the breast, endometrium, colon, liver, kidney, and esophagus. 6. Melanoma has been increasing annually at rates of 2% to 7% for white
3. Biologic mechanisms of the association of obesity with cancer include populations but mortality rates have not risen as rapidly. The pathogenesis
insulin resistance, hyperinsulinemia, increased IGFs, increased steroid hor- of melanoma is complex, including genetic and environmental factors.
mones, and increased tissue-derived hormones, cytokines, and/or inflamma-
tory mediators. Electromagnetic Radiation (EMR)
4. Adipose tissue is active endocrine and metabolic tissue. Increased release 1. EMRs are a type of nonionizing and low-frequency radiation. Health risks
of free fatty acids, resistin, and TNF-α and reduced release of adiponectin associated with EMRs are controversial. Exposure to electric and magnetic
lead to insulin resistance. Adipose tissue cells produce steroid hormone–­ fields is widespread.
metabolizing enzymes and are an important source of estrogens in post- 2. EMRs of varying strength include microwaves, radar, power frequency radia-
menopausal women. IGF-1 regulates cell proliferation and inhibits apoptosis tion associated with electricity and radio waves, fluorescent lights, comput-
and the synthesis and biologic availability of female and male sex hormones. ers, electric equipment, cell and cordless phones, and others.
5. Numerous dietary factors are associated with cancer risk. 3. Data regarding the effects of EMR have been slow because of methods
to accurately measure exposure, the lack of clear dose-response relation-
Alcohol Consumption ships, reproducing effects, financial interests, and other priorities such as
1. Chronic alcohol consumption is a strong risk factor for cancer of the oral cav- convenience.
ity, pharynx, hypopharynx, larynx, esophagus, and liver. 4. Studies differ on findings, however, a pooled analysis with low and high
2. Alcohol consumption is less strongly but consistently related to breast can- exposures showed at the highest average exposures increased risks affect-
cer and colorectal cancer. Also, it is known to increase cell growth of human ing few children with childhood cancer. The WHO requested studies in high-
breast cancer cells in vitro. exposure areas like Japan and found (case-control study) acute lymphocytic
leukemia in children in the highest exposure category.
Ionizing Radiation (IR) 5. Epidemiologic studies and a recent meta-analysis of low-bias studies found a
1. Human exposures to ionizing radiation include background radiation from consistent pattern of an increased risk for acoustic neuroma and glioma in those
soil or rocks, radon gas seeping into homes and other buildings, energy or using cell phones for more than 10 years. The concern is more for children.
matter moving through space, and sources within the human body.
2. Other sources of exposure to ionizing radiation include emissions from Sexual and Reproductive Behavior
x-rays, radioisotopes, and other radioactive sources. The NCRP is concerned 1. High-risk types of HPV are required for the development of most cervical can-
about the increased IR exposure from medical procedures, particularly CT cers. High-risk types include HPV-16 (50% to 60% of cervical cancer cases),
scans and nuclear medicine procedures. HPV-18 (10% to 12%), and HPV-31 and HPV-45 (4% to 5% each). HPV can
3. The risks from low-dose radiation are being debated among radiobiologists, cause other cancers including vaginal, vulva, penis, anus, and oropharyngeal.
geneticists, physicists, and others because of the potential effect on the 2. Biologic factors that may interact with HPV to promote persistent infection
health of current and future generations. include oral contraceptives and smoking. Newer risk factors include drug
4. IR is a mutagen and carcinogen; it can penetrate cells and tissues and addiction and reproductive factors such as age at menarche and menopause.
deposit energy in tissues at random in the form of ionizations. A second peak of high-risk HPV prevalence occurs in postmenopausal women.
5. IR affects many cellular processes, including gene expression, mitochon- 3. HPV may be transmitted by genital contact (oral, touching, or sexual inter-
drial function, nucleotide base damage, and single- and double-strand DNA course); therefore condoms are not necessarily protective. The incidence of
breaks. These changes can lead to carcinogenesis. oropharyngeal cancers caused by HPV is increasing worldwide.
6. It is now known that radiation may induce a type of genomic instability to the 4. HPV vaccination programs have made it possible to eliminate the majority of
progeny of the directly irradiated cells over many generations of cell radia- all invasive cervical cancer worldwide.
tion and can affect so-called innocent bystander cells.
7. New models of carcinogenesis identify ionizing radiation not only as an Physical Activity
initiator of premalignant cell clones but also as a promoter of preexisting- 1. Physical activity reduces the risk for breast and colon cancers and may
premalignant damage. reduce the risk for other cancers.
8. Epigenetic events after radiation include alterations in pathways affect- 2. Biologic mechanisms for the protective effects of physical activity include
ing cell adhesion, extracellular matrix interactions, and cell-to-cell decreasing insulin and IGF levels, decreasing obesity, increasing free radical
communication. scavenger systems, altering inflammatory mediators, decreasing levels of
circulating sex hormones and metabolic hormones, improving immune func-
Ultraviolet Radiation (UVR) tion, enhancing cytochrome P-450 activity (thus modifying carcinogen activa-
1. UVR causes basal cell carcinoma and squamous cell carcinoma. The princi- tion), and increasing gut motility.
pal source of UVR is sunlight. 3. Physical activity may prevent type 2 diabetes, which has been associated
2. The degree of damage in skin depends on the intensity and wavelength con- with cancer of the pancreas and colon.
tent—ultraviolet A (UVA) or ultraviolet B (UVB). 4. Many unanswered questions remain regarding frequency of exercise, inten-
3. UVR is known to cause specific gene mutations: for example, squamous cell sity, and duration.
carcinoma involves mutation in the TP53 gene, basal cell carcinoma in the 5. Recent data encourage 60 minutes of vigorous activity daily for decreasing
patched gene, and melanoma in the p16 gene. BMI, body fat, and intra-abdominal fat.
 CHAPTER 10  Cancer Epidemiology 283

DID YOU UNDERSTAND?—cont’d

Chemicals and Occupational Hazards 5. A substantial percentage of cancers of the upper respiratory passages, lung,
1. The International Agency for Research on Cancer (IARC) has classified carci- bladder, and peritoneum are attributed to occupational factors.
nogenic agents as known and probable. 6. Disentangling data related to lung cancer, air pollution, and occupational
2. An estimated 80,000 synthetic chemicals are used in the United States. Only factors is complex especially in combination with active and passive smok-
7% have been fully tested for their impact on health and another 1000 are ing, environmental factors, and multiple interacting genes.
added each year. 7. Air pollution is a concern in regard to cancer because of inhalation of ozone,
3. Chemicals are present in air, soil, food, water, personal care products, toys, particulate matter, carbon dioxide, and other emissions, including arsenicals,
household products, medications, workplaces, and homes. Table 10-1 is a benzene, chloroform, vinyl chloride, and acrylonitrile. Indoor pollution is con-
summary of environmental and occupational links to cancer. sidered worse than outdoor pollution because of cigarette smoke and pos-
4. Chemicals can persist in the environment and accumulate in body fat and sibly radon gas.
remain there indefinitely. Mechanisms of carcinogenesis for chemicals
include direct carcinogenic action, hormonal disruptors, interference with
cell signaling pathways, and other unknown effects.

 KEY TERMS
•  bscopal  272
A •  evelopmental plasticity  260
D •  adon  281
R
• Bystander effect  271 • Environmental tobacco smoke (ETS)  261 • Transgenerational inheritance  260
• Cadherin  275 • Genomic instability  273 • Transgeneration inheritance (effect)  260
• Chromosome instability (CIN)  273 • Individual carcinogen  253 • Xenobiotics  262
• Connexon  274 • “Nontargeted” effect  271

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CHAPTER

11
Cancer in Children
Nancy E. Kline

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Incidence and Types of Childhood Cancer, 288
Etiology, 289
Genetic Factors, 289
Environmental Factors, 291
Prognosis, 291

Cancer in children is rare; however, it is still the leading cause of death Most childhood cancers originate from the mesodermal germ layer,
in children that is attributable to disease. Survival rates in children with which develops into connective tissue, bone, cartilage, muscle, blood,
cancer have dramatically improved in the past 30 years. Some of the blood vessels, gonads, kidney, and the lymphatic system. Thus the more
factors leading to improved cure rates in children with cancer include common childhood cancers are leukemias, sarcomas, and embryonic
the use of combination chemotherapy, the incorporation of research tumors. Embryonic tumors originate during intrauterine life and con-
data obtained from clinical trials, and the utilization of multimodal tain abnormal cells that appear to be immature embryonic tissue unable
treatment for childhood solid tumors. to mature or differentiate into fully developed functional cells. Embry-
onic tumors (e.g., neuroblastoma, Wilms tumor) are diagnosed early in
life (usually by 5 years of age) and therefore are rare in adults.
INCIDENCE AND TYPES OF CHILDHOOD CANCER Sarcomas and lymphoreticular cancers seen in childhood also occur
In 2007 the mortality rates of children with cancer were 2.1 per 100,000 in adults, but most adult cancers involve epithelial tissue (and are there-
in children ages 1 to 4 years and 2.5 per 100,000 in children ages 5 to 14 fore carcinomas). Carcinomas rarely occur in children because these can-
years. In comparison, cancer is the second leading cause of death from cers most commonly result from environmental carcinogens and require
disease in adults (second to heart disease), with an overall mortality a long period from exposure to the appearance of the carcinoma. Carci-
rate of 185.2 per 100,000 individuals.1 nomas begin to increase in incidence between the ages of 15 and 19 years,
The types of malignancies in children are vastly different from becoming the most common cancer tissue type seen after adolescence.
those that affect adults. The most common types of cancer among By far the most common malignancy in children is leukemia, which
adults include prostate, breast, lung, and colon. Children tend to accounts for more than one third of childhood cancers. The second most
develop leukemias, brain tumors, and sarcomas. Although many adult common group of cancers is tumors of the nervous system, primarily
cancers have associated lifestyle factors that could theoretically be brain tumors. All other pediatric malignancies occur much less often.
avoided, such as smoking and exposure to sun, very few environmen- Neuroblastoma is a tumor of the sympathetic nervous system. Wilms
tal factors have been linked to pediatric malignancies. Yet more data tumor is a malignancy of the kidney (named after Max Wilms, who iden-
are emerging that the developing child may be affected by parental tified the tumor); the histologic name is nephroblastoma. Rhabdomyosar-
exposures before conception, exposures in utero, and the contents of coma is a soft tissue sarcoma of striated muscle. Two major bone tumors
breast milk.2,3 also occur in children. These are osteosarcoma and Ewing sarcoma.

288
 CHAPTER 11  Cancer in Children 289

Childhood cancers are usually diagnosed during peak times of than in other races (Table 11-2). In the United States childhood cancer
physical growth and maturation. In general, they are extremely fast- also is slightly more common in boys than in girls. The male/female
growing cancers. Many childhood cancers have a peak incidence ratio for childhood cancers is 1.2:1.0.1
before the child is 5 years of age. Among these are the leukemias, neu-
roblastoma, Wilms tumor, and retinoblastoma. Bone tumors, soft tis-
ETIOLOGY
sue sarcomas, and lymphomas are more likely to occur in children ages
15 to 19 years (Table 11-1). Cancer is more common in white children The causes of cancer in children are largely unknown. A few environ-
mental factors are known to predispose a child to cancer, but causal
factors have not been established for most childhood cancers. A num-
ber of host factors, many of which are genetic risk factors or congeni-
TABLE 11-1 CHILDHOOD AGE-ADJUSTED tal conditions, have been implicated in the development of childhood
INVASIVE CANCER cancer (Table 11-3).
INCIDENCE RATES BY Most childhood cancers, however, do not lend themselves to early
PRIMARY SITE AND AGE, cancer warning signs. Certainly the American Cancer Society’s seven
UNITED STATES* warning signs of cancer do not apply because they describe adult, envi-
ronmentally caused carcinomas. Although host factors are important
BIRTH TO BIRTH TO in identifying populations of children at risk for cancer, most children
SITE 14 YEARS 19 YEARS who are diagnosed with cancer do not demonstrate any predisposing
All sites 15.3 16.9 environmental or host factors.
Leukemia 4.7 4.2 The multiple causation concept is useful when the results of epi-
Acute lymphocytic 3.7 3.1 demiologic studies are interpreted. For example, laboratory and epi-
Acute myeloid 0.7 0.7 demiologic studies may indicate that exposure to a certain chemical
Brain and other nervous system 3.3 3.1 can cause leukemia, but not all children exposed to that chemical will
Soft tissue 1.0 1.0 develop leukemia. Additional studies will be needed to determine what
Kidney and renal 0.8 0.7 other factors must interact with chemical exposure to cause the disease.
Bones and joints 0.7 0.9
Non-Hodgkin lymphoma 0.9 1.1 Genetic Factors
Hodgkin lymphoma 0.6 1.2 Genetic factors may involve chromosome aberrations or single-gene
Other 3.3 4.7 defects. These chromosome abnormalities include aneuploidy, dele-
tions, amplifications, translocations, and fragility (see Chapter 2).
Data modified from U.S. Cancer Statistics Working Group: United
Some congenital malformations herald the onset of pediatric malig-
States cancer statistics: 1999–2006 incidence and mortality web-based
report, Atlanta, 2010, U.S. Department of Health and Human Services, nancies. Several syndromes with diagnosed abnormalities are known
Centers for Disease Control and Prevention, and National Cancer Insti- to be related to a higher incidence of cancer development. Children
tute; available at www.cdc.gov/uscs. identified with certain congenital syndromes can then be carefully fol-
*Rates are per 100,000 persons and are age-adjusted to the 2000 U.S. lowed and screened for tumor development. One of the more recog-
standard population (19 age groups–Census P25-1130). nized syndromes is the association of trisomy 21 (Down syndrome)

TABLE 11-2 CHILDHOOD AGE-ADJUSTED CANCER INCIDENCE RATES FOR CHILDREN

UP TO 19 YEARS OF AGE BY PRIMARY SITE AND RACE AND ETHNICITY,
UNITED STATES*
ASIAN/PACIFIC AMERICAN INDIAN/
CANCER SITE WHITE BLACK ISLANDER ALASKA NATIVE HISPANIC†
All cancer sites combined 18.7 12.9 13.9 10.7 18.0
Bones and joints 1.0 0.9 0.9 0.7 1.1
Brain and other nervous systems 3.4 2.3 2.1 1.6 2.8
Hodgkin lymphoma 1.3 1.0 1.0 —‡ 1.2
Kidney and renal pelvis 0.6 0.3 0.3 —‡ 0.5
Leukemia 5.0 4.5 4.5 3.7 5.9
Acute lymphocytic 3.8 3.3 3.3 2.5 4.6
Acute myeloid 0.7 0.8 0.8 —‡ 0.9
Non-Hodgkin lymphoma 1.5 1.2 1.2 0.7 1.4
Soft tissue 1.1 0.9 0.9 —‡ 0.9
Other 4.7 3.1 3.1 2.7 4.2

Data modified from U.S. Cancer Statistics Working Group: United States cancer statistics: 1999–2006 incidence and mortality web-based report,
Atlanta, 2010, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute; avail-
able at www.cdc.gov/uscs.
*Rates are per 100,000 persons and are age-adjusted to the 2000 U.S. standard population (19 age groups–Census P25-1130).
†Hispanic origin is not mutually exclusive from race categories (white, black, Asian/Pacific Islander, American Indian/Alaska Native).

‡Rates are suppressed if fewer than 16 cases were reported in a specific category (area, race, ethnicity).
290 CHAPTER 11  Cancer in Children

TABLE 11-3 CONGENITAL FACTORS TABLE 11-4 SELECTED ONCOGENES

ASSOCIATED WITH AND TUMOR-SUPPRESSOR
CHILDHOOD CANCER GENES ASSOCIATED WITH
ASSOCIATED CHILDHOOD CANCER
SYNDROME CHILDHOOD CANCER GENE ASSOCIATED PEDIATRIC TUMOR
Chromosome Alterations Oncogenes
Down syndrome Acute leukemia bcr-abl Acute lymphoblastic leukemia
13q syndrome Retinoblastoma N-myc Neuroblastoma
c-myb Neural tumors, leukemia, lymphoma, rhabdomyosar-
Chromosome Instability coma, Wilms tumor, neuroblastoma
Ataxia-telangiectasia Lymphoma erb B Glioblastomas
Bloom syndrome Acute leukemia, lymphoma, Wilms tumor N-ras Neuroblastoma, leukemia
Fanconi anemia Nonlymphocytic leukemia, myelodysplastic H/K-ras Neuroblastoma, rhabdomyosarcoma, leukemia
syndrome, hepatic tumors ATM Lymphoma, leukemia

Hereditary Syndromes Tumor-Suppressor Genes

Beckwith-Wiedemann Wilms tumor, sarcoma, brain tumors, Rb1 Retinoblastoma, sarcoma
syndrome ­neuroblastoma, hepatoblastoma WT1, WT2 Wilms tumor, leukemia
Neurofibromatosis type I Brain tumor, sarcomas, neuroblastomas, WTC Wilms tumor
Wilms tumor, nonlymphocytic leukemia NF-1 Sarcoma, primitive neuroectodermal tumor, juvenile
Neurofibromatosis type II Meningioma (malignant or benign), chronic myelocytic leukemia
acoustic neuroma/schwannoma, gliomas, NF-2 Brain tumors, melanoma, meningiomas
­ependymomas p16 Brain tumors, leukemia
Tuberous sclerosis Glial tumors TP53 Sarcoma, leukemia, brain tumors, lymphoma
Li-Fraumeni syndrome Sarcoma, adrenocortical carcinoma DCC Ewing sarcoma, rhabdomyosarcoma
Von Hippel-Lindau disease Cerebellar hemangioblastoma, ­retinal p16 INK4a Glioma, leukemia
angioma, renal cell carcinoma, p15 ARF Glioblastoma, T cell ALL
­pheochromocytomas CDC2L1 Non-Hodgkin lymphoma, neuroblastoma
Ataxia-telangiectasia Leukemia, lymphoma, brain tumors
Gorlin syndrome Medulloblastoma, skin tumors Data from Dome JS, Coppes MS: Curr Opin Pediatr 14(1):5–11, 2002;
Linblom A, Nordenskjold M: Semin Cancer Biol 10(4):251–254, 2000;
Immunodeficiency Disorders Tischkowitz M, Rosser E: Eur J Cancer 40:2459–2470, 2004; Look A,
Congenital Kirsch IR: Molecular basis of childhood cancer. In Pizzo PA, Poplack DG,
Agammaglobulinemia Lymphoma, leukemia, brain tumors editors: Principles and practices of pediatric oncology, ed 4,
­Philadelphia, 2002, Lippincott Williams & Wilkins.
Immunoglobulin A (IgA) Lymphoma, leukemia, brain tumors
ALL, Acute lymphocytic leukemia.
deficiency
Wiskott-Aldrich syndrome Leukemia, lymphoma
(muscular overgrowth of half of the body or face), and mental retar-
Acquired
dation. Approximately 10% of children diagnosed with Wilms tumor
Aplastic anemia Leukemia
demonstrate one of these congenital abnormalities.5 Retinoblastoma,
Organ transplantation Leukemia, lymphoma
a malignant embryonic tumor of the eye, occurs either as an inherited
Congenital Malformation Syndromes
defect or as an acquired mutation (see Chapter 16).
Aniridia, hemihypertrophy, Wilms tumor
More than 150 single-gene defects, oncogenes and tumor-suppres-
hamartoma, genitourinary
sor genes, have been associated with the subsequent development of
anomalies
both childhood and adult cancers (Table 11-4). Fanconi anemia and
Cryptorchidism Testicular tumor
Bloom syndrome, two autosomal recessive conditions, are risk factors
Gonadal dysgenesis Gonadoblastoma
for the development of acute lymphocytic leukemia (ALL).
Although not determined to be genetically transmitted, a child who
Family Susceptibility has a sibling with leukemia has a risk for the development of leukemia
Twin or sibling with Leukemia that is two to four times greater than that for children with healthy
leukemia siblings. The occurrence of leukemia in monozygous twins is estimated
as being as high as 25%.
In families with Li-Fraumeni syndrome (LFS) (an autosomal domi-
with an increased susceptibility to acute leukemia. For children with nant disorder involving the TP53 tumor-suppressor gene), the risk of
Down syndrome, the risk of developing leukemia is 10 to 20 times developing cancer as a child or adult is significantly higher than the
greater than the risk in healthy children. The risk is greatest between 1 risk in the unaffected population. Children and adults in Li-Fraumeni
and 4 years of age.4 families are at risk for soft tissue sarcoma, breast cancer, leukemia,
Wilms tumor is particularly recognized for its association with osteosarcoma, melanoma, and cancer of the colon, pancreas, adrenal
a number of other abnormalities, including genitourinary anoma- cortex, and brain. Individuals with LFS are at increased risk for devel-
lies, aniridia (congenital absence of the iris), hemihypertrophy oping multiple primary cancers.6
 CHAPTER 11  Cancer in Children 291

TABLE 11-5 DRUGS THAT MAY INCREASE HEALTH ALERT

RISK OF CHILDHOOD CANCER Magnetic Fields and Development of Pediatric
DRUG CLASS USES CANCER RISK Cancer
Anabolic androgenic Stimulate bone growth and Hepatocellular Several recent reports have suggested that there is a possible association
steroids ­appetite carcinoma between environmental sources and the development of cancer in children.
Induce puberty The presence of low-frequency and magnetic fields has been a concern for
Increase muscle mass and many years as causing leukemia in children, and although hundreds of epi-
physical strength demiologic studies have been published few have suggested a positive cor-
Cytotoxic Cancer treatment Leukemia relation. Recently, a research study reported pooled results from seven of the
­chemotherapy latest studies on magnetic fields and development of childhood leukemia.
Immunosuppressive Prevent organ rejection following Lymphoma Although the samples of individual studies were small, the results support
agents transplantation surgery previous findings that magnetic fields are possibly carcinogenic to children.
The World Health Organization (WHO) research agenda identified the impor-
tance of such an analysis as a high research priority in 2007. Ongoing research
Environmental Factors needs to be done in this area because it may take many years for exposure to
environmental factors to cause disease. In addition, collection of the neces-
Finding the cause of any disease is typically a long, slow process. It may
sary epidemiologic data to examine the relationship between environmental
take years for an epidemiologic study to determine whether a risk fac-
exposure and childhood malignancies will be a time-consuming process.
tor is possibly related to the development of a disease. No one factor
determines whether an individual will develop cancer, even if a specific Data from Khefits L et al: Pooled analysis of recent studies on magnetic
environmental exposure explains a high proportion of the occurrence fields and childhood leukemia, Br J Cancer 103:1128–1135, 2010 World
of a specific cancer. Childhood cancer is no different. No single study, Health Organization (WHO): WHO research agenda for extremely low
or even multiple epidemiologic studies, will tell a parent why his or her frequency fields, 2007. Available at http://www.who.int/peh-emf/
child developed cancer. The many factors that may play a role in the research/elf_research_agenda_2007.pdf. Accessed October 25, 2010.
development of cancer include genetics, nutrition and diet, immune
function, occupational exposure, hormonal variations, viral illnesses,
and other individual characteristics such as biologic, social, or physical linked to Burkitt lymphoma, nasopharyngeal carcinoma, and Hodg-
environments. kin disease.8 Children with acquired immunodeficiency syndrome
(AIDS), caused by human immunodeficiency virus (HIV), have an
Prenatal Exposure increased risk of developing non-Hodgkin lymphoma and Kaposi sar-
Prenatal exposure to some drugs and to ionizing radiation has been coma. However, with the use of highly active antiretroviral therapy in
linked to childhood cancers. The most well-described drug is diethyl- the developed world, the incidence of AIDS-related malignancies has
stilbestrol (DES), which was prescribed by physicians to prevent spon- declined dramatically.9
taneous miscarriage (in women with previous miscarriage). In 1971
DES was identified as a transplacental chemical carcinogen because
PROGNOSIS
a small percentage of the daughters of women who took DES devel-
oped adenocarcinomas of the vagina. Since then, other studies have More than 70% of children diagnosed with cancer are cured. Survival
attempted to identify other drugs taken by pregnant women that may rates for children younger than 15 years of age have increased at a rate
cause cancer in their offspring, but no other drugs have been found. of 1.5% per year. Similar improvements have been noted in the sur-
Prior research suggested an association between antenatal x-ray expo- vival rates of adults older than 50 years of age. However, adolescents
sure and childhood cancer but this has not been replicated or sup- and young adults between 15 and 24 years of age have experienced
ported in recent literature. increases in survival of less than 0.5% per year.10 A partial explanation
for the relative lack of progress in curing the adolescent population at
Childhood Exposure the same rate as that realized in the younger pediatric population is
Childhood exposure to ionizing radiation, drugs, electromagnetic the lack of participation in clinical trials. Between 1997 and 2003, the
fields, or viruses has been associated with the risk of developing can- percentage of 15- to 19-year-olds with cancer participating in clini-
cer. Retrospective research has shown a significant correlation between cal trials was estimated at 10% to 15%. This value is approximately
radiation-induced malignancies and either radiotherapy (cancer treat- one fourth the clinical trial participation rate of children younger than
ment) or radiation exposure from diagnostic imaging.7 In addition to 15 years and is likely due to the fact that fewer trials are available for
the drug and environmental agents that are known to cause cancer young adolescents. The National Cancer Institute (NCI) and pediatric
in adults and therefore also are risks for exposure during childhood, and adult cooperative groups sponsored by the NCI have launched a
a few drugs may particularly increase cancer risk during childhood national initiative to increase the numbers of adolescents and young
(Table 11-5). adults in clinical trials.
The relationship between childhood cancer and other environ- Survivors of childhood cancer are at increased risk of developing
mental factors (for example, electromagnetic fields, small appliances, a second malignancy later in life. This risk may be associated with a
radon) has been the focus of many epidemiologic studies, yet no con- variety of factors, including previous chemotherapy or radiotherapy,
clusive evidence has been reported7 (see Health Alert: Magnetic Fields genetic factors, and type of primary cancer (e.g., soft tissue sarcoma,
and Development of Pediatric Cancer). neuroblastoma).
The strongest association between viruses and the development Because childhood cancer should be viewed as a chronic disease
of cancer in children has been the Epstein-Barr virus (EBV), which is instead of a fatal illness, the focus of treatment is on the quality of life
292 CHAPTER 11  Cancer in Children

and symptom management. Even those cancers that cannot be cured supportive care, development of research centers for comprehensive
generally can be treated, resulting in significantly improved quality of childhood cancer treatment, cooperation among treatment institu-
life. Although they may be cured, these children still face residual and tions, development of cooperative study groups, recognition of the
late effects of their treatment. These late effects are more significant psychologic effects of cancer treatment, and continued follow-up to
in children than in adults because treatment given during childhood track trends in the late effects of cancer treatment. Young children are
occurs in a physically immature, growing individual. Late effects that particularly prone to long-term sequelae of cancer therapy. It is imper-
need further study include physical impairments, reproductive dys- ative that more effective, targeted therapies with fewer side effects be
function, soft tissue and bone atrophy, learning disabilities, secondary found.
cancers, and psychologic sequelae. More must be learned about the
genetic factors associated with childhood malignancies and about the
genetic consequences of treatment. Genetic counseling is appropriate
for children cured of cancers known to be transmitted genetically (e.g.,
4 QUICK CHECK 11-1
1. What are the most common childhood cancers?
retinoblastoma). 2. Why are children less likely to develop carcinomas?
Some of the factors leading to improved cure rates in pediatric 3. How are different etiologic factors associated with the development of
oncology include the use of combination chemotherapy or multimodal childhood cancer?
treatment for childhood solid tumors, improvements in nursing and

DID YOU UNDERSTAND?

Incidence and Types of Childhood Cancers 3. Children with Down syndrome are at increased risk for developing leukemia.
1. Childhood cancer is a rare disease, but it remains the second leading cause of 4. Risk factors that may be associated with the development of childhood cancer
death in children. include genetics, nutrition and diet, immune function, occupational exposure,
2. The most common type of childhood cancer is leukemia, and the second most hormonal variations, and viral illnesses, as well as other individual character-
common type of pediatric malignancy is a tumor involving the brain or central istics such as biologic, social, or physical environments.
nervous system.
Prognosis
Etiology 1. Survivors of childhood cancer are at increased risk for developing a second
1. Because most carcinomas are caused by environmental exposure, these can- cancer during their lifetime, compared with the general population.
cers are extremely rare in children because they have not lived long enough 2. Improved survival for children with cancer is because of research aimed at
to be exposed to carcinogens. identifying less toxic treatments that will minimize residual effects.
2. Children with immunodeficiencies are at increased risk for developing cancer
because of an ineffective immune system.

 KEY TERMS
• Embryonic tumor  288 • Mesodermal germ layer  288 • Multiple causation  289

REFERENCES 6. Tabori U, Malkin D: Risk stratification in cancer predisposition syn-

dromes: lessons learned from novel molecular developments in Li-­
1. Kochanek KD, et al: Deaths: final data for 2004, Natl Vital Stat Rep 59(4), Fraumeni syndrome, Cancer Res 68(7):2053–2057, 2008.
2011. Available at www.cdc.gov/nchs/data/nvsr/nvsr55/nvsr55_19.pdf. 7. Buka I, Koranteng S, Osomio Vargas AR: Trends in childhood cancer
Accessed May 20, 2011. incidence: review of environmental linkages, Pediatr Clin North Am
2. Clapp RW, Howe GK, Jacobs MM: Environmental and occupational 54(1):177–203, 2007.
causes of cancer: a call to act on what we know, Biomed Pharmacother 8. Powles T, et al: Head and neck cancer in patients with human immunode-
61(10):631–639, 2007. ficiency virus-1 infection: incidence, outcome and association with Epstein-
3. Wigle DT, et al: Epidemiologic evidence of relationships between repro- Barr virus, J Laryngol Otol 118(3):207–212, 2004.
ductive and child health outcomes and environmental chemical contami- 9. Mbulaiteye SM, et al: Spectrum of cancer among HIV-infected persons
nants, J Toxicol Environ Health B Crit Rev 11(5–6):373–517, 2008. in Africa: the Uganda AIDS-Cancer Registry Match Study, Int J Cancer
4. Look AT, Aplan PD: Molecular and genetic basis of childhood cancer. In 118(4):985–990, 2006.
Pizzo PA, Poplack DG, editors: Principles and practice of pediatric oncology, 10. Bleyer A, et al: Relative lack of conditional survival improvement in young
ed 5, Philadelphia, 2006, Lippincott Williams & Wilkins, pp 38–85. adults with cancer, Semin Oncol 36(5):460–467, 2009.
5. Dome JS, et al: Childhood cancer and heredity. In Pizzo PA, Poplack DG,
editors: Principles and practice of pediatric oncology, ed 5, Philadelphia,
2006, Lippincott Williams & Wilkins, pp 905–932.
 CHAPTER

12
Structure and Function
of the Neurologic System
Richard A. Sugerman and Sue E. Huether

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Overview and Organization of the Nervous System, 293 Motor Pathways, 307
Cells of the Nervous System, 293 Sensory Pathways, 307
The Neuron, 294 Protective Structures of the Central Nervous System, 307
Neuroglia and Schwann Cells, 296 Blood Supply of the Central Nervous System, 310
Nerve Injury and Regeneration, 297 The Peripheral Nervous System, 311
The Nerve Impulse, 297 The Autonomic Nervous System, 313
Synapses, 297 Anatomy of the Sympathetic Nervous System, 316
Neurotransmitters, 298 Anatomy of the Parasympathetic Nervous System, 317
The Central Nervous System, 299 Neurotransmitters and Neuroreceptors, 317
The Brain, 299 Functions of the Autonomic Nervous System, 320
The Spinal Cord, 304 GERIATRIC CONSIDERATIONS: Aging & the Nervous System, 321
 

The human nervous system is a remarkable structure responsible for pathways), which carry sensory impulses toward the CNS, and effer-
conscious and unconscious muscle synergy and for the regulation of ent pathways (descending pathways), which innervate skeletal muscle
activities involving internal organs. The nervous system literally drives or effector organs by transmitting motor impulses away from the CNS.
the other systems of the body. It is a network composed of complex Functionally, the PNS can be divided into the somatic nervous sys-
structures that transmit electrical and chemical signals between the tem and the autonomic nervous system. The somatic nervous system
brain and the body’s many organs and tissues. consists of pathways that regulate voluntary motor control (e.g., skel-
etal muscle). The autonomic nervous system (ANS) is involved with
OVERVIEW AND ORGANIZATION regulation of the body’s internal environment (viscera) through invol-
untary control of organ systems. The ANS is further divided into sym-
OF THE NERVOUS SYSTEM pathetic and parasympathetic divisions. Organs innervated by specific
Although the nervous system functions as a unified whole, structures components of the nervous system are called effector organs.
and functions have been divided here to facilitate understanding. Struc-
turally, the nervous system is divided into the central nervous system
CELLS OF THE NERVOUS SYSTEM
and the peripheral nervous system. The central nervous system (CNS)
consists of the brain and spinal cord, enclosed within the protective Two basic types of cells constitute nervous tissue: neurons and sup-
cranial vault and vertebrae, respectively. The peripheral nervous system porting cells. The neuron is the primary cell of the nervous system,
(PNS) is composed of the cranial nerves and the spinal nerves. Peripheral whereas cells such as neuroglial cells (in the CNS) and Schwann cells
nerve pathways are differentiated into afferent pathways (ascending (in the PNS) provide structural support and nutrition for the neurons.1

293
294 CHAPTER 12  Structure and Function of the Neurologic System

The Neuron the cellular constituents of neurons are microtubules (transport sub-
Working alone or in units, neurons detect environmental changes and stances within the cell), neurofibrils, microfilaments (thought to
initiate body responses to maintain a dynamic steady state. Neuronal be involved in transport of cellular products), and Nissl substances
structure varies markedly, so that each neuron is adapted to perform (involved in protein synthesis).
specialized functions. A neuron (Figure 12-1) has three components: a cell body (soma),
The fuel source for the neuron is predominantly glucose; insulin, the dendrites (thin branching fibers of the cell), and the axons. Most
however, is not required for cellular glucose uptake in the CNS. Among cell bodies are located within the CNS; those in the PNS usually are

Dendrite
Golgi
apparatus

Endoplasmic reticulum
Mitochondrion
Cell body (soma)

Nucleus

Axon hillock

Axon

Schwann cell

Myelin sheath

Axon collateral

Node of Ranvier

Synaptic knobs

Telodendria
FIGURE 12-1  Neuron With Composite Parts. Multipolar neuron: neuron with multiple extensions
from the cell body. (Modified from Patton KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis,
2010, Mosby.)
 CHAPTER 12  Structure and Function of the Neurologic System 295

found in groups called ganglia (or plexuses). The dendrites are exten- rather than along the entire length of the membrane, yielding the
sions that carry nerve impulses toward the cell body. Axons are long, increased velocity. This mechanism is referred to as saltatory con-
conductive projections from the cell body that carry nerve impulses duction. Disorders of the myelin sheath (demyelinating diseases),
away from the cell body. The axon hillock is the cone-shaped pro- such as multiple sclerosis and Guillain-Barré syndrome, demonstrate
cess where the axon leaves the cell body. The first part of the axon the important role myelin plays in nerve function (see Chapter 15).
hillock has the lowest threshold for stimulation, so action potentials Conduction velocities depend not only on the myelin coating but
begin there. A typical neuron has only one axon, which may be covered also on the diameter of the axon. Larger axons transmit impulses at
with a segmented layer of lipid material called myelin, an insulating a faster rate.
substance that speeds impulse propagation. This entire membrane is Neurons are structurally classified on the basis of the number of
referred to as the myelin sheath (see Figures 12-2 and 12-24, B) and is processes (projections) extending from the cell body. There are four
the cell membrane portion of a Schwann cell. The myelin sheaths are basic types of cell configuration: (1) unipolar, (2) pseudounipolar,
interrupted at regular intervals by the nodes of Ranvier. Axons can (3) bipolar, and (4) multipolar. Unipolar neurons have one process
branch at the nodes of Ranvier. that branches shortly after leaving the cell body. One example is found
The principle of divergence refers to the ability of axonal branches in the retina. Pseudounipolar neurons (some authors call them unipo-
to influence many different neurons. Convergence applies when lar) also have one process; the dendritic portion of each of these neu-
branches of various numbers of neurons “converge” on and influ- rons extends away from the CNS and the axon portion projects into
ence a single neuron. Nutrient exchange is not possible through the CNS (Figure 12-2). This configuration is typical of sensory neurons
the myelin sheath, although it can occur at the nodes of Ranvier. in both cranial and spinal nerves. Bipolar neurons have two distinct
Where there is myelin, the velocity of nerve impulses increases. processes arising from the cell body. This type of neuron connects
Myelin acts as an insulator that allows ions to flow between segments the rod and cone cells of the retina. Multipolar neurons are the most

Golgi
apparatus
Nucleus Mitochondria
Vesicle pool Nucleolus

CELL A
Pseudounipolar
cell

Endoplasmic
Anterograde reticulum
Nodes of Ranvier
transport Cell body
Synaptic vesicles returning
Microtubules
back for recycling
Synaptic
vesicles Myelin sheath
Retrograde
transport
Vesicle storage pool

Release pool CELL B

Synaptic Multipolar
Dense projections
bouton cell
Synaptic cleft

Receptors Postsynaptic
membrane

Mitochondria Golgi
apparatus

Release of transmitter Vesicle pool

substances Endoplasmic reticulum
FIGURE 12-2  Neuronal Transmission and Synaptic Cleft. Electrical impulse travels along axon of
first neuron to synapse. Chemical transmitter is secreted into synaptic space to depolarize membrane
(dendrite or cell body) of next neuron in pathway. Cell A represents pseudounipolar cell; cell B repre-
sents multipolar cell.
296 CHAPTER 12  Structure and Function of the Neurologic System

CENTRAL NERVOUS SYSTEM NEUROGLIA

Oligodendrocyte

Foot
processes B Microglia

D
Cilia
Capillary Astrocytes
Ependymal Nerve fiber
cells
Myelin sheath

A C

PERIPHERAL NERVOUS SYSTEM NEUROGLIA

Satellite
F cells
Nucleus of
Schwann cell
Node of
Ranvier
G
E Unmyelinated Neuron
nerve fibers cell body

Myelin Neurolemmocyte
Schwann cell sheath Myelinated
Nucleus of nerve fiber
Neurilemma Axon
Schwann cell

FIGURE 12-3  Types of Neuroglial Cells. Neuroglia of the CNS: A, Astrocytes attached to the outside
of a capillary blood vessel in the brain. B, A phagocytic microglial cell. C, Ciliated ependymal cells form-
ing a sheet that usually lines fluid cavities in the brain. D, An oligodendrocyte with processes that wrap
around nerve fibers in the CNS to form myelin sheaths. Neuroglia of the peripheral nervous system
(PNS): E, A Schwann cell supporting a bundle of nerve fibers in the PNS. F, Another type of Schwann
cell encircling a peripheral nerve fiber to form a thick myelin sheath. G, Satellite cells, another type of
Schwann cell, surround and support cell bodies of neurons in the PNS. (From Thibodeau GA, Patton KT:
Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)

common and have multiple processes capable of extensive branching. Neuroglia and Schwann Cells
A motor neuron is typically multipolar (see Figure 12-2). Neuroglia (“nerve glue”) are the general classification of cells that
Functionally, there are three types of neurons (their direction of support the neurons of the CNS. They comprise approximately half
transmission and typical configuration are noted in parentheses): of the total brain and spinal cord volume and are 5 to 10 times more
(1) sensory (afferent, mostly pseudounipolar), (2) associational (inter- numerous than neurons. Different types of neuroglia serve different
neurons, multipolar), and (3) motor (efferent, multipolar). Sensory functions. Astrocytes, for example, fill the spaces between neurons
neurons carry impulses from peripheral sensory receptors to the CNS. and surround blood vessels in the CNS; oligodendroglia (oligo-
Associational neurons (interneurons) transmit impulses from neu- dendrocytes) deposit myelin sheaths within the CNS. Oligoden-
ron to neuron—that is, sensory to motor neurons. They are located droglia are the CNS counterpart of the Schwann cells. Ependymal
solely within the CNS. Motor neurons transmit impulses away from cells line the cerebrospinal fluid (CSF)-filled cavities of the CNS.
the CNS to an effector (i.e., skeletal muscle or organs). In skeletal mus- Microglia remove debris (phagocytosis) in the CNS. (Characteristics
cle the end processes form a neuromuscular (myoneural) junction of ­neuroglia and Schwann cells are summarized in Figure 12-3 and
(see Figure 12-14). Table 12-1.)
 CHAPTER 12  Structure and Function of the Neurologic System 297

TABLE 12-1 SUPPORT CELLS OF THE

Neuron
NERVOUS SYSTEM cell
CELL TYPE PRIMARY FUNCTIONS body
Astrocytes Form specialized contacts between neuronal
Axon
surfaces and blood vessels
Provide rapid transport for nutrients and metabolites Schwann
Believed to form an essential component of blood- cells
brain barrier
Appear to be scar-forming cells of CNS, which may
be foci for seizures Cut
Appear to work with neurons in processing informa-
tion and memory storage
Oligodendroglia Formation of myelin sheath in CNS
(oligodendrocytes)
Schwann cells Formation of myelin sheath in PNS
Microglia Responsible for clearing cellular debris (phagocytic
properties)
Ependymal cells Serve as a lining for ventricles and choroid plexuses
involved in production of cerebrospinal fluid
Muscle
Some data from Martinez Banaclocha MA: Magnetic storage of infor- cell
mation in the human cerebral cortex: a hypothesis for memory, Int J
Neurosci 115(3):329–337, 2005; Sofroniew MV, Vinters HV: Astro-
cytes: biology and pathology, Acta Neuropathol 119(1):7–35, 2010.
CNS, Central nervous system; PNS, peripheral nervous system.
FIGURE 12-4  Repair of a Peripheral Nerve Fiber. When cut, a
damaged motor axon can regrow to its distal connection only if the
Nerve Injury and Regeneration Schwann cells remain intact (to form a guiding tunnel) and if scar
Mature nerve cells do not divide, and injury can cause permanent loss tissue does not block its way.
of function. When an axon is severed, wallerian degeneration occurs in
the distal axon: (1) a characteristic swelling appears within the portion
of the axon distal to the cut; (2) the neurofilaments hypertrophy; (3) the
myelin sheath shrinks and disintegrates; and (4) the axon degenerates
and disappears. The myelin sheaths re-form into Schwann cells that align
4 QUICK CHECK 12-1
1. How do the functions of the somatic and autonomic nervous systems differ?
in a column between the severed part of the axon and the effector organ. 2. What are the three components of a neuron?
At the proximal end of the injured axon, similar changes occur 3. How does myelin affect nerve impulses?
but only back to the next node of Ranvier. The cell body responds to 4. Name the process through which injured axons are repaired, and describe
trauma by swelling and by dispersing the Nissl substance (chroma- the process.
tolysis). During the repair process, the cell increases all of the follow-
ing: metabolic activity, protein synthesis, and mitochondrial activity.
Approximately 7 to 14 days after the injury, new terminal sprouts pro­
ject from the proximal segment and may enter the remaining Schwann potential (see Chapter 1). When the membrane potential is sufficiently
cell pathway. (Figure 12-4 contains a more detailed representation of raised, an action potential is generated and the nerve impulse then flows
these events.) This process, however, is limited to myelinated fibers to all parts of the neuron. The action potential response occurs only
and generally occurs only in the PNS. The regeneration of axonal con- when the stimulus is strong enough; if it is too weak, the membrane
stituents in the CNS is limited by an increased incidence of scar forma- remains unexcited. This property is termed the all-or-none response
tion and the different nature of myelin formed by the oligodendrocyte. (see Chapter 1 for a discussion of electrical impulse conduction).
Nerve regeneration depends on many factors, such as location of
the injury, the type of injury, the presence of inflammatory responses, Synapses
and the process of scarring. The closer to the cell body of the nerve, Neurons are not physically continuous with one another. The region
the greater the chances that the nerve cell will die and not regenerate. between adjacent neurons is called a synapse (see Figure 12-2).
A crushing injury allows recovery more fully than does a cut injury. Impulses are transmitted across the synapse by chemical and electrical
Crushed nerves sometimes recover fully, whereas cut nerves form con- conduction (see Figure 12-2); only chemical conduction is discussed
nective tissue scars that block or slow regenerating axonal branches. here. Chapter 1 contains information on electrical conduction. The
neurons that conduct a nerve impulse are named according to whether
they relay impulses toward (presynaptic neurons) or away from (post-
THE NERVE IMPULSE
synaptic neurons) the synapse.
Neurons generate and conduct electrical and chemical impulses by Impulses are transmitted across the synapse by chemical con-
selectively changing the electrical potential of the plasma membrane duction. When an impulse originates in a presynaptic neuron, the
and influencing other nearby neurons by releasing chemicals (neu- impulse reaches the vesicles, where chemicals (neurotransmitters) are
rotransmitters). An unexcited neuron maintains a resting membrane stored in the synaptic bouton. Once released from the vesicles, the
298 CHAPTER 12  Structure and Function of the Neurologic System

TABLE 12-2 SUBSTANCES THAT ARE NEUROTRANSMITTERS OR NEUROMODULATORS

SUBSTANCE LOCATION EFFECT CLINICAL EXAMPLE
Acetylcholine Many parts of brain, spinal cord, Excitatory or inhibitory Alzheimer disease (a type of dementia) is associated with a decrease
neuromuscular junction of skeletal in acetylcholine-secreting neurons. Myasthenia gravis (weakness of
muscle, and many ANS synapses skeletal muscles) results from a reduction in acetylcholine receptors.

Monoamines
Norepinephrine Many areas of brain and spinal cord; Excitatory or inhibitory Cocaine and amphetamines,* resulting in overstimulation of postsyn-
also in some ANS synapses aptic neurons.
Serotonin Many areas of brain and spinal cord Generally inhibitory Involved with mood, anxiety, and sleep induction. Levels of serotonin
are elevated in schizophrenia (delusions, hallucinations, withdrawal).
Dopamine Some areas of brain and ANS Generally excitatory Parkinson disease (depression of voluntary motor control) results from
synapses destruction of dopamine-secreting neurons. Drugs used to increase
dopamine production induce vomiting and schizophrenia.
Histamine Posterior hypothalamus Excitatory (H1 and H2 No clear indication of histamine-associated pathologic conditions.
receptors) and inhibitory Histamine is involved with arousal and attention and links to other
(H3 receptors) brain transmitter systems.

Amino Acids
γ-Aminobutyric acid Most neurons of CNS have GABA Majority of postsynaptic Drugs that increase GABA function have been used to treat epilepsy by
(GABA) receptors inhibition in brain inhibiting excessive discharge of neurons.
Glycine Spinal cord Most postsynaptic Glycine receptors are inhibited by strychnine.
­inhibition in spinal cord
Glutamate and Widespread in brain and spinal cord Excitatory Drugs that block glutamate or aspartate, such as riluzole, used to treat
aspartate amyotrophic lateral sclerosis. These drugs might prevent overexcita-
tion from seizures and neural degeneration.

Neuropeptides
Endorphins and Widely distributed in CNS and PNS Generally inhibitory Morphine and heroin bind to endorphin and enkephalin receptors
enkephalins on presynaptic neurons and reduce pain by blocking release of
neurotransmitter.
Substance P Spinal cord, brain, and sensory neu- Generally excitatory Substance P is a neurotransmitter in pain transmission pathways.
rons associated with pain, GI tract Blocking release of substance P by morphine reduces pain.

From Seeley R, Stephens TD, Tate P: Anatomy and physiology, ed 7, New York, 2006, McGraw-Hill.
ANS, Autonomic nervous system; CNS, central nervous system; GI, gastrointestinal; PNS, peripheral nervous system.
*Increase the release and block the reuptake of norepinephrine.

neurotransmitters diffuse across the synaptic cleft (the space between potential. Two possible scenarios can then follow: (1) the postsynaptic
the neurons) and bind to receptor sites on the plasma membrane of the neuron may be excited (depolarized; excitatory postsynaptic poten-
postsynaptic neuron,2 relaying the impulse (see Figure 12-2). Synapses tials [EPSPs]) or (2) the postsynaptic neuron’s plasma membrane
can change in strength and number throughout life and this is known as may be inhibited (hyperpolarized; inhibitory postsynaptic potentials
synaptic plasticity or neuroplasticity (see Health Alert: Neuroplasticity). [IPSPs]). Cannabinoid transmitters have been discovered that are
released from postsynaptic neurons and modulate neurotransmitter
Neurotransmitters release from the presynaptic neurons.3,4 (Chapter 1 reviews electrical
More than 30 substances are thought to be neurotransmitters, including impulses and membrane potentials.)
norepinephrine, acetylcholine, dopamine, histamine, and serotonin. Many Usually a single EPSP cannot induce a neuron’s action poten-
of these transmitters have more than one function.3 For example, norepi- tial and the propagation of the nerve impulse. Whether this occurs
nephrine in the brain probably helps regulate mood, functions in dream- depends on the number and frequency of potentials the postsynaptic
ing sleep, and maintains arousal. Some neurotransmitters are amino acids, neuron receives—a concept known as summation. Temporal sum-
including gamma-aminobutyric acid (GABA), glutamic acid, and aspartic mation (time relationship) refers to the effects of successive, rapid
acid. Small chains of amino acids (neuropeptides), such as enkephalins impulses received from a single neuron at the same synapse. Spatial
and endorphins, also function as neurotransmitters. Neurotransmitter summation (spacing effect) is the combined effects of impulses from
and neuromodulator substances are summarized in Table 12-2. a number of neurons onto a single neuron at the same time. Facili-
Because the neurotransmitter is normally stored on one side of tation refers to the effect of EPSP on the plasma membrane poten-
the synaptic cleft and the receptor sites are on the other side, chemi- tial. The plasma membrane is facilitated when summation brings the
cal synapses operate in one direction. Therefore action potentials are membrane closer to the threshold potential and decreases the stimulus
transmitted along a multineuronal pathway in one direction. The required to induce an action potential. The effect that a chemical neu-
binding of the neurotransmitter at the receptor site changes the per- rotransmitter has on the plasma membrane potential depends on the
meability of the postsynaptic neuron and, consequently, its membrane balance of these effects.
 CHAPTER 12  Structure and Function of the Neurologic System 299

HEALTH ALERT TABLE 12-3 DIVISIONS OF THE CENTRAL

Neuroplasticity NERVOUS SYSTEM
Neuroplasticity is the lifelong ability of the brain to adapt to new conditions STRUCTURES
by reorganizing neural pathways and forming new synapses, resulting in PRIMARY BRAIN SECONDARY IN SECONDARY
development, learning, and memory. The process is complex and the under- VESICLES VESICLES VESICLES
lying mechanisms include environmental influences, genetics, neurochemical Forebrain ­(prosencephalon) Telencephalon Cerebral hemispheres
alterations, functional changes in excitatory and inhibitory synapses, and axo- Cerebral cortex
nal and dendritic sprouting and turnover. Research is currently in progress to Limbic system
identify ways of delivering agents and therapies to promote neurorestoration Basal ganglia
and enhance brain or spinal cord reorganization of motor and sensory function Diencephalon Epithalamus
following injury or disease. The new clinical area of neuro-optometry provides Thalamus
an example of neuroplasticity within the brain. The utilization of external Hypothalamus
prisms and computerized vision programs for visual rehabilitation can modify Subthalamus
the visual processing system in children and adults to significantly improve Midbrain ­(mesencephalon) Mesencephalon Corpora quadrigemina
visual performance. Cerebral peduncles
Data from Alvarez TL et al: Vision therapy in adults with convergence Hindbrain ­(rhombencephalon) Metencephalon Cerebellum
insufficiency: clinical and functional magnetic resonance imaging Pons
measures, Optom Vis Sci 87(12):1–17, 2010; Barker AJ, Ullian EM: Myelencephalon Medulla oblongata
Astrocytes and synaptic plasticity, Neuroscientist 16(1):40–50, 2010; Spinal cord Spinal cord Spinal cord
Galván A: Neural plasticity of development and learning, Hum Brain
Mapp 31(6):879–890, 2010; Kujala T, Näätänen R: The adaptive brain:
a neurophysiological perspective, Prog Neurobiol 91(1):55–67, 2010;
Saver JL: Target brain: neuroprotection and neurorestoration in isch-
emic stroke, Rev Neurol Dis 7(suppl 1):S14–S21, 2010. Thalamus Radiations to cortex

4 QUICK CHECK 12-2

1. Explain the process of the chemical conduction of impulses.
2. What are neurotransmitters? Give several examples.
3. Compare summation and facilitation.

THE CENTRAL NERVOUS SYSTEM

The Brain
The human brain enables a person to reason, function intellectually,
Visual impulses
express personality and mood, and interact with the environment. This
pinkish gray organ weighs approximately 3 pounds and receives 15%
to 20% of the total cardiac output. The three major divisions of the Reticular formation
brain are (1) the forebrain, formed by the two cerebral hemispheres;
(2) the midbrain, which includes the corpora quadrigemina and cere-
bral peduncles; and (3) the hindbrain, which includes the cerebellum, Auditory impulses
pons, and medulla (Table 12-3). The midbrain, medulla, and pons Projection to spinal cord
comprise the brain stem, which connects the hemispheres of the brain, Ascending sensory tracts
cerebellum, and spinal cord. A collection of nerve cell bodies (nuclei)
FIGURE 12-5  Reticular Activating System. System consists of
within the brain stem makes up the reticular formation (Figure 12-5).
nuclei in the brain stem reticular formation plus fibers that conduct
The reticular formation is a large network of diffuse nuclei that control to the nuclei from below and fibers that conduct from the nuclei to
vital reflexes, such as those controlling cardiovascular function and widespread areas of the cerebral cortex. Functioning of the reticular
respiration. It is essential for maintaining wakefulness and therefore is activating system is essential for consciousness.
referred to as the reticular activating system (see Figure 12-5). Some
nuclei within the reticular formation cause specific motor movements.3
Divisions of the brain are associated with different functions, but
attributing specific functions to definite regions of the brain is not Forebrain
entirely accurate. However, for clinical considerations functional spec- Telencephalon. The telencephalon consists of the cerebrum (the
ificity is very useful for localizing pathologic conditions in various ner- largest portion of the brain), the limbic system, and some basal gan-
vous system regions. A neuropsychiatrist (Brodmann) is credited with glia (composed of several nuclei). The surface of the cerebrum (cere-
postulating that various activities are correlated to many regions of bral cortex) is covered with convolutions called gyri (see Figure 12-6),
the cerebral cortex. (Figure 12-6 illustrates these regions and describes which greatly increases the cortical surface area and the number of
some of the areas.)5 neurons. Grooves between adjacent gyri are termed sulci; deeper
300 CHAPTER 12  Structure and Function of the Neurologic System

Superior Precentral gyrus Central (rolandic) sulcus

frontal
Middle gyrus Postcentral gyrus
frontal
gyrus
PARIETAL
FRONTAL LOBE
LOBE

OCCIPITAL
LOBE
TEMPORAL
LOBE
Inferior
frontal
gyrus

Lateral Cerebellum Parietooccipital

(sylvian)
Pons sulcus
sulcus
(fissure) Inferior Medulla Calcarine
Middle temporal oblongata 4
3,1,2 sulcus
temporal gyrus
Superior gyrus
temporal
gyrus

A 19
Thalamus
18
Precentral gyrus
(primary 17
somatic motor)
Brodmann area 4
Postcentral gyrus 18
Premotor Central (primary somatic
Brodmann area 6 sulcus sensory) Hypothalamus
Brodmann
areas 3, 1, 2 Epithalamus
Frontal eye field (pineal gland)
Brodmann area 8 Primary visual
Brodmann
Prefrontal area 17
area B Cerebellum

Somatic
sensory
association
area

Visual association
Brodmann areas 18,19
Broca area
(motor speech area)
Brodmann areas 44, 45 Visual cortex
Auditory association
Brodmann area 22 Wernicke (sensory speech)
Brodmann area 22
Primary auditory Primary
C Brodmann areas 41, 42 taste area
FIGURE 12-6  The Cerebral Hemispheres. A, Left hemisphere of cerebrum, lateral view. B, Functional
areas of the cerebral cortex, midsagittal view. C, Functional areas of the cerebral cortex, lateral view.
 CHAPTER 12  Structure and Function of the Neurologic System 301

grooves are fissures. The cerebral cortex contains the cell bodies of
neurons (gray matter). White matter lies beneath the cerebral cortex
and is composed of myelinated nerve fibers. Primary
The two cerebral hemispheres are separated by a deep groove somatic
sensory area

Trunk
Le

Hip
known as the longitudinal fissure. The surface of each hemisphere is

Neck
Shouldedr
g

Hea
Arm
w
Foot

m
divided into lobes named after the region of the skull under which each

Elbo
ear

H ist
Toes

M Rinttle f and
Wr
lobe lies. The frontal lobe’s posterior margin is on the central sulcus

de f ge r
For

In dle fin ge
x f ing r
id g in

in er
Genitals
(fissure of Rolando), and it borders inferiorly on the lateral sulcus

r
ge
b
um

Li
(sylvian fissure, lateral fissure) (see Figure 12-6). The prefrontal area Th Eye
is responsible for goal-oriented behavior (e.g., ability to concentrate), se
No e
short-term or recall memory, the elaboration of thought, and inhibi- Fac
Left
tion of the limbic areas of the CNS. The premotor area (Brodmann hemisphere h,
area 6) (see Figure 12-6, C) is involved in programming motor move- Lips, teet w
nd ja
gums, a
ments. This area contains the cell bodies that form part of the basal
ganglia system (extrapyramidal system—efferent pathways outside Tongue
the pyramids of the medulla oblongata). The frontal eye fields (the Intr Pha
aab ryn
x
lower portion of Brodmann area 8), which are involved in controlling dom
ina
l
eye movements, are located on the middle frontal gyrus.
The primary motor area (Brodmann area 4) is located along the
precentral gyrus forming the primary voluntary motor area, which
has a somatotropic organization that is often referred to as a homuncu- A
lus (little man) (Figure 12-7). Electrical stimulation of specific areas of
this cortex causes specific muscles of the body to move. For example,
stimulation of Brodmann area 4 in the medial longitudinal fissure Motor
affects the lower limb and foot, whereas stimulation of the superior Sensory
lateral surface of the precentral gyrus affects the torso and arm, the
middle third of the hand, and the lower third of the face and mouth/
throat. The axons traveling from the cell bodies in and on either
side of this gyrus project fibers (axons) that form the corticospinal
tracts (pyramidal system) that descend into the spinal cord. Cerebral
impulses control function on the opposite side of the body, a phenom-
enon called contralateral control (Figure 12-8, A). The Broca speech
area (Brodmann areas 44, 45) is rostral on the inferior frontal gyrus.
It is usually on the left hemisphere and is responsible for the motor
aspects of speech. Damage to this area, commonly as a result of a cere-
Primary
Trunk

brovascular accident (stroke), results in the inability to form words or

Shoulder

Hip
rm

somatic
Elbow
Upper a

Arm

at least some difficulty in forming words (expressive aphasia or dys- Knee

motor area
Litt H rist
Mid Ring finge d
Ind dle fi inger r
le an

phasia) (see Chapter 14).

W

fing r

Ankle
ex nge
er

The parietal lobe lies within the borders of the central, parietooc-
f

b
um

cipital, and lateral sulci. This lobe contains the major area for somatic Toes
Th

ck
sensory input, located primarily along the postcentral gyrus (Brod- Ne
ll
mann areas 3, 1, 2), which is adjacent to the primary motor area. Com- yeba
and e
Eyelid
munication between the motor and sensory areas (and among other Face
regions in the cortex) is provided by association fibers. Much of this Left hemisphere
Lips and jaw
region is involved in sensory association (storage, analysis, and inter-
pretation of stimuli). (Figure 12-7 shows the distribution of functions Tongue

associated with both the primary motor area and the primary sensory
area of the cerebral cortex.) Swallo
wing
The occipital lobe lies caudal to the parietooccipital sulcus and is
superior to the cerebellum. The primary visual cortex (Brodmann area
17) is located in this region and receives input from the retinas. Much
of the remainder of this lobe is involved in visual association (Brod- B
mann areas 18, 19). The temporal lobe lies inferior to the lateral fissure
and is composed of the superior, middle, and inferior temporal gyri. FIGURE 12-7  Primary Somatic Sensory (A) and Motor (B) Areas
The primary auditory cortex (Brodmann area 41) and its related asso- of the Cortex. This illustration shows which parts of the body are
ciation area (Brodmann area 42) lie deep within the lateral sulcus on “mapped” to specific cortical areas. The exaggerated face indicates
the superior temporal gyrus. The Wernicke area, along with adjacent that more cortical area is devoted to processing information to and
portions of the parietal lobe, constitutes a sensory speech area. This area from the many receptors and motor units of the face than for the
leg or arm, for example. (From Patton KT, Thibodeau GA: Anatomy
is responsible for reception and interpretation of speech, and dysfunc-
& physiology, ed 7, St Louis, 2010, Mosby.)
tion may result in receptive aphasia or dysphasia. The temporal lobe
also is involved in memory consolidation and smell.
302 CHAPTER 12  Structure and Function of the Neurologic System

Somatic
motor
area Thalamus
of
cerebral Lentiform
cortex nucleus
Internal
capsule Red
nucleus
Midbrain Substantia
Basis nigra
pedunculus
Upper
motor
neuron Reticular
Pons formation

Pyramid
Medulla
Lateral Pyramidal Rubrospinal
corticospinal decussation tract
tract
Reticulospinal
Interneuron Spinal Spinal
tract
cord cord
Motor
end-plate Lower
(anterior horn)
A motor neuron

Somatic
sensory
area of
cerebral
cortex
Cerebrum
Tertiary
sensory Tertiary
neuron sensory
Thalamus neuron
Medial
lemniscus
Midbrain

Secondary
Medial sensory
lemniscus neuron

Nucleus Collateral
Secondary Pons fibers to
gracilis sensory reticular
Decussation of neuron Dorsal root formation
medial lemniscus Medial ganglion
Medulla
Dorsal root lemniscus Primary
ganglion Medulla sensory Lateral
spinothalamic
Fasciculus neuron
tract
gracilis
Spinal
Primary Spinal Receptor cord
sensory cord
B neuron
FIGURE 12-8  Examples of Somatic Motor and Sensory Pathways. A, Motor: pyramidal pathway
illustrated by the lateral corticospinal tract and extrapyramidal pathways illustrated by the rubrospinal
and reticulospinal tracts. B, Sensory: pathways of the medial lemniscal system that conducts informa-
tion about discriminating touch and kinesthesis and the spinothalamic pathway that conducts informa-
tion about pain and temperature. (Modified from Patton KT, Thibodeau GA: Anatomy & physiology,
ed 7, St Louis, 2010, Mosby.)
 CHAPTER 12  Structure and Function of the Neurologic System 303

Lentiform nucleus
Basal ganglia
Caudate nucleus

Thalamus

Amygdala

Substantia nigra
(in midbrain)

Body of
caudate nucleus

Corpus Internal capsule

striatum
Lentiform Putamen
nucleus
Globus
pallidus Putamen

Thalamus
Mamillary body
Head of caudate nucleus

B
FIGURE 12-9  Basal Nuclei. A, The basal nuclei seen through the cortex of the left cerebral hemi-
sphere. B, The basal nuclei seen in a frontal (coronal) section of the brain. (From Patton KT, Thibodeau
GA: Anatomy & physiology, ed 7, p 432, St Louis, 2010, Mosby.)

Another lobe, the insula (insular lobe), lies hidden from view in the indirect interconnections with the thalamus, premotor cortex, red
lateral sulci between the temporal and frontal lobe of each hemisphere. nucleus, reticular formation, and spinal cord have been considered part
The insula processes sensory and emotional information and routes of the basal ganglia system (extrapyramidal system). The basal ganglia
the information to other areas of the brain. Lying directly beneath system is believed to exert a stabilizing effect on motor movements.
the longitudinal fissure is a mass of white matter pathways called the Parkinson disease and Huntington disease are conditions associated
corpus callosum (transverse or commissural fibers). This structure with defects of the basal ganglia. They are characterized by various
connects the two cerebral hemispheres and is essential in coordinating involuntary or exaggerated motor movements (see Chapter 14).
activities between hemispheres (see Figure 12-6). The limbic system is a group of structures surrounding the corpus
Inside the cerebrum are numerous tracts (white matter) and nuclei callosum that mediate emotion through connections in the prefrontal
(gray matter). The major cerebral nuclei are called basal ganglia and cortex. It is composed of the Papez circuit (amygdala, parahippocam-
include the corpus striatum and amygdala. The corpus striatum con- pal gyrus, hippocampus, fornix, mamillary body of the hypothala-
sists of the lentiform nucleus (lens-shaped) (Figure 12-9), the puta- mus, thalamus, and cingulate gyrus), septal area, habenula, other
men and globus pallidus, and the ram’s horn–shaped caudate nucleus. portions of the hypothalamus, and related autonomic nuclei. It is an
The internal capsule (see Figure 12-9) is a thick white matter region in extension or modification of the olfactory system. Its principal effects
which afferent and efferent pathways, to and from the cerebral cortex, are believed to be involved in primitive behavioral responses, visceral
pass through the center of the cerebral hemispheres between the cau- reaction to emotion, feeding behaviors, biologic rhythms, and the
date and lentiform nuclei (see Figure 12-9). sense of smell.
Functionally, basal ganglia include, in addition to the corpus stria- Diencephalon. The diencephalon (interbrain), surrounded by
tum, the subthalamic nucleus of the diencephalon and the substantia the cerebrum, has four divisions: epithalamus, thalamus, hypo-
nigra of the mesencephalon. The basal ganglia plus their direct and thalamus, and subthalamus (see Table 12-3 and Figure 12-6).
304 CHAPTER 12  Structure and Function of the Neurologic System

BOX 12-1 FUNCTIONS OF THE Hindbrain

HYPOTHALAMUS Metencephalon. The major structures of the metencephalon are
• Visceral and somatic responses the cerebellum and the pons. The cerebellum (see Figure 12-6) is com-
• Affectual responses posed of gray and white matter, and its cortical surface is convoluted
• Hormone synthesis like the surface of the cerebrum. It also is divided by a central fissure
• Sympathetic and parasympathetic activity into two lobes connected by the vermis.
• Temperature regulation The cerebellum is responsible for reflexive, involuntary fine-tuning
• Feeding responses of motor control and for maintaining balance and posture through
• Physical expression of emotions extensive neural connections with the medulla (through the inferior
• Sexual behavior cerebellar peduncle) and with the midbrain (through the superior cer-
• Pleasure-punishment centers ebellar peduncle). The two hemispheres are connected to the pons by
• Level of arousal or wakefulness the middle cerebellar peduncles. These connections allow extensive
sampling of visual, vestibular, and proprioceptive data from other
Data from Purves D et al: Neuroscience, ed 3, Sunderland, Mass, regions of the CNS and periphery.
2004, Sinauer Associates; Kiernan JA: Barr’s the human nervous
The pons (bridge) is easily recognized by its bulging appearance
system: an anatomical viewpoint, ed 9, Philadelphia, 2009, Lippincott
Williams & Wilkins.
below the midbrain and above the medulla. Primarily it transmits
information from the cerebellum to the brain stem and between the
The epithalamus forms the roof of the third ventricle (a brain cav- two cerebellar hemispheres. The nuclei of the fifth through eighth cra-
ity) and composes the most superior portion of the diencephalon. nial nerves are located in this structure.
Its connections and functions are closely associated with those of Myelencephalon. The myelencephalon usually is called the
the limbic system. medulla oblongata and forms the lowest portion of the brain stem.
The thalamus borders and surrounds the third ventricle. It is a Reflex activities, such as heart rate, respiration, blood pressure, cough-
major integrating center for afferent impulses to the cerebral cortex. ing, sneezing, swallowing, and vomiting, are controlled in this area.
Various sensations are perceived at this level, but cortical processing is The nuclei of cranial nerves IX through XII also are located in this
required for interpretation. The thalamus serves also as a relay center region.
for information from the basal ganglia and cerebellum to the appropri- A major portion of the descending motor pathways (i.e., cortico-
ate motor area. spinal tracts) cross to the other side, or decussate, at the medulla (see
The hypothalamus forms the base of the diencephalon. The hypo- Figure 12-8). These pathways, together with other areas of decussation
thalamus functions to (1) maintain a constant internal environment in the CNS, are the basis for the phenomenon of contralateral con-
and (2) implement behavioral patterns. Integrative centers control trol. Sleep-wake rhythms also are processed by neural influences from
autonomic nervous system (ANS) function, regulate body temperature lower brain centers and are associated with a complex group of dif-
and endocrine function, and adjust emotional expression. The hypo- fuse structures and functions (see Chapter 13), including the reticular
thalamus exerts its influence through the endocrine system, as well as activating system (cells that receive collateral signals from the afferent
through neural pathways (Box 12-1). sensory pathways and project the signals to the higher brain centers,
The subthalamus flanks the hypothalamus laterally. It serves as an thus controlling CNS activity) (see Figure 12-5).
important basal ganglia center for motor activities.

Midbrain 4 QUICK CHECK 12-3

Mesencephalon. The midbrain (mesencephalon) is composed of 1. Name the three major divisions of the brain and their component parts.
three structures: the corpora quadrigemina (tectum) (composed of 2. Describe the limbic system’s functions.
the superior and inferior colliculi), the tegmentum (containing the red 3. What are the two major functions of the hypothalamus?
nucleus and substantia nigra), and the basis pedunculi. (The tegmen-
tum and basis pedunculi are collectively called the cerebral peduncles.)
The superior colliculi are involved with voluntary and involun- The Spinal Cord
tary visual motor movements (e.g., the ability of the eyes to track The spinal cord is the portion of the CNS that lies within the vertebral
moving objects in the visual field). The inferior colliculi accom- canal and is surrounded and protected by the vertebral column. The
plish similar motor activities but involve movements affecting the spinal cord has many functions, which include a long nerve cable that
auditory system (e.g., positioning the head to improve hearing). connects the brain and body, somatic and autonomic reflexes, motor
The red nucleus receives ascending sensory information from the pattern control centers, and sensory and motor modulation. It origi-
cerebellum and projects a minor motor pathway, the rubrospinal nates in the medulla oblongata and ends at the level of the first or sec-
tract, to the cervical spinal cord. The last portion of the basal ganglia ond lumbar vertebra in adults (Figure 12-10). The end of the spinal
is the substantia nigra, which synthesizes dopamine, a neurotrans- cord, the conus medullaris, is cone shaped. Spinal nerves continue
mitter and precursor of norepinephrine. Its dysfunction is associ- from the end of the spinal cord and form a nerve bundle called the
ated with Parkinson disease and schizophrenia. The basis pedunculi cauda equina. The filament anchor from the conus medullaris to the
are made up of efferent fibers of the corticospinal, corticobulbar, coccyx is the filum terminale (see Figure 12-10).
and corticopontocerebellar tracts. Grossly, the spinal cord is divided into vertebral sections (8 cervi-
Other notable structures of this region are the nuclei of the third cal, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal) that correspond
and fourth cranial nerves. The cerebral aqueduct (aqueduct of Syl- to paired nerves (see Figure 12-10). A cross section of the spinal cord
vius), which carries cerebrospinal fluid, also traverses this structure. (Figure 12-11) is characterized by a butterfly-shaped inner core of gray
Obstruction of this aqueduct is often the cause of hydrocephalus. matter (containing nerve cell bodies). The central canal lies in the
 CHAPTER 12  Structure and Function of the Neurologic System 305

Thalamus
T12
C1
Cervical Cerebellum C2
C3 L1 Conus
plexus Cervical C4
C5 medullaris
Brachial enlargement C6
C7 L2
plexus C8
T1
T2
T3 L3
T4 Cauda equina
T5
T6
L4
T7
T8 L5
T9
T10
Lumbar T11 S1
T12
Lumbar enlarge- L1
plexus ment L2 S2
L3
Femoral Filum L4 S3
nerve termi- L5

Sacral nale S1
S2 S4
S3
plexus S4 S5
S5
Coccyx
Sciatic Coccyx
nerve Posterior cutaneous
nerve of thigh Filum terminale
Pudendal
nerve
A B C
FIGURE 12-10  Spinal Cord Within Vertebral Canal and Exiting Spinal Nerves. A, Posterior view of
brain stem and spinal cord in situ with spinal nerves and plexus. B, Lateral view of brain stem and spinal
cord. C, Enlargement of caudal area showing termination of spinal cord (conus medullaris) and group of
nerve fibers constituting the cauda equina. (Redrawn from Rudy EB, editor: Advanced neurological and
neurosurgical nursing, St Louis, 1984, Mosby.)

center of this region and extends through the spinal cord from its ori- Substantia gelatinosa
gin in the fourth ventricle. The gray matter of the spinal cord is divided Central Posterior horn
canal Spinal cord
into three regions and displays specific functional characteristics. Lateral horn
These regions include the posterior horn, or dorsal horn (composed Posterior
root
primarily of interneurons and axons from sensory neurons whose cell Anterior
bodies lie in the dorsal root ganglion). At the tip of the posterior horn horn
is the substantia gelatinosa, a structure involved in pain transmission Spinal
Anterior ganglion
(see Chapter 13). The lateral horn contains cell bodies involved with root
the ANS. The anterior horn, or ventral horn, contains the nerve cell
bodies for efferent pathways that leave the spinal cord by way of spinal Pia mater
nerves. Arachnoid
Surrounding the gray matter is white matter that forms ascending
Dura mater Spinal
and descending pathways called spinal tracts. Spinal tracts are named
nerves
to denote their beginning and ending points. For example, the spi-
nothalamic tract (see Figure 12-8, B) carries nerve impulses from the
spinal cord to the thalamus in the diencephalon. Numerous spinal
tracts are grouped into columns according to their location within the
white matter. These include the anterior columns, lateral columns,
and posterior (dorsal) columns (Figure 12-12). Transverse
process of
Neural circuits in the spinal cord, when activated, display specific vertebrae
sets of motor responses. Reflex arcs form basic units that respond to
stimuli and provide protective circuitry for motor output. Structures
needed for a reflex arc are a receptor, an afferent (sensory) neuron, an
efferent (motor) neuron, and an effector muscle or gland. A simple
reflex arc may contain only two neurons (Figure 12-13). Interneurons
Sympathetic
are usually present and provide a link between sensory and motor
Body of vertebra ganglion
neurons.
The motor effects of reflex arcs generally occur before the event is FIGURE 12-11  Coverings of the Spinal Cord. The dura mater is
perceived in the brain’s higher centers. Much internal environmental shown in natural color. Note how it extends to cover the spinal
regulation is mediated by reflex activity involving the ANS. nerve roots and nerves. The arachnoid is highlighted in blue and the
Afferent pathways transmit information from peripheral recep- pia mater in pink. (Modified from Thibodeau GA, Patton KT: Struc-
tors and eventually terminate in the cerebral or cerebellar cortex, or ture and function of the human body, ed 3, St Louis, 2008, Mosby.)
306 CHAPTER 12  Structure and Function of the Neurologic System

both. Efferent pathways primarily relay information from the cere- interneurons, which then form synapses with lower motor neurons
brum to the brain stem or spinal cord. Upper motor neurons are that project into the periphery. Lower motor neurons directly influ-
completely contained within the CNS. Their primary roles are con- ence muscles. Their cell bodies lie in the gray matter of the brain stem
trolling fine motor movement and influencing/modifying spinal reflex and spinal cord, but their processes extend out of the CNS and into
arcs and circuits. Generally, upper motor neurons form synapses with the PNS. Destruction of upper motor neurons usually results in initial

Dorsal (posterior) Columns (tracts)

Fasciculus gracilis
Fasciculus cuneatus

Posterior spinocerebellar

Lateral corticospinal
Lateral spinothalamic
Rubrospinal
Anterior spinocerebellar

Anterior corticospinal
Spinotectal

Anterior spinothalamic Reticulospinal

Vestibulospinal

Tectospinal
Anterior median fissure

Ventral (anterior) Columns

FIGURE 12-12  Major Tracts of the Spinal Cord. The major ascending (sensory) tracts, shown only
on the left here, are highlighted in blue. The major descending (motor) tracts, shown only on the right,
are highlighted in red. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010,
Mosby.)

Gray Interneuron
matter Dorsal root
ganglion

Sensory
neuron Stretch
receptor

Patella

Spinal cord Motor

neuron
Patellar
Quadriceps tendon
muscle
(effector)

FIGURE 12-13  Cross Section of Spinal Cord Showing Simple Reflex Arc. (From Patton KT,
Thibodeau GA­: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)
 CHAPTER 12  Structure and Function of the Neurologic System 307

Motor neuron
Myelin Sensory Pathways
fiber
sheath
The three clinically important spinal afferent pathways are the poste-
Sarcoplasm
Schwann cell rior column, anterior spinothalamic tract, and lateral spinothalamic
Synaptic tract (see Figures 12-7 and 12-8, B, and 12-12). The posterior (dor-
vesicles sal) column (fasciculus gracilis and fasciculus cuneatus) carries
Sarcolemma fine-touch sensation, two-point discrimination, and proprioceptive
information (i.e., epicritic information). The posterior column is
formed by a three-neuron chain. The primary afferent neuron is the
sensory neuron (of the reflex arc), but it sends its axon ipsilaterally up
the spinal cord to a specific part of the posterior funiculus and synapses
in the posterior column nuclei in the medulla oblongata. A basketball
playing center has primary afferent neurons that could be more than 6
Acetylcholine
feet long, running from the great toe up to the medulla oblongata. The
receptor sites
second-order neuron crosses contralaterally at the medial lemniscus
Synaptic and ascends and synapses with a specific nucleus of the thalamus. The
cleft Motor end-plate third-order neuron, originating in the thalamus, continues the tract
FIGURE 12-14  Neuromuscular Junction. This figure shows how into the internal capsule, corona radiata, and postcentral gyrus (Brod-
the distal end of a motor neuron fiber forms a synapse, or “chemi- mann areas 3, 1, 2) (see Figures 12-6, 12-7, A, and 12-8, B). The ante-
cal junction,” with an adjacent muscle fiber. Neurotransmitters rior and lateral spinothalamic tracts are responsible for vague touch
(specifically, acetylcholine) are released from the neuron’s synaptic
sensation and for pain and temperature perception, respectively (see
vesicles and diffuse across the synaptic cleft. There they stimulate
Figure 12-8, B). These modalities are referred to as protopathic. These
receptors in the motor end-plate region of the sarcolemma. (From
Patton KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis, tracts also form a three-neuron chain. However, their primary afferent
2010, Mosby.) neurons synapse in the posterior horn of the spinal cord, not just at the
level they enter the intervertebral foramen but in a number of spinal
segments above and below their point of entry. This is an example of
divergence. The second-order neurons in the posterior horn cross to
paralysis followed within days or weeks by partial recovery, whereas the contralateral side in the spinal cord, ascend to the same thalamic
destruction of the lower motor neurons leads to paralysis. Peripheral nucleus as the posterior column pathway, and continue with the pos-
nerve damage may be followed by nerve regeneration and recovery (see terior column pathway to the postcentral gyrus.
Figure 12-4).
Muscle activity (i.e., stimulation and contraction) is regulated by Protective Structures of the Central Nervous System
nerve impulses. Motor neurons innervate one or more muscle cells, Cranium
forming motor units, which consist of a neuron and the skeletal mus- The cranium is composed of eight bones. The cranial vault encloses
cles it stimulates. The junction between the axon of the motor neuron and protects the brain and its associated structures.
and the plasma membrane of the muscle cell is called the neuromuscu- The galea aponeurotica, which is a thick, fibrous band of tissue
lar (myoneural) junction (Figure 12-14). (Injury to motor neurons is overlying the cranium between the frontal and occipital muscles,
discussed in Chapter 15.) affords added protection to the skull. The subgaleal space has venous
connections with the dural sinuses, and with increased intracranial
Motor Pathways pressure, blood can be shunted to the space, thus reducing pressure in
The four clinically relevant motor pathways are the lateral cortico- the intracranial cavity. The subgaleal space is also a common site for
spinal, corticobulbar, reticulospinal, and vestibulospinal tracts.5 The wound drains after intracranial surgery.
corticospinal (see Figure 12-8, A) and corticobulbar pathways are The floor of the cranial vault is irregular and contains many foram-
essentially the same tract and consist of a two-neuron chain. The cell ina (openings) for cranial nerves, blood vessels, and the spinal cord to
bodies originate in and around the precentral gyrus; pass through the exit. The cranial floor is divided into three fossae (depressions). The
corona radiata of the cerebrum, the internal capsule, middle three frontal lobes lie in the anterior fossa, the temporal lobes and base of
fifths of the cerebral pedunculus, pons, and pyramid; and decussate the diencephalon lie in the middle fossa (temporal fossa), and the cer-
(cross contralaterally) in the medulla oblongata and form the lateral ebellum lies in the posterior fossa. These terms are commonly used
corticospinal tract of the spinal cord (see Figure 12-12). The corti- anatomic landmarks to describe the location of intracranial lesions.
cobulbar tract synapses on motor cranial nuclei within the brain stem.
The lateral corticospinal tract axons (upper motor neurons) leave the Meninges
tract to go to specific interneurons or motor neurons in the anterior Surrounding the brain and spinal cord are three protective mem-
horn. The lateral corticospinal tract has the same somatropic organi- branes: the dura mater, the arachnoid, and the pia mater. Collec-
zation as the body (see Figures 12-7 and 12-8, A). These lower motor tively they are called the meninges (Figure 12-15, B). The dura mater
neurons project through nerves to specific muscles. These tracts are (meaning literally “hard mother”) is composed of two layers, with the
involved in precise motor movements. The reticulospinal tract (see venous sinuses formed between them. The outermost layer forms the
Figure 12-12) modulates motor movement by inhibiting and excit- periosteum (endosteal layer) of the skull. The inner dura (meningeal
ing spinal activity. The vestibulospinal tract arises from a vestibular layer) is responsible for forming rigid membranes that support and
nucleus in the pons and causes the extensor muscles of the body to separate various brain structures.
rapidly contract, most dramatically witnessed when a person starts to One of these membranes, the falx cerebri, dips between the two
fall backward. cerebral hemispheres along the longitudinal fissure. The falx cerebri
308 CHAPTER 12  Structure and Function of the Neurologic System

Bone of
skull
Epidural space
Arachnoid villus Dura
Arachnoid villus mater
Superior sagittal sinus
(venous blood)
Arachnoid mater
Subarachnoid
space
Superior sagittal Cerebral cortex
sinus
Pia mater
Choroid plexus of Falx cerebri
lateral ventricle (dura mater)
Choroid plexus of Arachnoid
Interventricular
third ventricle layer
foramen
Subarachnoid
Cerebral aqueduct space
B
Lateral foramen
Choroid plexus of fourth ventricle
Fourth ventricle
Median foramen
Cisterna magna
Central canal of spinal cord
Dura mater

A
FIGURE 12-15  Flow of Cerebrospinal Fluid and Meninges of the Brain. A, The fluid produced by
filtration of blood by the choroid plexus of each ventricle flows inferiorly through the lateral ventricles,
interventricular foramen, third ventricle, cerebral aqueduct, fourth ventricle, and subarachnoid space
to the blood. B, Meninges of the brain in relation to CSF and venous blood flow. (From Patton KT,
Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)

is anchored anteriorly to the base of the brain at the crista galli of TABLE 12-4 COMPOSITION OF
the ethmoid bone. The tentorium cerebelli, a common landmark,
CEREBROSPINAL FLUID
is a membrane that separates the cerebellum below from the cere-
bral structures above. Internal to the dura mater lies the arachnoid, CONSTITUENT NORMAL VALUE
a spongy, weblike structure that loosely follows the contours of the Na+ 148 mM
cerebral structures. K+ 2.9 mM
The subdural space lies between the dura and arachnoid. Many Cl− 125 mM
small bridging veins that have little support traverse the subdural space. HCO−3 22.9 mM
Their disruption results in a subdural hematoma (see Chapter 15). The Glucose (fasting) 50-75 mg/dl (60% of serum glucose)
subarachnoid space lies between the arachnoid and the pia mater and pH 7.3
contains cerebrospinal fluid (CSF) (see Figure 12-15, A and B). Unlike Protein 15-45 mg/dl
the dura mater and arachnoid, the delicate pia mater adheres to the Albumin 80%
contours of the brain and spinal cord. It provides support for blood Globulin 6-10%
vessels serving brain tissue. The choroid plexuses, structures that pro- Cells
duce CSF, arise from the pial membrane (see Figure 12-15, B). The White (lymphocyte) 0-6/mm3
spinal cord is anchored to the vertebrae by extension of the meninges. Red 0
The meninges continue beyond the end of the spinal cord (at vertebrae
levels L1 and L2) to the lower portion of the sacrum. CSF contained
within the subarachnoid space also circulates inferiorly to about the
second sacral vertebra. Cerebrospinal Fluid and the Ventricular System
The meninges form potential and real spaces important to under- Cerebrospinal fluid (CSF) is a clear, colorless fluid similar to blood
standing functional and pathologic mechanisms. For example, between plasma and interstitial fluid. The intracranial and spinal cord struc-
the dura mater and skull lies a potential space termed the epidural tures float in CSF and are thereby protected from jolts and blows. The
space (see Figure 12-15, B). The arterial supply to the meninges con- buoyant properties of the CSF also prevent the brain from tugging on
sists of blood vessels that lie within grooves in the skull. A skull fracture meninges, nerve roots, and blood vessels. (Constituents of CSF are
can severe one of these vessels and produce an epidural hematoma. listed in Table 12-4.) Between 125 and 150 ml of CSF is circulating
 CHAPTER 12  Structure and Function of the Neurologic System 309

Atlas Axis Spinous process

Superior Vertebral foramen

curvature
Cervical
Cervical articular Lamina
vertebrae process Superior articular
facet
(7)
Transverse
process
Pedicle
cic curvature

Thoracic Body
vertebrae
Thora

(12)

Blood vessels
Lumb

Vertebral body
Inter-
ar curvature

Nucleus pulposus
vertebral Annulus fibrosus Intervertebral
foramina Lumbar disk
vertebrae
(5)
Vertebral
spine Cavity for
re

B spinal cord
ic curvatu

FIGURE 12-17  A, Lumbar Vertebra, Superior View; B, Interver-

tebral Disk. (A from Thibodeau GA, Patton KT: Anatomy & physiol-
Pelv

Sacrum ogy, ed 6, St Louis, 2007, Mosby; B from Patton KT, Thibodeau GA:
Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)
Coccyx

A Right lateral view B Anterior view within the blood flow of the venous sinuses. CSF is reabsorbed through
FIGURE 12-16  Vertebral Column. A, Right lateral view. B, Ante- a pressure gradient between the arachnoid villi and the cerebral venous
rior view. (From Patton KT, Thibodeau GA: Anatomy & physiology, sinuses. The villi function as one-way valves directing CSF outflow into
ed 7, St Louis, 2010, Mosby.) the blood but preventing blood flow into the subarachnoid space. Thus
CSF is formed from the blood, and after circulating throughout the
CNS, it returns to the blood.
within the ventricles (small cavities) and subarachnoid space at any
given time. Approximately 600 ml of CSF is produced daily. Vertebral Column
The choroid plexuses in the lateral, third, and fourth ventricles pro- The vertebral column (Figure 12-16) is composed of 33 vertebrae: 7
duce the major portion of CSF. (Ventricles are illustrated in Figure cervical, 12 thoracic, 5 lumbar, 5 fused sacral, and 4 fused coccygeal.
12-15.) These plexuses are characterized by a rich network of blood Between each interspace (except for the fused sacral and coccygeal
vessels, supplied by the pia mater, that lie close to the ependymal cells vertebrae) is an intervertebral disk (Figure 12-17). At the center of
of the ventricles. the intervertebral disk is the nucleus pulposus, a pulpy mass of elastic
The CSF exerts pressure within the brain and spinal cord. When a fibers. The intervertebral disk absorbs shocks, preventing damage to
person is supine, CSF pressure is about 80 to 180 mm of water pres- the vertebrae. The intervertebral disk is also a common source of back
sure, or approximately 5 to 14 mm of mercury pressure, but doubles problems. If too much stress is applied to the vertebral column, the
when the person moves to an upright position. CSF flow results from disk contents may rupture and protrude into the spinal canal, causing
the pressure gradient between the arterial system and the CSF-filled compression of the spinal cord or nerve roots.
cavities. Beginning in the lateral ventricles, the CSF flows through the
interventricular foramen (foramen of Monro) into the third ventricle
and then passes through the cerebral aqueduct (aqueduct of Sylvius)
into the fourth ventricle. From the fourth ventricle the CSF may pass
through either the paired lateral apertures (foramen of Luschka) or
4 QUICK CHECK 12-4
1. What information is conveyed in the ascending and descending spinal
the median aperture (foramen of Magendie) before communicat- tracts?
ing with the subarachnoid spaces of the brain and spinal cord. The 2. Contrast the functions of upper and lower motor neurons.
CSF does not, however, accumulate. Instead, it is reabsorbed into the 3. Name the protective structures of the central nervous system, and briefly
venous circulation through the arachnoid villi. The arachnoid villi describe each one.
protrude from the arachnoid space, through the dura mater, and lie
310 CHAPTER 12  Structure and Function of the Neurologic System

Superficial Blood Supply of the Central Nervous System

temporal artery Blood Supply to the Brain
The brain receives approximately 20% of the cardiac output, or 800 to
Posterior 1000 ml of blood flow per minute. Carbon dioxide is a primary regula-
auricular tor for blood flow within the CNS. It is a potent vasodilator, and its
artery
effects ensure an adequate blood supply.
The brain derives its arterial supply from two systems: the inter-
Occipital
artery nal carotid arteries and the vertebral arteries (Figure 12-18). The
internal carotid arteries supply a proportionately greater amount of
Ascending blood flow. They originate at the common carotid arteries, enter the
Maxillary artery
pharyngeal
artery cranium through the base of the skull, and pass through the cavernous
Lingual artery
sinus. After forming some small branches, these arteries divide into the
Internal carotid Facial anterior and middle cerebral arteries. The vertebral arteries originate
artery artery at the subclavian arteries and pass through the transverse foramina of
External carotid Superior thyroid artery the cervical vertebrae, entering the cranium through the foramen mag-
artery num. They join at the junction of the pons and medulla to form the
Subclavian artery
Vertebral artery
basilar artery (Figure 12-19). The basilar artery divides at the level of
Brachiocephalic the midbrain to form paired posterior cerebral arteries.
artery The circle of Willis (see Figure 12-19) provides an alternative route
Common
carotid for blood flow when one of the contributing arteries is obstructed (col-
artery lateral blood flow). The circle of Willis is formed by the posterior cere-
FIGURE 12-18  Major Arteries of the Head and Neck. (From bral arteries, posterior communicating arteries, internal carotid arteries,
Patton KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis, anterior cerebral arteries, and anterior communicating artery. The ante-
2010, Mosby.) rior cerebral, middle cerebral, and posterior cerebral arteries leave the

Anterior cerebral
artery Anterior communicating
cerebral artery
Posterior communicating
artery Internal carotid artery

Posterior cerebral Middle cerebral artery

artery

Pontine branches
Superior cerebellar artery
Basilar artery Anterior inferior
cerebellar artery
Vertebral artery Posterior inferior
cerebellar artery

Anterior
spinal artery

Anterior communicating Anterior cerebral artery

artery
Middle cerebral artery
Posterior communicating
artery Internal carotid artery

Superior Posterior cerebral artery

cerebellar artery
Pontine branches
Anterior inferior
cerebellar artery Basilar artery
Vertebral artery
Posterior inferior
cerebellar artery Anterior spinal artery
FIGURE 12-19  Arteries at the Base of the Brain. The arteries that compose the circle of Willis are
the two anterior cerebral arteries, joined to each other by the anterior communicating artery and two
short segments of the internal carotids, off of which the posterior communicating arteries connect to
the posterior cerebral arteries. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis,
2010, Mosby.)
 CHAPTER 12  Structure and Function of the Neurologic System 311

TABLE 12-5 ARTERIAL SYSTEMS SUPPLYING THE BRAIN

ARTERIAL ORIGIN STRUCTURES SERVED CONDITIONS CAUSED BY OCCLUSION
Anterior ­cerebral artery Basal ganglia; corpus callosum; medial surface of cerebral hemispheres; Hemiplegia on ­contralateral side of body, greater in
superior ­surface of frontal and parietal lobes lower than in upper extremities
Middle cerebral artery Frontal lobe; parietal lobe; temporal lobe (primarily cortical surfaces) Aphasia in ­dominant hemisphere and ­contralateral
hemiplegia (see Chapter 14)
Posterior ­cerebral artery Part of diencephalon and ­temporal lobe; occipital lobe Visual loss; sensory loss; contralateral hemiplegia if
cerebral peduncle affected

Occlusion of
anterior
cerebral artery

Occlusion of
middle
cerebral artery
Occlusion of
anterior
cerebral artery
Occlusion of
posterior
cerebral artery
Occlusion of
Occlusion of posterior
Cerebellum middle cerebral artery
cerebral artery

Cerebellum

A B
FIGURE 12-20  Areas of the Brain Affected by Occlusion of the Anterior, Middle, and Posterior
Cerebral Artery Branches. A, Inferior view. B, Lateral view.

circle of Willis and extend to various brain structures. (Table 12-5 and certain types of antibiotics and chemotherapeutic drugs show a greater
Figure 12-20 illustrate structures served, functional relationships, and propensity than others for crossing this barrier.
pathologic considerations related to occlusion of cerebral arteries.)
Cerebral venous drainage does not parallel its arterial supply, Blood Supply to the Spinal Cord
whereas the venous drainage of the brain stem and cerebellum does par- The spinal cord derives its blood supply from branches off the ver-
allel the arterial supply of these structures. The cerebral veins are classi- tebral arteries and from branches from various regions of the aorta
fied as superficial and deep veins. The veins drain into venous plexuses (­Figure 12-23). The anterior spinal artery and the paired posterior
and dural sinuses (formed between the dural layers) and eventually join spinal arteries branch from the vertebral artery at the base of the cra-
the internal jugular veins at the base of the skull (Figure 12-21). Ade- nium and descend alongside the spinal cord. Arterial branches from
quacy of venous outflow can significantly affect intracranial pressure. vessels exterior to the spinal cord follow the spinal nerve through the
For example, head-injured individuals who turn or let their heads fall intervertebral foramina, pass through the dura, and divide into the
to the side partially occlude venous return, and the intracranial pressure anterior and posterior radicular arteries.
can increase then because of decreased flow through the jugular veins. The radicular arteries eventually connect to the spinal arter-
ies. Branches from the radicular and spinal arteries form plexuses
Blood-Brain Barrier whose branches penetrate the spinal cord, supplying the deeper tis-
The blood-brain barrier describes cellular structures that selectively sues. Venous drainage parallels the arterial supply closely and drains
inhibit certain potentially harmful substances in the blood from into venous sinuses located between the dura and periosteum of the
entering the interstitial spaces of the brain or CSF. Supporting cells vertebrae.
(neuroglia), particularly the astrocytes, and tight junctions between
endothelial cells of brain cell capillaries (see Chapter 1) are likely
THE PERIPHERAL NERVOUS SYSTEM
involved in forming this barrier (Figure 12-22). The exact nature of
this mechanism is controversial, but it appears that certain metabo- The cranial and spinal nerves, including their branches and ganglia,
lites, electrolytes, and chemicals can cross into the brain to varying constitute the peripheral nervous system (PNS). A peripheral nerve
degrees. This has substantial implications for drug therapy because (cranial or spinal) is composed of individual axons wrapped in a
312 CHAPTER 12  Structure and Function of the Neurologic System

Superior
sagittal sinus
Inferior
sagittal sinus
Straight sinus
Transverse sinus Cavernous
sinus
Occipital sinus

Sigmoid sinus Ophthalmic

veins
(Superficial veins)
Superior petrosal sinus
Facial vein

Inferior petrosal sinus

Internal jugular vein

(Deep vein) Emissary veins
FIGURE 12-21  Large Veins of the Head. Deep veins and dural sinuses are projected on the skull.
Note two superficial veins in the face are tributaries that send blood through emissary veins in the
skull foramen into deep veins inside the skull terminating in the internal jugular vein. (From Patton KT,
Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)

Cell
Tight membrane Basement
junction membrane
proteins

Cytoplasm

Red
blood
cell
Astrocyte
Capillary foot processes
lumen

Tight Capillary
junction endothelial
cell Astrocyte

FIGURE 12-22  Blood-Brain Barrier. Cell membranes with tight junctions create a physical barrier
between capillary blood and the cytoplasm of astrocytes. (From Bradley WG, editor: Neurology in
­clinical practice, ed 5, London, 2007, Butterworth-Heinemann.)
 CHAPTER 12  Structure and Function of the Neurologic System 313

Basilar artery Anterior Posterior

spinal artery Posterior central artery
inferior Posterior
cerebellar spinal artery Neural
artery branch
Posterior
Anterior radicular
radicular artery
artery
Vertebral
artery
Posterior
spinal artery
Posterior
radicular
artery Internal
spinal
arteries

Postcentral
Anterior branch
central artery Anterior
A B spinal artery
FIGURE 12-23  Arteries of the Spinal Cord. A, Arteries of cervical cord exposed from the rear.
B, Arteries of spinal cord diagrammatically shown in horizontal section. (Redrawn from Rudy EB, editor:
Advanced neurological and neurosurgical nursing, St Louis, 1984, Mosby.)

myelin sheath. These individual fibers are arranged in bundles called although some are purely sensory or purely motor. Cranial nerves (see
fascicles (Figure 12-24, B). Figure 12-24, A) connect to nuclei in the brain and brain stem. (Figure
The 31 pairs of spinal nerves derive their names from the vertebral 12-24 illustrates their structure, and Table 12-6 describes structural
level from which they exit. There are 8 cervical, 12 thoracic, 5 lumbar, and functional characteristics.)
5 sacral pair of spinal nerves, and 1 coccygeal. The first cervical nerve
exits above the first cervical vertebra, and the rest of the spinal nerves
exit below their corresponding vertebrae. From the thoracic region
(and inferiorly), nerves correspond to the vertebral level above their
4 QUICK CHECK 12-5
1. Describe the circle of Willis and explain its role in supplying blood to the
exit. brain.
Spinal nerves contain both sensory and motor neurons and are 2. What is the source of the spinal cord’s blood supply?
called mixed nerves. They arise as rootlets lateral to anterior and pos- 3. What are the plexuses? Give two examples in the PNS.
terior horns of the spinal cord. These two spinal nerve roots converge 4. What are the cranial nerves? Give three examples.
in the region of the intervertebral foramen to form the spinal nerve 5. Describe the anatomy and function of the PNS.
trunk. Shortly after converging, the spinal nerve divides into anterior
and posterior rami (branches). The anterior rami (except the thoracic)
initially form plexuses (networks of nerve fibers), which then branch
into the peripheral nerves. Instead of forming plexuses, the thoracic
THE AUTONOMIC NERVOUS SYSTEM
nerves pass through the intercostal spaces and innervate regions of the Components of the autonomic nervous system (ANS) are located
thorax. in both the CNS and the PNS; however, the ANS is considered to be
The main spinal nerve plexuses innervate the skin and the underly- part of the efferent division of the PNS, even though visceral affer-
ing muscles of the limbs. The brachial plexus, for example, is formed ent neurons are certainly an important part of this system. Many neu-
by the last four cervical nerves (C5 to C8) and the first thoracic nerve rons of the ANS travel in the spinal nerves and certain cranial nerves.
(T1). The brachial plexus innervates the nerves of the arm, wrist, and The widespread activity of this system indicates that its components
hand. The lumbar plexus (L1 to L4) and sacral plexus (L5 to S5) con- are distributed all over the body. The peripheral autonomic nerves
tain nerves that innervate the anterior and posterior portions of the carry mainly efferent fibers. The motor component of the ANS is a
lower body, respectively. two-neuron system consisting of preganglionic neurons (myelinated)
The posterior rami of each spinal nerve, with their many processes, and postganglionic neurons (unmyelinated) (Figure 12-25). This
are distributed to a specific area in the body. Sensory signals thus arise arrangement contrasts with the somatic nervous system, where a single
from specific sites associated with a specific spinal cord segment. Spe- motor neuron travels from the CNS to the innervated structure. Vis-
cific areas of cutaneous innervation at these spinal cord segments are ceral afferent neurons have their cell bodies in some sensory and cra-
called dermatomes. nial ganglia and their fiber processes traveling in peripheral nerves. The
Like spinal nerves, cranial nerves are categorized as periph- CNS has autonomic areas in the intermediolateral horns of the spinal
eral nerves. Most of these are mixed nerves (like the spinal nerves), cord, cardiovascular and respiratory centers in the reticular formation,
314 CHAPTER 12  Structure and Function of the Neurologic System

Trochlear nerve (IV) Olfactory nerve (I)

Optic nerve (II)

Oculomotor
nerve (III)
Abducens
nerve (VI)
Trigeminal
Facial nerve nerve (V)
(VII)

Vestibulocochlear
nerve (VIII) Glossopharyngeal
nerve (IX)

Accessory
Vagus nerve nerve (XI)
(X) Hypoglossal
nerve (XII)

Spinal Motor
Posterior Epineurium Perineurium
cord end-plate
root Spinal Endoneurium Skin
ganglion Axon

Node of
Ranvier

Anterior Myelin
root sheath
Nerve bundle
(fasciculi) Muscle
Blood vessels Pain
B receptors
FIGURE 12-24  Cranial and Peripheral Nerves. A, Ventral surface of the brain showing attachment of
the cranial nerves. B, Peripheral nerve trunk and coverings. (A from Patton KT, Thibodeau GA: Anatomy
& physiology, ed 7, St Louis, 2010, Mosby.)
 CHAPTER 12  Structure and Function of the Neurologic System 315

TABLE 12-6 THE CRANIAL NERVES

NUMBER AND
NAME ORIGIN AND COURSE FUNCTION HOW TESTED
I. Olfactory Fibers arise from nasal olfactory Purely sensory; carries impulses for sense Person is asked to sniff aromatic substances, such
epithelium and form synapses with of smell as oil of cloves and vanilla, and to identify them
olfactory bulbs, which transmit
impulses to temporal lobe
II. Optic Fibers arise from retina of eye to Purely sensory; carries impulses for vision Vision and visual field tested with an eye chart
form optic nerve, which passes and by testing point at which person first sees
through sphenoid bone; two optic an object (finger) moving into visual field; inside
nerves then form optic chiasma of eye is viewed with ophthalmoscope to
(with partial crossover of fibers) observe blood vessels of eye interior
and eventually end in occipital
cortex
III. Oculomotor Fibers emerge from midbrain and exit Contains motor fibers to inferior oblique and Pupils examined for size, shape, and equality;
from skull to run to eye to superior, inferior, and medial rectus pupillary reflex tested with a penlight (pupils
extraocular muscles that direct eyeball; should constrict when illuminated); ability to
levator muscles of eyelid; smooth muscles follow moving objects
of iris and ciliary body; and proprioception
(sensory) to brain from extraocular muscles
IV. Trochlear Fibers emerge from posterior Proprioceptor and motor fibers for superior Tested in common with cranial nerve III relative to
midbrain and exit from skull to run oblique muscle of eye (extraocular muscle) ability to follow moving objects
to eye
V. Trigeminal Fibers emerge from pons and form Both motor and sensory for face; conducts Sensations of pain, touch, and temperature tested
three divisions that exit from skull sensory impulses from mouth, nose, surface with safety pin and hot and cold objects; corneal
and run to face and cranial dura of eye, and dura mater; also contains motor reflex tested with a wisp of cotton; motor
mater fibers that stimulate chewing muscles branch tested by asking subject to clench teeth,
open mouth against resistance, and move jaw
from side to side
VI. Abducens Fibers leave inferior pons and exit Contains motor fibers to lateral rectus muscle Tested in common with cranial nerve III relative to
from skull to run to eye and proprioceptor fibers from same muscle ability to move each eye laterally
to brain
VII. Facial Fibers leave pons and travel through Mixed: (1) supplies motor fibers to muscles Anterior two thirds of tongue tested for ability to
temporal bone to reach face of facial expression and to lacrimal and taste sweet (sugar), salty, sour (vinegar), and
salivary glands and (2) carries sensory fibers bitter (quinine) substances; symmetry of face
from taste buds of anterior part of tongue checked; subject asked to close eyes, smile,
whistle, and so on; tearing tested with ammonia
fumes
VIII. Vestibulocochlear Fibers run from inner ear (hear- Purely sensory; vestibular branch transmits Hearing checked by air and bone conduction by
(acoustic) ing and equilibrium receptors in impulses for sense of equilibrium; cochlear use of a tuning fork; vestibular tests: Bárány and
temporal bone) to enter brain stem branch transmits impulses for sense of caloric tests
just below pons hearing
IX. Glossopharyngeal Fibers emerge from medulla and Mixed: (1) motor fibers serve pharynx (throat) Gag and swallow reflexes checked; subject asked
leave skull to run to throat and salivary glands, and (2) sensory fibers to speak and cough; posterior one third of
carry impulses from pharynx, posterior tongue may be tested for taste
tongue (taste buds), and pressure receptors
of carotid artery
X. Vagus Fibers emerge from medulla, pass Fibers carry sensory and motor impulses Same as for cranial nerve IX (IX and X are tested
through skull, and descend through for pharynx; a large part of this nerve is in common) because they both serve muscles
neck region into thorax and parasympathetic motor fibers, which supply of throat
abdominal region smooth muscles of abdominal organs;
receives sensory impulses from viscera
XI. Spinal accessory Fibers arise from medulla and Provides sensory and motor fibers for sterno- Sternocleidomastoid and trapezius muscles
superior spinal cord and travel to cleidomastoid and trapezius muscles and checked for strength by asking subject to rotate
muscles of neck and back muscles of soft palate, pharynx, and larynx head and shrug shoulders against resistance
XII. Hypoglossal Fibers arise from medulla and exit Carries motor fibers to muscles of tongue and Subject asked to stick out tongue, and any posi-
from skull to travel to tongue sensory impulses from tongue to brain tion abnormalities are noted
316 CHAPTER 12  Structure and Function of the Neurologic System

SYMPATHETIC DIVISION NE
released
Ach Cholinergic (nicotinic) receptors
released
Myelin

Postganglionic neuron Adrenergic

(alpha or beta) Effector
receptors cell
A Preganglionic neuron
Cholinergic
Ach Cholinergic (nicotinic) receptors (muscarinic)
released Ach receptors
released
Myelin

Postganglionic neuron

Preganglionic neuron
Effector
B cell

Cholinergic
PARASYMPATHETIC DIVISION Cholinergic (nicotinic) receptors (muscarinic)
Ach Ach receptors
released released
Myelin

Postganglionic
neuron
Preganglionic neuron
Effector cell
C
FIGURE 12-25  Locations of Neurotransmitters and Receptors of the Autonomic Nervous System.
In all pathways, preganglionic fibers are cholinergic, secreting acetylcholine (Ach), which stimulates
nicotinic receptors in the postganglionic neuron. Most sympathetic postganglionic fibers are adrener-
gic, A, secreting norepinephrine (NE), thus stimulating α- or β-adrenergic receptors. A few sympathetic
postganglionic fibers are cholinergic, stimulating muscarinic receptors in effector cells, B, all parasym-
pathetic postganglionic fibers are cholinergic, C, stimulating muscarinic receptors in effector cells.
(From Patton KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)

and both sympathetic and parasympathetic areas in the hypothalamus. the same ganglion level to form a synapse with the cell bodies of the
CNS pathways interconnect all these areas. postganglionic neuron, (2) up or down the sympathetic chain before
The ANS coordinates and maintains a steady state among visceral forming synapses with a higher or lower postganglionic neuron, or
(internal) organs, such as regulation of cardiac muscle, smooth muscle, (3) through the chain ganglion without synapsing (see Figure 12-26).
and the glands of the body. This system is considered an involuntary Some preganglionic axons form pathways called splanchnic nerves,
system because one generally cannot will these functions to happen. which lead to collateral ganglia on the front of the aorta. The collateral
The ANS is separated both structurally and functionally into two divi- ganglia are named according to the branches of the aorta nearest them,
sions: (1) the sympathetic nervous system (Figure 12-26) and (2) the namely, the celiac, superior mesenteric, and inferior mesenteric. The
parasympathetic nervous system (Figure 12-27). preganglionic neurons synapse with postganglionic neurons within the
collateral ganglia. These postganglionic neurons leave the collateral
Anatomy of the Sympathetic Nervous System ganglia and innervate the viscera below the diaphragm.
The sympathetic nervous system mobilizes energy stores in times of Preganglionic sympathetic neurons that innervate the adrenal
need (e.g., in the “fight or flight” response) (see Figure 8-1; see also medulla also travel in the splanchnic nerves and do not synapse before
Chapter 8). The sympathetic division is innervated by cell bodies located reaching the gland. The secretory cells in the adrenal medulla are con-
from the first thoracic (T1) through the second lumbar (L2) regions of sidered modified postganglionic neurons. Because preganglionic sym-
the spinal cord and therefore is called the thoracolumbar division. The pathetic fibers are all myelinated, travel to the adrenal medulla is quick,
preganglionic axons of the sympathetic division form synapses shortly and innervation causes the rapid release of epinephrine and norepi-
after leaving the cord in the sympathetic (paravertebral) ganglia. nephrine. Epinephrine and norepinephrine are mediators of the fight
At this point the impulse may travel several ways: (1) directly across or flight response (see Chapter 8).
 CHAPTER 12  Structure and Function of the Neurologic System 317

Preganglionic neuron
Postganglionic neuron

Intracranial vessels

Eye
CiG
C1 Lacrimal gland
C2 SCG SpG
Parotid gland
C3 OG Sublingual and
C4
C5 submaxillary glands
SG
C6 Peripheral cranial vessels
C7
C8 Larynx
T1 Trachea
T2
T3
T4 Bronchi and lungs
T5
T6 Heart
T7 CG Stomach
T8
Liver and gallbladder
T9
T10 Adrenal gland
T11 Pancreas
SMG Kidney
T12
Intestines
L1
IMG
L2
Distal colon
L3
L4
L5 Bladder
S1
S2 PP External genitalia
S3
S4
S5
Coccyx
Sympathetic
chain
FIGURE 12-26  Sympathetic Division of the Autonomic Nervous System. CG, Celiac ganglion; CiG, cili-
ary ganglion; IMG, inferior mesenteric ganglion; OG, otic ganglion; PP, pelvic plexus; SCG, superior cervical
ganglion; SG, submandibular ganglion; SMG, superior mesenteric ganglion; SpG, sphenopalatine ganglion.
(Redrawn from Rudy EB, editor: Advanced neurological and neurosurgical nursing, St Louis, 1984, Mosby.)

Anatomy of the Parasympathetic Nervous System which innervates the viscera of the pelvic cavity. These preganglionic
The parasympathetic nervous system conserves and restores energy. axons synapse with postganglionic neurons in terminal ganglia located
The nerve cell bodies of this division are located in the cranial nerve close to the organs they innervate.
nuclei and in the sacral region of the spinal cord and therefore con-
stitute the craniosacral division. Unlike the sympathetic branch, the Neurotransmitters and Neuroreceptors
preganglionic fibers in the parasympathetic division travel close to Sympathetic preganglionic fibers and parasympathetic pregangli-
the organs they innervate before forming synapses with the relatively onic and postganglionic fibers release acetylcholine—the same neu-
short postganglionic neurons (see Figure 12-27). Parasympathetic rotransmitter released by somatic efferent neurons (see Figures 12-26
nerves arising from nuclei in the brain stem travel to the viscera of and 12-28). These fibers are characterized by cholinergic transmis-
the head, thorax, and abdomen within cranial nerves—including the sion. Most postganglionic sympathetic fibers release norepinephrine
oculomotor (III), facial (VII), glossopharyngeal (IX), and vagus (X) (adrenaline) and thus are considered to function by adrenergic trans-
nerves. mission. A few postganglionic sympathetic fibers, such as those that
Preganglionic parasympathetic nerves that originate from the sacral innervate the sweat glands, release acetylcholine.
region of the spinal cord run either separately or together with some The action of catecholamines varies with the type of neurorecep-
spinal nerves. The preganglionic axons unite to form the pelvic nerve, tor stimulated. It should be remembered that catecholamines also are
318 CHAPTER 12  Structure and Function of the Neurologic System

Thalamus

Hypothalamus

CiG Lacrimal gland

Preganglionic
Postganglionic Eye
III SpG
C1 Nasal mucosa
C2 VII
OG Parotid gland
C3 X IX
C4 Sublingual and
C5 SG submaxillary glands
C6
C7
C8 Larynx
T1 VN Trachea
T2
T3 Bronchi and lungs
T4
T5
T6 Heart
T7
T8 Stomach
T9 Liver, gallbladder,
T10 and bile ducts
T11 Pancreas
T12 Kidney

L1
L2 Intestines
L3 Distal colon
L4
L5
Bladder
S1
S2 External genitalia
S3
S4 PP
S5 PN
Coccyx
FIGURE 12-27  Parasympathetic Division of the Autonomic Nervous System. CiG, Ciliary ganglion;
OG, otic ganglion; PN, pelvic nerve; PP, pelvic plexus; SG, submandibular ganglion; SpG, sphenopala-
tine ganglion; VN, vagus nerve. (Redrawn from Rudy EB, editor: Advanced neurological and neurosurgi-
cal nursing, St Louis, 1984, Mosby.)

Central nervous system Peripheral nervous system Effector organs

Somatic nervous Spinal cord

Skeletal muscle
system or brain Acetylcholine

Spinal cord Peripheral

Parasympathetic Organ
Autonomic nervous system

or brain Acetylcholine ganglion (Ach)

Organ
Chain or (α- and β-
Spinal cord
Acetylcholine collateral ganglia Norepinephrine adrenergic receptors)
Sympathetic Epinephrine
Spinal cord Adrenal medulla
Acetylcholine Norepinephrine
(No ganglia)

Preganglionic axon
Postganglionic axon
FIGURE 12-28  The Autonomic Nervous System and the Type of Neurotransmitters Secreted by
Preganglionic and Postganglionic Fibers. Note that all preganglionic fibers are cholinergic (Ach).
A somatic nerve is used for comparison.
 CHAPTER 12  Structure and Function of the Neurologic System 319

TABLE 12-7 ACTIONS OF AUTONOMIC NERVOUS SYSTEM NEURORECEPTORS

EFFECTOR ADRENERGIC CHOLINERGIC EFFECTS (NICOTINE
ORGAN OR TISSUE RECEPTORS ADRENERGIC EFFECTS AND MUSCARINIC* RECEPTORS)
Eye, iris
  Radial muscle α1 Contraction (mydriasis) —
  Sphincter muscle — — Contraction (miosis)
Eye, ciliary muscle β2 Relaxation for far vision Contraction for near vision
Lacrimal glands α Secretion Secretion
Nasopharyngeal glands — — Secretion
Salivary glands α1 Secretion of potassium and water Secretion of potassium and water
β Secretion of amylase —
Heart
  SA node β1, β2 Increase heart rate Decrease heart rate; vagus arrest
  Atrial β1, β2 Increase contractility and conduction velocity Decrease contractility; shorten action potential
duration
  AV junction β1, β2 Increase automaticity and propagation velocity Decrease automaticity and propagation velocity
  Purkinje system β1, β2 Increase automaticity and propagation velocity —
  Ventricles β1, β2 Increase contractility Slight decrease in contraction
Arterioles
  Coronary α1, α2, β2 Constriction, dilation Dilation 1
  Skin and mucosa α1, α2 Constriction Dilation 1
  Skeletal muscle α, β2 Dilation, constriction Dilation 1
  Cerebral α1 Constriction (slight) Dilation 1
  Pulmonary α1, β2 Constriction, dilation Dilation 1
  Mesenteric α1 Constriction Dilation 1
  Renal α1, β1, β2, D2 Constriction, dilation Dilation 1
  Salivary glands α1, α2 Constriction Dilation
Veins, systemic α1, α2, β2 Constriction, dilation —
Lung
  Bronchial muscle α2 Relaxation Contraction
  Bronchial glands α1, β2 Decrease secretion; increase secretion Stimulation
Stomach
  Motility α1, α2, β1, β2 Decrease (usually) Increase
  Sphincters α1 Contraction (usually) Relaxation (usually)
  Secretion α2 Inhibition Stimulation
Liver α1, β2 Glycogenolysis and gluconeogenesis —
Gallbladder and ducts β2 Relaxation Contraction
Pancreas
  Acini α Decrease secretion Secretion
  Islet cells α2, β2 Decrease secretion; increase secretion —
Intestine
  Motility and tone α1, α2, β1, β2 Decrease Increase
  Sphincters α1 Contraction Relaxation (usually)
  Secretion α2 Inhibition Stimulation
Adrenal medulla — Secretion of epinephrine and norepinephrine (nicotinic effect)
Kidney
  Renin secretion α1, β1 Decrease; increase —
Ureter
  Motility and tone β1 Increase Increase (?)
Urinary bladder
  Detrusor β2 Relaxation Contraction
  Trigone and sphincter α1 Contraction Relaxation
Sex organs, male α1 Ejaculation Erection
Skin
  Pilomotor muscles α1 Contraction —
  Sweat glands α1 Localized secretion —
Fat cells α2, β1, β2, β3 Inhibition of lipolysis; stimulation of lipolysis —
Pineal gland β Melatonin synthesis —

Modified from Brunton LL, Lazo JS, Parker KL, editors: Goodman & Gilman’s: the pharmacological basis of therapeutics, ed 11, New York, 2006,
McGraw-Hill.
*Muscarinic receptors respond to circulating muscarinic antagonists.
320 CHAPTER 12  Structure and Function of the Neurologic System

Sympathetic activation

Adrenal medulla activation Contraction of arteriolar

smooth muscles

Release of epinephrine
and norepinephrine Vasoconstriction

Increased strength of Increased peripheral

contraction of heart resistance

Increased blood pressure

A

Sympathetic activation

Peripheral Stimulation of Stimulation of Metabolic effects

vasoconstriction β receptors of β receptors of
muscle vasculature bronchiole vasculature

Increased Shifts cardiac Vasodilation Increased Increased release

venous output to bronchodilation of epinephrine
return muscles

Increased blood Increased

Increased flow to muscles oxygenation
cardiac output

Glycogenolysis Glycolysis Breakdown

in the liver in muscle of adipose
tissue

Increased blood Increased Release

sugar lactic acid of free
fatty acids
B
FIGURE 12-29  Some Important Functions of the Sympathetic Nervous System. A, Regulation of
vasomotor tone. B, Regulation of strenuous muscular exercise (“fight or flight” response). (See also
Chapter 8 and Figure 8-3 for more detail on the stress response.)

released by the adrenal medulla gland that physiologically and bio- Norepinephrine stimulates all α1 and β1 receptors and only certain β2
chemically resembles the sympathetic nervous system. Two types of receptors. The primary response from norepinephrine, however, is
adrenergic receptors exist, α and β. Cells of the effector organs may stimulation of the α1-adrenergic receptors that cause vasoconstriction.
have only one or both types of adrenergic receptors. The α-adrenergic Epinephrine strongly stimulates all four types of receptors and induces
receptors have been further subdivided according to the action pro- general vasodilation because of the predominance of β receptors in
duced. α1-Adrenergic activity is associated mostly with excitation or muscle vasculatures. (Table 12-7 summarizes the effects of neurore-
stimulation; α2-adrenergic activity is associated with relaxation or inhi- ceptors on their effector organs.)
bition. Most of the α-adrenergic receptors on effector organs belong to
the α1 class. The β-adrenergic receptors are classified as β1-adrenergic Functions of the Autonomic Nervous System
receptors (which facilitate increased heart rate and contractility and Many body organs are innervated by both the sympathetic and para-
cause the release of renin from the kidney) and β2-adrenergic recep- sympathetic nervous systems. The two divisions often cause oppo-
tors (which facilitate all remaining effects attributed to β receptors).6 site responses; for example, sympathetic stimulation of the stomach
 CHAPTER 12  Structure and Function of the Neurologic System 321

causes decreased peristalsis, whereas parasympathetic stimulation of secretion. Stimulation of the sacral division of the parasympathetic sys-
the intestine increases peristalsis. In general, sympathetic stimulation tem contracts the urinary bladder and facilitates the process of genital
promotes responses for the protection of the individual. For example, erection.
sympathetic activity increases blood glucose levels and temperature and The parasympathetic system lacks the generalized and widespread
raises the blood pressure. In emergency situations, a generalized and response of the sympathetic system. Specific parasympathetic fibers
widespread discharge of the sympathetic system occurs. This is accom- are activated to regulate particular functions. Although the actions of
plished by an increased firing frequency of sympathetic fibers and by the parasympathetic and sympathetic systems are usually antagonis-
activation of sympathetic fibers normally silent and at rest (fibers to tic, there are exceptions. Peripheral vascular resistance, for example,
the sweat glands, pilomotor muscles, and the adrenal medulla, as well is increased dramatically by sympathetic activation but is not altered
as vasodilator fibers to muscle). Regulation of vasomotor tone is con- appreciably by activity of the parasympathetic system. Most blood
sidered the single most important function of the sympathetic nervous vessels involved in the control of blood pressure are innervated by
system. (Figure 12-29 illustrates some of the most important functions sympathetic nerves. To decrease blood pressure, therefore, it is more
of the sympathetic nervous system.) important to block or paralyze the continuous (tonic) discharge of the
Increased parasympathetic activity promotes rest and tranquility sympathetic system than to promote parasympathetic activity.
and is characterized by reduced heart rate and enhanced visceral func-
tions concerned with digestion. Stimulation of the vagus nerve (cranial
nerve X) in the gastrointestinal tract increases peristalsis and secre-
4 QUICK CHECK 12-6
1. What are the structural and functional divisions of the ANS?
tion, as well as the relaxation of sphincters. Activation of parasympa- 2. Compare cholinergic and adrenergic transmission.
thetic fibers in the head, provided by cranial nerves III, VII, and IX, 3. What are the functions of the ANS?
causes constriction of the pupil, tear secretion, and increased salivary

GERIATRIC CONSIDERATIONS
Aging & the Nervous System
Structural Changes With Aging Cerebrovascular Changes With Aging
Decreased brain weight and size, particularly frontal regions Arterial atherosclerosis (may cause infarcts and scars)
Fibrosis and thickening of the meninges Increased permeability of blood-brain barrier
Narrowing of gyri and widening of sulci Decreased vascular density
Increase in size of ventricles
Functional Changes With Aging
Cellular Changes With Aging Decreased tendon reflexes
Decrease in number of neurons not consistently related to changes in mental Progressive deficit in taste and smell
function Decreased vibratory sense
Decreased myelin Decrease in accommodation and color vision
Lipofuscin deposition (a pigment resulting from cellular autodigestion) Decrease in neuromuscular control with change in gait and posture
Decreased number of dendritic processes and synaptic connections Sleep disturbances
Intracellular neurofibrillary tangles; significant accumulation in cortex associated Memory impairments
with Alzheimer dementia Cognitive alterations associated with chronic disease
Imbalance in amount and distribution of neurotransmitters Functional changes and nervous system aging have significant individual variation

Data from Kumar A, Foster TC: Neurophysiology of old neurons and synapses. In Riddle DR, ed: Brain aging: models, methods, and mechanisms,
Boca Raton, FL, 2007, CRC Press; Glorioso C, Sibille E: Between destiny and disease: genetics and molecular pathways of human central nervous
system aging, Prog Neurobiol 93(2):165–181, 2011; Jang YC, Van Remmen H: Age-associated alterations of the neuromuscular junction, Exp
Gerontol 46(2-3):193–198, 2011; Crowley K: Sleep and sleep disorders in older adults, Neuropsychol Rev 21(1):41–53, 2011; Brown WR, Thore
CR: Review: cerebral microvascular pathology in ageing and neurodegeneration, Neuropathol Appl Neurobiol 37(1):56–74, 2011; Hof P, Mobbs C:
Neuroscience of aging, Oxford, 2009, Academic Press.

DID YOU UNDERSTAND?

Overview and Organization of the Nervous System Cells of the Nervous System
1. The divisions of the nervous system have been categorized as either 1. The neuron and neuroglial cells constitute nervous tissue. The neuron is spe-
structural (central nervous system [CNS] and peripheral nervous system cialized to transmit and receive electrical and chemical impulses, whereas
[PNS]) or functional (somatic nervous system and autonomic nervous system the neuroglial cell provides supportive functions. The neuron is further
[ANS]). divided into unipolar, pseudounipolar, bipolar, and multipolar categories,
2. The CNS is contained within the brain and spinal cord. according to its structure and particular mechanics of impulse transmission.
3. The PNS is composed of cranial and spinal nerves, which carry impulses 2. The neuron is composed of a cell body, dendrite(s), and an axon. A myelin
toward the CNS (afferent) and away from the CNS (efferent) to target organs sheath around selected axons forms insulation that allows quicker nerve
or skeletal muscle. impulse conduction.

Continued
322 CHAPTER 12  Structure and Function of the Neurologic System

DID YOU UNDERSTAND?—cont’d

The Nerve Impulse 7. The paired carotid and vertebral arteries supply blood to the brain and con-
1. The region between the neurons is the synapse, and the region between the nect to form the circle of Willis. The major branches projecting from the circle
neuron and muscle is the myoneural junction. of Willis are the anterior, middle, and posterior cerebral arteries. Drainage of
2. Neurotransmitters are responsible for chemical conduction across the syn- blood from the brain is accomplished through the venous sinuses and jugular
apse, and myoneural junction nerve impulse is regulated predominantly by a veins.
balance of inhibitory postsynaptic potentials (IPSPs) and excitatory postsyn- 8. The blood-brain barrier is provided by tight junctions between the cells of
aptic potentials (EPSPs), temporal and spatial summation, and convergence brain capillaries and surrounding supporting cells.
and divergence. 9. Blood supply to the spinal cord originates from the vertebral arteries and
branches arising from the aorta.
The Central Nervous System
1. The brain is contained within the cranial vault and is divided into three dis- The Peripheral Nervous System
tinct regions: (a) forebrain, (b) hindbrain, and (c) midbrain. 1. The PNS relays information from the CNS to muscle and effector organs
2. The forebrain comprises the two cerebral hemispheres and allows conscious through cranial and spinal nerve tracts arranged in fascicles (multiple fas-
perception of internal and external stimuli, thought and memory processes, cicles bound together form the peripheral nerve).
and voluntary control of skeletal muscles. The deep portion of the forebrain is
termed the diencephalon and processes incoming sensory data. The center for The Autonomic Nervous System
voluntary control of skeletal muscle movements is located along the precen- 1. The ANS is responsible for maintaining a steady state in the internal envi-
tral gyrus in the frontal lobe, whereas the center for perception is along the ronment. Two opposing systems make up the ANS: (a) the sympathetic ner-
postcentral gyrus in the parietal lobe. The Broca area (inferior frontal gyrus) vous system responds to stress by mobilizing energy stores and prepares the
and the Wernicke area (superior temporal gyrus) are major speech centers. body to defend itself, and (b) the parasympathetic nervous system conserves
3. The hindbrain allows sampling and comparison of sensory data, which are energy and the body’s resources. Both systems function, more or less, at the
received from the periphery and motor impulses of the cerebral hemispheres, same time.
for the purpose of coordination and refinement of skeletal muscle movement.
4. The midbrain is primarily a relay center for motor and sensory tracts, as well GERIATRIC CONSIDERATIONS: Aging & the Nervous
as a center for auditory and visual reflexes. System
5. The spinal cord contains most of the nerve fibers that connect the brain with 1. Major structural changes with aging include a decrease in the number of
the periphery. Reflex arcs are completed in the spinal cord and influenced by neurons and a decrease in brain weight and size.
the higher centers in the brain. 2. Deposition of lipofuscin and the presence of multiple neurofibrillary tangles
6. The CNS is protected by the scalp, bony cranium, meninges, vertebral col- are common cellular changes with aging.
umn, and cerebrospinal fluid (CSF). CSF is formed from blood components in 3. A progressive slowing of neurologic function occurs with advancing age.
the choroid plexuses of the ventricles and is reabsorbed in the arachnoid villi
(located in the dural venous sinuses) after circulating through the brain and
subarachnoid space.

 KEY TERMS
•  cetylcholine  317
A • B asal ganglia system (extrapyramidal •  erebral peduncle  304
C
• α-Adrenergic receptor  320 system)  301 • Cerebrospinal fluid (CSF)  308
• β-Adrenergic receptor  320 • Basilar artery  310 • Cholinergic transmission  311
• Adrenergic transmission  317 • Basis pedunculi  304 • Choroid plexus  308
• Afferent (sensory) neuron  305 • Bipolar neuron  295 • Circle of Willis  310
• Afferent pathway (ascending pathway)  293 • Blood-brain barrier  311 • Collateral ganglia  316
• Amygdala  303 • Brachial plexus  313 • Contralateral control  301
• Anterior column  305 • Brain stem  299 • Conus medullaris  304
• Anterior fossa  307 • Broca speech area (Brodmann • Corpora quadrigemina (tectum)  304
• Anterior horn (ventral horn)  305 areas 44, 45)  301 • Corpus callosum (transverse fibers or
• Anterior spinal artery  311 • Cauda equina  304 commissural fibers)  303
• Anterior spinothalamic tract  307 • Caudate nucleus  303 • Corpus striatum  303
• Arachnoid  308 • Cavernous sinus  310 • Corticobulbar tract  307
• Arachnoid villi  309 • Celiac  316 • Corticospinal tract (pyramidal
• Association fiber  301 • Central canal  304 system)  301
• Associational neuron • Central nervous system (CNS)  293 • Cranial nerve  313
(interneuron)  296 • Central sulcus (fissure of Rolando)  301 • Craniosacral division  317
• Astrocyte  296 • Cerebellum  304 • Dendrite  295
• Autonomic nervous system (ANS)  293 • Cerebral aqueduct (aqueduct of • Dermatome  313
• Axon  295 Sylvius)  304 • Diencephalon (interbrain)  303
• Axon hillock  295 • Cerebral cortex  301 • Dopamine  304
• Basal ganglia  303 • Cerebral nuclei  303 • Dorsal root ganglion  305
 CHAPTER 12  Structure and Function of the Neurologic System 323

 KEY TERMS—cont’d
•  ura mater  307
D •  icrofilament  294
M •  rimary voluntary motor area  301
P
• Efferent (motor) neuron  305 • Microglia  296 • Protopathic  307
• Effector organ  293 • Microtubule  294 • Pseudounipolar neuron  295
• Efferent pathway (descending • Midbrain (mesencephalon)  304 • Red nucleus  304
pathway)  293 • Middle fossa (temporal fossa)  307 • Reflex arc  305
• Ependymal cell  296 • Mixed nerve  313 • Reticular activating system  299
• Epicritic information  307 • Motor neuron  305 • Reticular formation  299
• Epidural space  308 • Motor unit  307 • Reticulospinal tract  307
• Epithalamus  303 • Multipolar neuron  295 • Sacral plexus  313
• Excitatory postsynaptic potential • Myelencephalon (medulla • Saltatory conduction  295
(EPSP)  298 oblongata)  304 • Schwann cell  293
• Facilitation  298 • Myelin  295 • Sensory neuron  296
• Falx cerebri  307 • Myelin sheath  295 • Somatic nervous system  293
• Fascicle  313 • Neurofibril  294 • Spatial summation  298
• Filum terminale  304 • Neuroglia  296 • Spinal cord  304
• Fissure  301 • Neuroglial cell  293 • Spinal nerve  313
• Frontal lobe  301 • Neuromuscular (myoneural) • Spinal tract  305
• Galea aponeurotica  307 junction  296 • Spinothalamic tract  305
• Ganglia (plexus)  295 • Neuron  293 • Splanchnic nerve  316
• Gray matter  301 • Neurotransmitter  297 • Subarachnoid space  308
• Hippocampus  303 • Nissl substance  294 • Subdural space  308
• Hypothalamus  303 • Node of Ranvier  295 • Substantia gelatinosa  305
• Inferior colliculi  304 • Norepinephrine  317 • Substantia nigra  304
• Inferior mesenteric  316 • Nucleus pulposus  309 • Subthalamus  303
• Inhibitory postsynaptic potential • Occipital lobe  301 • Sulci  299
(IPSP)  298 • Oligodendroglia (oligodendrocyte)  296 • Summation  298
• Inner dura (meningeal layer)  307 • Papez circuit  303 • Superior colliculi  304
• Insula (insular lobe)  303 • Parasympathetic nervous system  316 • Superior mesenteric  316
• Internal capsule  303 • Parietal lobe  301 • Sympathetic (paravertebral) ganglia  316
• Internal carotid artery  310 • Pelvic nerve  317 • Sympathetic nervous system  316
• Interventricular foramen (foramen of • Periosteum (endosteal layer)  307 • Synapse  297
Monro)  309 • Peripheral nervous system (PNS)  311 • Synaptic bouton  297
• Intervertebral disk  309 • Pia mater  308 • Synaptic cleft  298
• Lateral aperture (foramen of • Plexus  313 • Tegmentum  304
Luschka)  309 • Pons  304 • Telencephalon  299
• Lateral column  305 • Postcentral gyrus  301 • Temporal lobe  301
• Lateral corticospinal tract  307 • Posterior (dorsal) column (fasciculus • Temporal summation  298
• Lateral horn  305 gracilis, fasciculus cuneatus)  307 • Tentorium cerebelli  308
• Lateral spinothalamic tract  307 • Posterior fossa  307 • Thalamus  303
• Lateral sulcus (sylvian fissure, lateral • Posterior horn (dorsal horn)  305 • Thoracolumbar division  316
fissure)  301 • Posterior spinal artery  311 • Unipolar neuron  295
• Lentiform nucleus  303 • Postganglionic neuron  313 • Upper motor neuron  306
• Limbic system  303 • Postsynaptic neuron  297 • Ventricle  309
• Longitudinal fissure  301 • Precentral gyrus  301 • Vermis  304
• Lower motor neuron  306 • Prefrontal area  301 • Vertebral artery  310
• Lumbar plexus  313 • Preganglionic neuron  313 • Vertebral column  304
• Median aperture (foramen of • Premotor area (Brodmann area 6)  301 • Vestibulospinal tract  307
Magendie)  309 • Presynaptic neuron  297 • Wallerian degeneration  297
• Meninges  307 • Primary motor area • Wernicke area  301
• Metencephalon  304 (Brodmann area 4)  301 • White matter  301

REFERENCES 4. S zabo B, Schlicker E: Effects of cannabinoids on neurotransmission,

Handb Exp Pharmacol (168):327–365, 2005.
1. M artin JH: Neuroanatomy: text and atlas, ed 4, New York, 2012, 5. Kiernan JA: Barr’s the human nervous system: an anatomical viewpoint,
McGraw-Hill. ed 9, Philadelphia, 2009, Lippincott Williams & Wilkins.
2. Purves D, et al: Neuroscience, ed 3, Sunderland, Mass, 2008, Sinauer 6. Siegel R, et al: Basic neurochemistry: molecular, cellular, and medical aspects,
Associates. ed 8, Philadelphia, 2012, Academic Press.
3. Kolb B, Whishaw IQ: An introduction to brain and behavior, ed 3, New
York, 2011, Worth.
CHAPTER

13
Pain, Temperature, Sleep,
and Sensory Function
Jan Belden, Curtis DeFriez, and Sue E. Huether

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Pain, 324 Sleep, 333
The Experience of Pain, 324 Sleep Disorders, 334
Evolution of Pain Theories, 324 The Special Senses, 335
Neuroanatomy of Pain, 325 Vision, 335
Clinical Descriptions of Pain, 327 Hearing, 338
Temperature Regulation, 330 GERIATRIC CONSIDERATIONS: Aging & Changes in Hearing, 340
Control of Body Temperature, 330 Olfaction and Taste, 341
Temperature Regulation in Infants and Elderly Persons, 330 GERIATRIC CONSIDERATIONS: Aging & Changes in Olfaction
Pathogenesis of Fever, 331 and Taste, 341
Benefits of Fever, 331 Somatosensory Function, 341
Disorders of Temperature Regulation, 331 Touch, 341
Proprioception, 341
 

Alterations in sensory function may involve dysfunctions of the gen- PAIN

eral or the special senses. Dysfunctions of the general senses include
chronic pain, abnormal temperature regulation, and tactile or pro- The Experience of Pain
prioceptive dysfunction. Pain is an unpleasant but protective phenom- Pain is a complex experience. It is comprised of dynamic interactions
enon that is uniquely experienced by each individual and it cannot be between physical, cognitive, spiritual, emotional, and environmen-
adequately defined, identified, or measured by an observer. Like pain, tal factors and cannot be characterized as only a response to injury.
variations in temperature can signal disease. Fever is a common mani- McCaffery defined pain as “whatever the experiencing person says it is,
festation of dysfunction and is often the first symptom observed in an existing whenever he says it does.”1 The International Association for
infectious or inflammatory condition. the Study of Pain and the American Pain Society defined pain as “an
Sleep is a normal cyclic process that restores the body’s energy and unpleasant sensory and emotional experience associated with actual or
maintains normal functioning. Sleep is so essential to both physiologic potential tissue damage or described in terms of such damage.”2
and psychologic function that sleep deprivation causes a wide range
of clinical manifestations. The special senses of vision, hearing, touch, Evolution of Pain Theories
smell, and taste are the means by which individuals perceive stimuli The specificity theory of pain was described by Descartes in the sev-
that are essential in interacting with the environment. Dysfunctions enteenth century and proposes that there are specific pain receptors
of the special senses include visual, auditory, vestibular, olfactory, and in the body that project to the brain3 and that the intensity of pain is
gustatory (taste) disorders. directly related to the amount of associated tissue injury. This theory is

324
 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function 325

useful for pain associated with specific injury and acute pain but does we have learned about peripheral inflammation, spinal modulation,
not account for chronic pain or cognitive and emotional elements and midbrain descending control over the past 50 years. Gate control
that contribute to more complex types of pain.4 The pattern theory, theory is an established part of our current conceptual model, and
initially proposed in the late nineteenth century, describes the role of the proposition of the neuromatrix expounds upon that foundation
impulse intensity and the repatterning of the central nervous system by explicating a body-self that provides a holistic, integrated, dynamic
(CNS). Although the theory evolved to provide an explanation for consideration of pain.
neuropathic pain, the pattern theory does not account for all types of
pain experiences.5,6 Neuroanatomy of Pain
The gate control theory (GCT) proposed in 1965 by Melzack and Three portions of the nervous system are responsible for the sensation
Wall4 integrates and builds upon features of other theories to explain and perception of pain:
the complex multidimensional aspects of pain perception. According 1. The afferent pathways, which begin in the peripheral nervous sys-
to this theory, pain transmission is modulated by a balance of impulses tem (PNS), travel to the spinal gate in the dorsal horn and then
conducted to the spinal cord, where cells in the substantia gelatinosa ascend to higher centers in the central nervous system (CNS).
function as a “gate” that regulates the nociceptive (pain) transmission 2. The interpretive centers located in the brain stem, midbrain, dien-
to higher centers in the CNS. Large myelinated A-delta fibers and small cephalon, and cerebral cortex.
unmyelinated C fibers respond to a broad range of painful stimuli, 3. The efferent pathways that descend from the CNS back to the dorsal
including mechanical, thermal, and chemical (Figure 13-1). Nocicep- horn of the spinal cord.
tive transmissions on these fibers “open” the spinal gate and increase The processing of potentially harmful (noxious) stimuli through a
the perception of pain. Partial closure of the spinal gates can occur normally functioning nervous system is called nociception.2 Nocicep-
from stimulating touch sensors in the skin, with impulses carried on tion involves four phases: transduction, transmission, perception, and
non-nociceptive larger A-beta fibers. Non-nociceptive transmissions modulation.5,9
that serves to “close the gate,” decrease pain perception. This is why Pain transduction begins when tissue is damaged by exposure to
rubbing a sore area may alleviate some of the discomfort. Other effer- chemical, mechanical, or thermal noxious stimuli. This causes acti-
ent pathways in the CNS descending to the spinal cord also may close, vation of nociceptors, which are free nerve endings in the afferent
partially close, or open the gate. The gate control theory, bolstered by peripheral nervous system that selectively respond to different types
progresses in understanding neuronal pathways in the peripheral and of stimuli. Nociceptors are located throughout the body (Table 13-1)
central nervous system, have greatly advanced our understanding of but are not evenly distributed so the relative sensitivity to pain differs
pain. according to their location.
As good as the GCT has been, however, there are observations on Activation of nociceptors causes ion channels (sodium, calcium)
pain in paraplegics that “do not fit the theory.” In 1999 Melzack and to open, creating electrical impulses that travel through two primary
Wall outlined the concept of a “neuromatrix” to address these issues. types of nociceptors: A-delta (Aδ) fibers and C fibers. The medium
The neuromatrix theory proposes that the brain produces patterns of sized thinly myelinated Aδ fibers rapidly transmit sharp, well-localized
nerve impulses drawn from various inputs, including genetic, psycho- “fast” pain sensations. These fibers are responsible for causing reflex
logic, and cognitive experiences.7 The qualities we normally feel from withdrawal of the affected body part from the stimulus before a pain
the body, including pain, also can be felt in the absence of inputs from sensation is perceived.6 The smaller, unmyelinated C fibers slowly
the body (as noted with phantom limb pain). In other words, stimuli transmit dull, aching, or burning sensations that are poorly localized
may trigger the patterns but do not produce them—neuromatrix pat- and often constant.5,6,10 A-beta (Aβ) fibers are large myelinated fibers
terns are normally activated by sensory inputs from the periphery but that transmit touch and vibration sensations. They normally do not
may originate independently in the brain with no external input.8 transmit pain, but play a role in pain modulation.10
The neuromatrix theory illustrates the plasticity of the brain, but Pain transmission is the conduction of pain impulses along the Aδ
it does not supplant our understanding of the gate theory, and what and C fibers into the dorsal horn of the spinal cord (Figure 13-2). They

Central Nervous System

Pain modulation may increase
or decrease pain

Large fiber
impulses
(excitation - blocks pain)
+ closes pain gate
Actions
Spinal cord dorsal horn Pain
and
inhibitory interneuron transmission
responses
− (inhibition - promotes pain)
opens pain gate
Small fiber
impulses
FIGURE 13-1  Gate Control Theory of Pain. Schematic diagram of the gate control theory of pain
mechanism. Large A-beta (Aβ) fiber non-nociceptor impulses (i.e., mechanical and thermal) activate
inhibitory interneuron in spinal cord dorsal horn and decrease pain transmission (close pain gate). Small
fiber impulses block the inhibitory interneuron and promote pain transmission (open pain gate).
326 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function

form synapses with interneurons in the substantia gelatinosa and cross preferences, male and female roles, and life experience, including past
the midline of the spinal cord, and then ascend to the thalamus (the pain experiences and current expectations.11 Three systems interact
major relay station of sensory information), brain stem, and cerebral to produce the perception of pain.12 The sensory-discriminative sys-
cortex through multiple pathways, including the lateral spinothalamic tem is mediated by the somatosensory cortex and is responsible for
tract, for further processing and interpretation9 (see Figure 12-8, p. 302). identifying the presence, character, location, and intensity of pain. The
Pain perception is the conscious awareness of pain, which occurs affective-motivational system determines an individual’s conditioned
primarily in the reticular and limbic systems and the cerebral cortex. avoidance behaviors and emotional responses to pain. It is mediated
Interpretation of pain is influenced by many factors including cultural through the reticular formation, limbic system, and brain stem. The
cognitive-evaluative system overlies the individual’s learned behavior
concerning the experience of pain and therefore can modulate percep-
tion of pain. It is mediated through the cerebral cortex.
TABLE 13-1 STIMULI THAT ACTIVATE
Pain modulation involves many different mechanisms that increase
NOCICEPTORS (PAIN or decrease the transmission of pain signals throughout the nervous
RECEPTORS) system. Depending on the mechanism, modulation can occur before,
LOCATION during, or after pain is perceived.10 Pain modulation is discussed in the
OF RECEPTOR PROVOKING STIMULI next section.
Skin Pricking, cutting, crushing, burning, freezing
Neuromodulation of Pain
Gastrointestinal tract Engorged or inflamed mucosa, distention or
spasm of smooth muscle, traction on mesenteric Neuromodulators of pain are found in the pathways that mediate
attachment information about painful stimuli throughout the nervous system.13,14
Skeletal muscle Ischemia, injuries of connective tissue sheaths, Triggering mechanisms that initiate release of neuromodulators
necrosis, hemorrhage, prolonged contraction, include tissue injury (prostaglandins, bradykinin) and chronic inflam-
injection of irritating solutions matory lesions (lymphokines). Other excitatory neuromodulators
Joints Synovial membrane inflammation include such substances as substance P, histamine, glutamate, and
Arteries Piercing, inflammation calcitonin gene–related peptide. These substances sensitize nocicep-
Head Traction, inflammation, or displacement of tors in the peripheral nervous system (peripheral sensitization) or
arteries, meningeal structures, and sinuses; CNS (central sensitization), leading to an increased responsiveness
prolonged muscle contraction and reduced threshold of nociceptors that cause them to fire with
Heart Ischemia and inflammation increased frequency, resulting in hyperalgesia (increased sensitivity
Bone Periosteal injury: fractures, tumor, inflammation to painful stimuli) and allodynia, (the perception of innocuous stim-
uli. A progressive buildup of repeated stimulation of neurons in the

Cerebral cortex

Periaqueductal
Midbrain gray and other
centers Thalamus

(pain modulation) Fast pain—

Brain stem neospinothalamic
tract Lateral
reticular spinothalamic
Brain stem
formation Slow pain— tract
A fiber paleospinothalamic
(fast) precise tract
localization

C fiber
(slow) poor Laminae
localization

FIGURE 13-2  Transmission of Pain Sensations. The Aδ and C fibers synapse in the laminae of the
dorsal horn, crossover to the contralateral spinothalamic tract, and then ascend to synapse in the mid-
brain through the neospinothalamic and paleospinothalamic tracts. Impulses are then conducted to the
sensory cortex.
 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function 327

Interneuron

Opiate Impulse from brain

(endorphins) (efferent pathway)

Opiate Excitatory impulse

(afferent pathway) FIGURE 13-3  Descending Pathway and
receptor
Endorphin Response. Endorphin receptors
To thalamus are located close to known pain receptors in
s Interneuron
lamu the periphery and ascending and descending
Pain a pain pathways.
transmission th
To
blocked by
release of Dorsal root
endorphins ganglion

Pain
receptors
(afferent pathway)

dorsal horn by peripheral nerves leads to wind-up, which can result in Diffuse noxious inhibitory control (DNIC) is an inhibitory
pathologic changes in the CNS (central pain sensitization), prolonged pain system that involves a spinal-medullary-spinal pathway. Pain is
pain, and increased sensitivity to future pain in the same location.5,9,15 relieved when two noxious stimuli occur at the same time in different
Inhibitory neuromodulators include gamma-aminobutyric acid sites (pain inhibiting pain). This is the basis for pain relief with acu-
(GABA), glycine, 5-hydroxytryptamine (serotonin), norepinephrine, puncture, deep massage, or intense cold or heat.21a
and endogenous opioids (see below). Some neuromodulators, such as
5-hydroxytryptamine (serotonin) and norepinephrine, excite periph- Clinical Descriptions of Pain
eral nerves but inhibit central nerves.9 Pain can be described in a variety of ways, including temporal aspects
Endogenous opioids are a family of morphine-like neuropeptides (e.g., duration), inferred neurophysiologic mechanisms, etiology, and
that block transmission of pain impulses in the spinal cord, brain, and region affected (Box 13-1). Pain is commonly classified on the basis of
periphery by binding with specific opioid receptors (mu [μ], kappa [κ], duration (acute versus chronic) and inferred neurophysiologic mecha-
and delta [δ]). They inhibit the release of excitatory neurotransmitters, nisms (nociceptive versus non-nociceptive). Because of the complex
such as substance P in the dorsal horn or in other areas of the brain (Fig- nature of pain, however, many terms overlap and more than one
ure 13-3), and may also be responsible for general sensations of well- approach is often used.
being.16,17 Enkephalins are the most prevalent of the natural opioids. Acute pain is a protective mechanism that alerts the individual to
The best studied endorphin is β-endorphin, which is purported to pro- a condition or experience that is immediately harmful to the body and
duce the greatest sense of exhilaration as well as substantial natural pain mobilizes the individual to take prompt action to relieve it.11 Acute
relief. It is a strong μ receptor agonist. Dynorphins are the most potent pain is transient, usually lasting seconds to days, sometimes up to
of the endogenous opioids, binding strongly with κ receptors to impede 3 months.22 It begins suddenly and is relieved after the chemical medi-
pain signals. They can also incite pain by activating bradykinin receptors ators that stimulate pain receptors are removed.23 Stimulation of the
and may play a role in neuropathic pain.18,19 Dynorphins are found in autonomic nervous system results in physical manifestations includ-
the hypothalamus, medulla, periaqueductal gray, and spinal dorsal horn. ing increased heart rate, hypertension, diaphoresis, and dilated pupils.
Endomorphins bind with μ receptors and have potent analgesic effects.20 Anxiety related to the pain experience, including its cause, treatment,
Opiate drugs (exogenous opioids) relieve pain by attaching to and prognosis, is common as is the hope of recovery.11
the opiate receptors and enhancing the natural endogenous opioid Acute pain arises from cutaneous, deep somatic, or visceral struc-
response. Stress, excessive physical exertion, acupuncture, sexual inter- tures and can be classified as (1) somatic, (2) visceral, or (3) referred.
course, and other factors increase the levels of circulating neuromodu- Somatic pain is superficial, arising from the skin. It is typically well
lators, thereby raising the pain threshold. localized and described as sharp, dull, aching, or throbbing. Visceral
Descending inhibitory pathways and nuclei also inhibit pain. pain refers to pain in internal organs and lining of body cavities and
Afferent stimulation of particularly the ventromedial medulla and tends to be poorly localized with an aching, gnawing, throbbing, or
periaqueductal gray (PAG) (gray matter surrounding the cerebral intermittent cramping quality. It is carried by sympathetic fibers and is
aqueduct) in the midbrain stimulates efferent pathways, which modu- associated with nausea and vomiting, hypotension, and, in some cases,
late or inhibit afferent pain signals at the dorsal horn.21 shock. Visceral pain often radiates (spreads away from the actual site
328 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function

BOX 13-1 CATEGORIES OF PAIN Lung and Liver

I. Neurophysiologic pain diaphragm
Liver
A. Nociceptive pain
Heart
1. Somatic (e.g., skin, muscle, bone) Small
2. Visceral (e.g., intestine, liver, stomach) intestine Pancreas
B. Neuropathic (non-nociceptive) Stomach
1. Central pain (lesion in brain or spinal cord) Ovary
2. Peripheral pain (lesion in PNS) Kidney
Kidney
II. Neurogenic pain
A. Neuralgia (pain in the distribution of a nerve) Colon
B. Constant Bladder
1. Sympathetically independent Appendix
2. Sympathetically dependent Ureter
 III. Temporal pain (time related, duration)
A. Acute pain A B
1. Somatic
FIGURE 13-4  Sites of Referred Pain. A, Anterior view. B, Posterior
2. Visceral
view.
B. Chronic
IV. Regional pain
A. Abdominal pain
B. Chest pain thought to be due, in part, to the stress of coping with continuous pain
C. Headache and may be reversible when pain is controlled.27-29 Chronic pain often
D. Low back pain does not respond to usual therapy. Because it is not yet possible to pre-
E. Orofacial pain dict when acute pain will develop into chronic pain, early treatment of
F. Pelvic pain acute pain is encouraged.10
V. Etiologic pain Physiologic responses to intermittent chronic pain are similar to
A. Cancer pain those for acute pain, whereas persistent pain allows for physiologic
B. Dental pain adaptation, producing normal heart rate and blood pressure. This
C. Inflammatory pain leads many to mistakenly conclude that people with chronic pain are
D. Ischemic pain malingering because they do not appear to be in pain. As chronic pain
E. Vascular pain progresses, certain behavioral and psychologic changes often emerge,
including depression, difficulty eating and sleeping, preoccupation
Adapted from Derasari MD: Taxonomy of pain syndromes: classifica-
with the pain, and avoidance of pain-provoking stimuli.30,31 The desire
tion of chronic pain syndromes. In Raj PP, editor: Practical manage-
ment of pain, ed 3, St Louis, 2000, Mosby.
to relieve pain and the need to hide it become conflicting drives for
those with chronic pain, who fear being labeled complainers.32 Chronic
pain is perceived as meaningless and is often associated with a sense of
hopelessness as more time elapses and no cure seems possible. Com-
of the pain) or is referred. Referred pain is felt in an area removed or mon chronic pain conditions are listed in Table 13-2. Comparison of
distant from its point of origin—the area of referred pain is supplied acute and chronic pain is summarized in Table 13-3.
by the same spinal segment as the actual site of pain. Referred pain Neuropathic pain is initiated or caused by a primary lesion or
can be acute or chronic. Impulses from many cutaneous and visceral dysfunction in the nervous system and leads to long-term changes in
neurons converge on the same ascending neuron, and the brain cannot pain pathway structure (neuroplasticity) and abnormal processing of
distinguish between the different sources of pain. Because the skin has sensory function.2,33 It is often described as burning, shooting, shock-
more receptors, the painful sensation is experienced at the referred site like, or tingling and is characterized by increased sensitivity to painful
instead of at the site of origin.24 Figure 13-4 illustrates common areas stimuli hyperalgesia, allodynia, and the development of spontaneous
of referred pain and their associated sites of origin. pain.34 Neuropathic pain is primarily chronic so individuals present
Chronic or persistent pain has been defined as lasting for more with some or all of the physiologic and behavioral changes described
than 3 to 6 months; however, a more accurate definition is pain last- for chronic pain.
ing well beyond the expected normal healing time following the ini- Neuropathic pain is classified as either peripheral or central.35,36
tial onset of tissue damage or injury. “Normal healing time” varies Peripheral neuropathic pain is due to trauma or disease to one or
depending on the type of injury.25 more peripheral nerves. Examples include nerve entrapment and dia-
Chronic or persistent pain serves no purpose and is poorly under- betic neuropathy. Central neuropathic pain is caused by a lesion or
stood. It often appears to be out of proportion to any observable tissue dysfunction in the brain or spinal cord. Examples include phantom
injury. It may be ongoing (e.g., low back pain) or intermittent (e.g., pain or complex regional pain syndrome.
migraine headaches). Changes in the peripheral and central nervous
systems that cause dysregulation of nociception and pain modulation Pain Threshold and Pain Tolerance
processes are thought to lead to chronic pain.11,26 Additionally, neuro- Pain threshold and tolerance are subjective phenomena that influence
imaging studies have demonstrated brain atrophy in individuals with an individual’s perception of pain. They can be influenced by genetics,
chronic pain, which may lead to cognitive deficits and decreased ability gender,31,37 cultural perceptions, expectations, role socialization, and
to cope with pain. These negative manifestations of chronic pain are physical and mental health.
 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function 329

TABLE 13-2 COMPARISON OF ACUTE AND CHRONIC PAIN

CHARACTERISTIC ACUTE PAIN CHRONIC PAIN
Experience An event A situation; state of existence
Source External agent or internal disease, injury, or inflammation Unknown; if known, treatment is prolonged or ineffective
Onset Usually sudden May be sudden or develop insidiously
Duration Transient (up to 3 months); usually of short duration Prolonged (months to years); lasts beyond expected normal healing time
Resolves with treatment and healing
Pain identification Painful and nonpainful areas generally well identified Painful and nonpainful areas less easily differentiated; change in sensa-
tions becomes more difficult to evaluate
Clinical signs Typical response pattern with more visible signs Response patterns vary; fewer overt signs (adaptation)
Anxiety and emotional distress common Can interfere with sleep, productivity, and quality of life
Significance Significant (informs person something is wrong); protective Person looks for significance and meaning; serves no useful purpose
Pattern Self-limiting or readily corrected Continuous or intermittent; intensity may vary or remain constant
Course Suffering usually decreases over time Suffering usually increases over time
Actions Leads to actions to relieve pain Leads to actions to modify pain experience
Prognosis Likelihood of eventual complete relief Complete relief usually not possible

Data from Black RG: Surg Clin North Am 55(4):999, 1975.

TABLE 13-3 COMMON CHRONIC PAIN CONDITIONS

CONDITION DESCRIPTION
Persistent low back pain Most common chronic pain condition
Results from poor muscle tone, inactivity, muscle strain, or sudden, vigorous exercise
Myofascial pain syndromes Pain results from muscle spasm, tenderness, stiffness, or injury to muscle and fascia
Examples include myositis, fibrositis, myalgia, fibromyalgia, and muscle strain
Trigger points—small hypersensitive regions in muscle or connective tissues that, when stimulated, produce pain in a specific area
As disorder progresses, pain becomes increasingly generalized
Chronic postoperative pain Persistent pain that can occur with disruption or cutting of sensory nerves; examples include post-thoracotomy, post-mastectomy;
risk factors may include preexisting pain and genetic susceptibility
Cancer pain Attributed to advance of disease, treatment, or coexisting disease entities
Deafferentation pain Pain due to loss of sensory input into CNS caused by lesion in peripheral nerves (e.g., brachial plexus injury) or pathology of CNS
(e.g., complex regional pain syndrome); described as constant, vicelike ache with paroxysms of burning or shocklike sensations
Common types include severe burning pain triggered by various stimuli, such as cold, light touch, or sound, and complex regional
pain syndromes (occur after peripheral nerve injury and are characterized by continuous, severe, burning pain associated with
vasomotor changes and muscle wasting)
Hyperesthesias Increased sensitivity and decreased pain threshold to tactile and painful stimuli
Pain is diffuse, modified by fatigue and emotion, and mixed with other sensations
May result from chronic irritation of CNS areas
Hemiagnosia Loss of ability to identify source of pain on one side of body
Painful stimuli on that side produce discomfort, anxiety, moaning, agitation, and distress but no attempt to withdraw from stimulus
Associated with stroke
Phantom limb pain Pain experience in amputated limb after stump has completely healed; may be immediate or occur months later; associated with
preamputation pain, acute postoperative pain
Exact cause is unknown, thought to originate in brain; can be influenced by emotions/sympathetic stimulation

The pain threshold is defined as the lowest intensity of pain that a pain, fatigue, anger, boredom, apprehension, and sleep deprivation,
person can recognize.2 Intense pain at one location may increase the and may increase with alcohol consumption, persistent use of opioid
threshold in another location. For example, a person with severe pain medications, hypnosis, distracting activities, and strong beliefs or faith.
in one knee is more likely to experience less intense chronic back pain
(this is called perceptual dominance). This means an individual with
many painful sites may report only the most painful one. When the
dominant pain is diminished, other painful areas are identified.
4 QUICK CHECK 13-1
1. Define the major categories of pain.
Pain tolerance is the duration of time or the intensity of pain that 2. What portions of the nervous system are responsible for the sensation and
an individual will endure before initiating overt pain responses. It var- perception of pain?
ies greatly among people and in the same person over time because 3. What physiologic responses are seen in acute pain?
of the body’s ability to respond differently to noxious stimuli (Table 4. List three common chronic pain conditions.
13-4). Pain tolerance generally decreases with repeated exposure to
330 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function

TABLE 13-4 PAIN PERCEPTION IN INFANTS, CHILDREN, AND ELDERLY PERSONS

INFANTS CHILDREN ELDERLY PERSONS
Pain threshold Painful neonatal experiences increase pain sensitivity Lower or same Individual responses may vary but pain threshold may
(lower threshold); pain may be increased with as adults be lower
future procedures
Physiologic symptoms Increased heart rate, blood pressure, and respiratory Same as infants; Same as infants and children; nausea and vomiting; may
rate; flushing or pallor, sweating, and decreased ­nausea and vomit- be decreased in individuals with cognitive impairment
oxygen saturation ing
Behavioral responses Changes in facial expression, crying, and body move- Individual responses Individual responses vary and may be influenced by
ments, with lowered brows drawn together; vertical vary presence of painful chronic diseases; individuals with
bulge and furrows in forehead between brows; cognitive impairment may demonstrate changes in
broadened nasal root; tightly closed eyes; angular, behavior (e.g., combative or withdrawn, increased
square-shaped mouth, chin quiver; withdrawal of confusion)
affected limbs, rigidity, flailing

Data from American Geriatric Society Panel in Persistent Pain in Older Adults: The management of persistent pain in older adults, J Am Geriatr
Soc 50:S211, 2002; Fine PG: Chronic pain management in older adults: special considerations, J Pain Symptom Manage 38(2 suppl):S4–S14,
2009; Kunz M et al: Effects of age and mild cognitive impairment on the pain response system, Gerontology 55(6):674–682, 2009; Slover R, Coy J,
Davids H: Advances in the management of pain in children: acute pain, Adv Pediatr 56:341–358, 2009; Weber F: Evidence for the need for anaes-
thesia in the neonate, Best Pract Res Clin Anaesthesiol 24(3):475-484, 2010.

The hypothalamus also triggers heat conservation by stimulating

TEMPERATURE REGULATION the sympathetic nervous system, which stimulates the adrenal cortex
Human thermoregulation is achieved through precise balancing of and results in increased skeletal muscle tone, initiating the shivering
heat production, heat conservation, and heat loss. Body temperature response and producing vasoconstriction. By constricting periph-
is maintained in a range around 37° C (98.6° F). The normal range is eral blood vessels, centrally warmed blood is shunted away from the
considered to be 36.2° to 37.7° C (96.2° to 99.4° F) overall, but a per- periphery to the core of the body where heat can be retained. This
son’s individual body parts will vary in temperature. Body tempera- involuntary mechanism takes advantage of the insulating layers of the
ture rarely exceeds 41° C. The extremities are generally cooler than skin and subcutaneous fat to protect core temperature. The hypothala-
the trunk and the temperature at the core of the body (as measured mus relays information to the cerebral cortex about cold and voluntary
by rectal temperature) is generally 0.5° C higher than the surface responses result. Individuals typically bundle up, keep moving, or curl
temperature (as measured by oral temperature). Internal tempera- up in a ball. These types of voluntary physical activities respectively
ture varies in response to activity, environmental temperature, and provide insulation, increase skeletal muscle activity, and decrease the
daily fluctuation (circadian rhythm). Oral temperatures fluctuate amount of skin surface available for heat loss through radiation, con-
within 0.2° to 0.5° C during a 24-hour period. Women tend to have vection, and conduction.39
wider fluctuations that follow the menstrual cycle with a sharp rise in The hypothalamus responds to warmer core and peripheral tem-
temperature just before ovulation. The daily fluctuating temperature peratures by reversing the same mechanisms resulting in heat loss.
in both genders peaks around 6 pm and is at its lowest during sleep. Heat loss is achieved through (1) radiation, (2) conduction, (3) con-
Maintenance of body temperature within the normal range is neces- vection, (4) vasodilation, (5) evaporation, (6) decreased muscle tone,
sary for life. (7) increased respiration, (8) voluntary measures, and (9) adaptation
to warmer climates. Table 13-5 contains further information about
Control of Body Temperature heat production and loss.
Temperature regulation (thermoregulation) is mediated primarily by
the hypothalamus. Peripheral thermoreceptors in the skin and central Temperature Regulation in Infants and Elderly Persons
thermoreceptors in the hypothalamus, spinal cord, abdominal organs, Infants (particularly low-birthweight infants) and elderly persons
and other central locations provide the hypothalamus with informa- require special attention to maintenance of body temperature. Term
tion about skin and core temperatures. If these temperatures are low infants produce sufficient body heat, primarily through metabo-
or high, the hypothalamus triggers heat production and heat conserva- lism of brown fat, but cannot conserve heat produced because of
tion or heat loss mechanisms. The endocrine system also operates to their small body size, greater ratio of body surface to body weight,
control body temperature. and inability to shiver. Infants also have little subcutaneous fat and
Body heat is produced by the chemical reactions of metabolism and thus are not as well insulated as adults.40 Elderly persons respond
skeletal muscle tone and contraction. The heat-producing mechanism poorly to environmental temperature extremes because of their
(chemical thermogenesis) begins with hypothalamic thyrotropin- slowed blood circulation, structural and functional skin changes, and
stimulating hormone-releasing hormone (TSH-RH); it stimulates overall decreased heat-producing activities.41 In addition, they have
the anterior pituitary to release thyroid-stimulating hormone (TSH), a decreased shivering response (delayed onset and decreased effec-
which acts on the thyroid gland and stimulates the release of thyroxine. tiveness), slowed metabolic rate, decreased vasoconstrictor response,
Thyroxine then acts on the adrenal medulla, causing the release of epi- diminished or absent ability to sweat, decreased peripheral sensation,
nephrine into the bloodstream. Epinephrine causes vasoconstriction, desynchronized circadian rhythm, decreased perception of heat and
stimulates glycolysis, and increases metabolic rate, thus increasing heat cold, decreased thirst, decreased nutritional reserves, and decreased
production.38 Heat is distributed by the circulatory system. brown adipose tissue.42
 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function 331

Pathogenesis of Fever production, conservation, and loss to maintain body core tempera-
Fever (febrile response) is a temporary “resetting of the hypotha- ture at a normal level. During fever, this level is raised so that the
lamic thermostat” to a higher level in response to endogenous or thermoregulatory center now adjusts heat production, conserva-
exogenous pyrogens. The thermoregulatory mechanisms adjust heat tion, and loss to maintain the core temperature at the new, higher
temperature, which functions as a new set point. This response
is mediated in part by cytokines associated with the inflammatory
response.43 ­Exogenous pyrogens, or endotoxins produced by patho-
TABLE 13-5 MECHANISMS OF HEAT gens (see Chapter 7), stimulate the release of endogenous pyrogens
PRODUCTION AND HEAT from phagocytic cells, including tumor necrosis factor-alpha (TNF-
LOSS α), interleukin-1 (IL-1), interleukin-6 (IL-6), and interferon (IFN),
CONDITION DESCRIPTION which raise the set point by inducing the hypothalamic synthesis of
prostaglandin E2 (PGE2). In response, there is an increase in heat
Heat Production
production and conservation to raise body temperature to the new
Chemical reactions Occur during ingestion and metabolism of food and
set point (Figure 13-5). The individual feels colder, dresses more
of metabolism while maintaining body at rest (basal metabolism);
warmly, decreases body surface area by curling up, and may go to bed
occur in body core (e.g., liver)
in an effort to get warm. Body temperature is maintained at the new
Skeletal muscle Gradual increase in muscle tone or rapid muscle oscil-
level until the fever “breaks,” when the set point begins to return to
contraction lations (shivering)
normal with decreased heat production and increased heat reduction
Chemical Epinephrine is released and produces rapid, transient
mechanisms. The ­individual feels very warm, dons cooler clothes,
­thermogenesis increase in heat production by raising basal meta-
throws off the covers, and stretches out. Once the body has returned
bolic rate; quick, brief effect that counters heat lost
to a normal temperature the individual feels more comfortable and
through conduction and convection; involves brown
the hypothalamus adjusts thermoregulatory mechanisms to maintain
adipose tissue, which decreases markedly in older
the new temperature.
adults; thyroid hormone increases metabolism
Fever of unknown origin (FUO) is a body temperature of greater
Heat Loss than 38.3° C (101° F) that remains undiagnosed after 3 days of hospital
Radiation Heat loss through electromagnetic waves emanat- investigation or two or more outpatient visits. The clinical categories
ing from surfaces with temperature higher than of FUO include infectious, rheumatic/inflammatory, neoplastic, and
surrounding air miscellaneous disorders.44
Conduction Heat loss by direct molecule-to-molecule transfer
Benefits of Fever
from one surface to another, so that warmer surface
loses heat to cooler surface Fever helps the body respond to infectious processes through several
Convection Transfer of heat through currents of gases or liquids; mechanisms45,46:
exchanges warmer air at body’s surface with cooler 1. Raising of body temperature kills many microorganisms and
air in surrounding space adversely affects their growth and replication.
Vasodilation Diverts core-warmed blood to surface of body, with 2. Higher body temperatures decrease serum levels of iron, zinc, and
heat transferred by conduction to skin surface and copper—minerals needed for bacterial replication.
from there to surrounding environment; occurs in 3. Increased temperature causes lysosomal breakdown and autode-
response to autonomic stimulation under control of struction of cells, preventing viral replication in infected cells.
hypothalamus 4. Heat increases lymphocytic transformation and motility of poly-
Evaporation Body water evaporates from surface of skin and morphonuclear neutrophils, facilitating the immune response.
linings of mucous membranes; major source of heat 5. Phagocytosis is enhanced, and production of antiviral interferon is
reduction connected with increased sweating in augmented.
warmer surroundings Suppression of fever by treatment with antipyrogenic medications
Decreased ­ Exhausted feeling caused by moderately reduced should be used when a fever produces serious side effects, such as car-
muscle tone muscle tone and curtailed voluntary muscle activity diovascular stress, nerve damage, brain damage, or convulsion.47,48
Increased ­ Air is exchanged with environment through normal Infection and fever responses in elderly persons and children may
respiration process; minimal effect vary from those in normal adults. Box 13-2 lists the principal features
Voluntary “Stretching out” and “slowing down” in response to associated with fever at these extremes of age.49
­mechanisms high body temperatures; increasing body surface
area available for heat loss; dressing in light-
Disorders of Temperature Regulation
colored, loose-fitting garments Hyperthermia
Adaptation to Gradual process beginning with lassitude, weakness, Hyperthermia is elevation of the body temperature without an
warmer climates and faintness; proceeding through increased sweat- increase in the hypothalamic set point. Hyperthermia can produce
ing, lowered sodium content, decreased heart rate, nerve damage, coagulation of cell proteins, and death. At 41° C (105.8°
and increased stroke volume and extracellular fluid F), nerve damage produces convulsions in the adult. Death results at
volume; and terminating in improved warm weather 43° C (109.4° F). Hyperthermia may be therapeutic, accidental, or
functioning and decreased symptoms of heat intoler- associated with stroke or head trauma. Prevention of hyperthermia in
ance (work output, endurance, and coordination stroke and head trauma assists in limiting brain injury.50
increase; subjective feelings of discomfort Therapeutic hyperthermia is a form of local or general body-
decrease) induced hyperthermia used to destroy pathologic microorganisms or
tumor cells by facilitating the host’s natural immune process or tumor
332 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function

Exogenous pyrogens
from bacteria (endotoxin)
virus, fungi

Hypothalamic
temperature-regulating
Activation of center
monocyte-macrophage
and T cells

Release of
IL-1, IL-6, IFN, TNF

Production of PGE2
raised thermostatic
set point

Autonomic nervous system

Heat conservation Heat generation

• Cutaneous • Increased muscle
vasoconstriction contraction
• Decreased sweating • Shivering reflex

FEVER
FIGURE 13-5  Production of Fever. Pathogens release exogenous pyrogens and activate monocytes/
macrophages and other inflammatory cells that secrete endogenous pyrogenic cytokines, such as
interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF), and interferon (IFN), which promote
the synthesis and secretion of prostaglandin E2 (PGE2) in the anterior hypothalamus. PGE2 increases
the thermostatic set point, and the autonomic nervous system is stimulated, resulting in shivering,
muscle contraction, peripheral vasoconstriction, and the production of fever. (From Lewis SM et al:
Medical-surgical nursing: assessment and management of clinical problems, ed 7, St Louis, 2007,
Mosby.)

2. Heat exhaustion—results from prolonged high core or environ-

BOX 13-2 EFFECTS OF FEVER
mental temperatures, which cause profound vasodilation and pro-
AT THE EXTREMES OF AGE fuse sweating, leading to dehydration, decreased plasma volumes,
Elderly Persons hypotension, decreased cardiac output, and tachycardia. Symp-
Show decreased or no fever response to infection; therefore benefits of fever toms include weakness, dizziness, confusion, nausea, and fainting.
are reduced. 3. Heat stroke—a potentially lethal result of an overstressed ther-
High morbidity and mortality result from lack of beneficial aspects. moregulatory center. With very high core temperatures (>40° C;
104° F), the regulatory center ceases to function and the body’s
Children heat loss mechanisms fail. Symptoms include high core tempera-
Develop higher temperatures than adults for relatively minor infections. ture, absence of sweating, rapid pulse rate, confusion, agitation,
Febrile seizures before age 5 years are not uncommon. and coma. Complications include cerebral edema, degeneration
of the CNS, swollen dendrites, renal tubular necrosis, and hepatic
failure with delirium, coma, and eventually death if treatment is not
blood flow.51 The four forms of accidental hyperthermia are summa- undertaken.
rized as follows52: 4. Malignant hyperthermia—a potentially lethal complication of
1. Heat cramps—severe, spasmodic cramps in the abdomen and a rare inherited muscle disorder that may be triggered by inhaled
extremities that follow prolonged sweating and associated sodium anesthetics and depolarizing muscle relaxants.53,54 The syndrome
loss. Usually occur in those not accustomed to heat or those per- involves altered calcium function in muscle cells with hyperme-
forming strenuous work in very warm climates. Signs include fever, tabolism, uncoordinated muscle contractions, increased muscle
rapid pulse rate, and increased blood pressure. work, increased oxygen consumption, and a raised level of lactic
 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function 333

acid production. Acidosis develops, and body temperature rises,

BOX 13-3 DEFINING CHARACTERISTICS
with resulting tachycardia and cardiac dysrhythmias, hypotension,
decreased cardiac output, and cardiac arrest. Signs resemble those
OF HYPOTHERMIA
of coma—unconsciousness, absent reflexes, fixed pupils, apnea, Accidental Hypothermia
and occasionally a flat electroencephalogram. Oliguria and anuria The unintentional decrease in core temperature to less than 35° C (95° F)
are common. It is most common in children and adolescents. results from sudden immersion in cold water, prolonged exposure to cold
environments, or altered thermoregulatory mechanisms. It is most common
Hypothermia among young and elderly persons.
Hypothermia (marked cooling of core temperature) produces depres- Factors that increase risk:
sion of the central nervous and respiratory systems, vasoconstriction, 1. Hypothyroidism
alterations in microcirculation and coagulation, and ischemic tissue 2. Hypopituitarism
damage. Hypothermia may be accidental or therapeutic (Box 13-3). 3. Malnutrition
Most tissues can tolerate low temperatures in controlled situations, 4. Parkinson disease
such as surgery. However, in severe hypothermia, ice crystals form on 5. Rheumatoid arthritis
the inside of the cell, causing cells to rupture and die. Tissue hypother- 6. Chronic increased vasodilation
mia slows cell metabolism, increases the blood viscosity, slows micro- 7. Failure of thermoregulatory control resulting from cerebral injury, ketoaci-
circulatory blood flow, facilitates blood coagulation, and stimulates dosis, uremia, sepsis, and drug overdose
profound vasoconstriction (also see Frostbite, Chapter 39). Response mechanisms:
1. Peripheral vasoconstriction—shunts blood away from cooler skin to core to
Trauma and Temperature decrease heat loss and produces peripheral tissue ischemia
Major body trauma can affect temperature regulation through various 2. Intermittent reperfusion of extremities (Lewis phenomenon) helps preserve
mechanisms. Damage to the CNS, inflammation, increased intracra- peripheral oxygenation until core temperature drops dramatically
nial pressure, or intracranial bleeding typically produces a body tem- 3. Hypothalamic center induces shivering; thinking becomes sluggish, and
perature of greater than 39° C (102.2° F). This sustained noninfectious coordination is depressed
fever, often referred to as a “central fever,” appears with or without 4. Stupor; heart rate and respiratory rate decline; cardiac output diminishes;
bradycardia. A central fever does not induce sweating and is very resis- metabolic rate falls; acidosis; eventual ventricular fibrillation and asystole
tant to antipyretic therapy. occur at 30° C (86° F) and lower
Other traumatic mechanisms that produce temperature alterations Treatment:
include accidental injuries, hemorrhagic shock, major surgery, and 1. Most changes are reversible with rewarming
thermal burns. The severity and type of alteration (hyperthermia or 2. Core temperature greater than 30° C (86° F)—active rewarming (external)
hypothermia) vary with the severity of the cause and the body system 3. Core temperature less than 30° C (86° F) or with severe cardiovascular
affected. problems—active core rewarming (internal)

4 QUICK CHECK 13-2

Therapeutic Hypothermia
Used to slow metabolism and preserve ischemic tissue during surgery (e.g.,
1. Why is temperature regulation important? limb reimplantation), after cardiac arrest, or following neurologic injury
2. What are the principal heat production methods? Heat loss methods? Effects and cautions:
3. How does the hypothalamus alter its set point to change body temperature? 1. Stresses the heart, leading to ventricular fibrillation and cardiac arrest (may
4. Compare and contrast hyperthermia and hypothermia and their effects on be desired outcome in open heart surgery when heart must be stopped)
the body. 2. Exhausts liver glycogen stores by prolonged shivering
3. Surface cooling may cause burns, frostbite, and fat necrosis
4. Immunosuppression with increased infection risk
SLEEP 5. Slows drug metabolism
Sleep is an active brain process that provides restorative functions
From Arrich J et al: Cochrane corner: hypothermia for neuroprotection
and promotes memory consolidation. The suprachiasmatic nucleus
in adults after cardiopulmonary resuscitation, Anesth Analg 110(4):1239,
(SCN) in the hypothalamus controls the timing of the sleep-wake cycle 2010; Mallet ML: Pathophysiology of accidental hypothermia, QJM
and coordinates this cycle with circadian rhythms (24-hour rhythm 95(12):775–785, 2002; Lampe JW, Becker LB; State of the art in thera-
cycles) in other areas of the brain and other tissues.55 Normal sleep has peutic hypothermia, Annu Rev Med 62:79–93, 2011; Varon J: Therapeu-
two phases that can be documented by electroencephalogram (EEG): tic hypothermia: implications for acute care practitioners, Postgrad Med
rapid eye movement (REM) sleep (20% to 25% of sleep time) and 122(1):19–27, 2010.
slow-wave (non-REM) sleep. Non-REM sleep is further divided into
four stages (I to IV) from light to deep sleep. There are four to six cycles
of REM and non-REM sleep each night.56 associated with REM sleep include increased parasympathetic activity
REM (rapid eye movement) sleep is initiated by REM-on and and variable sympathetic activity associated with rapid eye movement;
REM-off neurons in the pons and mesencephalon. REM sleep occurs muscle relaxation; loss of temperature regulation; altered heart rate,
about every 90 minutes beginning 1 to 2 hours after non-REM sleep blood pressure, and respiration; penile erection in men and clitoral
begins. This sleep is known as paradoxical sleep because the EEG engorgement in women; release of steroids; and many memorable
pattern is similar to the normal awake pattern and the brain is very dreams. Respiratory control appears largely independent of metabolic
active with dreaming. REM and non-REM sleep alternate throughout requirements and oxygen variation. Loss of normal voluntary muscle
the night, with lengthening intervals of REM sleep and fewer inter- control in the tongue and upper pharynx may produce some respira-
vals of deeper stages of non-REM sleep toward morning. The changes tory obstruction. Cerebral blood flow increases.
334 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function

Non-REM sleep (NREM) accounts for 75% to 80% of sleep time

BOX 13-4 SLEEP CHARACTERISTICS
in adults and is initiated when inhibitory signals are released from the
hypothalamus. Sympathetic tone is decreased and parasympathetic
OF INFANTS AND ELDERLY
activity is increased during NREM sleep, creating a state of reduced PERSONS
activity. The basal metabolic rate falls by 10% to 15%; temperature Infants
decreases 0.5° to 1.0° C (0.9° to 1.8° F); heart rate, respiration, blood • Sleep 16 to 17 hours per day: 50% REM (active) sleep, 25% non-REM
pressure, and muscle tone decrease; and knee jerk reflexes are absent. (inactive) sleep.
Pupils are constricted. During the various stages, cerebral blood flow • Infant sleep cycles are 50 to 60 minutes in length; 10 to 45 minutes of REM
to the brain decreases and growth hormone is released, with corticoste- sleep accompanied by movement of the arms, legs, and facial muscles fol-
roid and catecholamine levels depressed. Box 13-4 summarizes sleep lowed by about 20 minutes of non-REM sleep.
characteristics in infants and elderly persons. • At 1 year, REM and non-REM sleep cycles are about equal in length and
Sleep is an active multiphase process with complex neural circuits, infants sleep through the night with about two naps per day.
interacting hormones, and neurotransmitters involving the hypo-
thalamus, thalamus, brain stem, and cortex. The hypothalamus is a Elderly Persons
major sleep center and the hypocretins (orexins), acetylcholine, and • Total sleep time is decreased with a longer time to fall asleep and poorer
glutamate are neuropeptides secreted by the hypothalamus that pro- quality sleep.
mote wakefulness. Prostaglandin D2, adenosine, melatonin, serotonin, • Total time in slow-wave and final phase of non-REM sleep decreases by
l-tryptophan, gamma-aminobutyric acid (GABA), and growth factors 15% to 30%.
promote sleep. The pontine reticular formation is primarily respon- • Alterations in sleep patterns occur about 10 years later in women than
sible for generating REM sleep, and projections from the thalamocorti- men.
cal network produce non-REM sleep.57,58 • Sleep disorders more likely in elderly and increase risk of morbidity and
mortality.
Sleep Disorders
From Espiritu JR: Aging-related sleep changes, Clin Geriatr Med
Because classification of sleep disorders is complex, a system has been
24(1):1–14, v, 2008; McLaughlin Crabtree V, Williams NA: Normal
established by the American Academy of Sleep Medicine and includes
sleep in children and adolescents, Child Adolesc Psychiatr Clin N Am
four classifications: (1) dyssomnias (disorders of initiating and main- 18(4):799–811, 2009; Neikrug AB, Ancoli-Israel S: Sleep disorders in
taining sleep and disorders of excessive sleepiness), (2) parasomnias the older adult—a mini-review, Gerontology 56(2):181–189, 2010.
(disorders that primarily do not cause a complaint of insomnia or
excessive sleepiness), (3) sleep disorders associated with medical/psy-
chiatric disorders, and (4) proposed sleep disorders.59 The most com- spells of muscle weakness). The disorder is associated with hypotha-
mon dyssomnias and parasomnias are summarized here. lamic hypocretin (orexin) deficiency and may be related to immune-
mediated destruction of hypocretin-secreting cells. There is a genetic
Common Dyssomnias component to the disorder.65
Insomnia. Insomnia is the inability to fall or stay asleep and may be Disorders of the sleep-wake schedule. Common disorders of the
mild, moderate, or severe. It may be transient, lasting a few days, and sleep-wake schedule (circadian rhythm sleep disorders) can result
related to travel across time zones or caused by acute stress. Long-term from rapid time-zone change (or jet-lag syndrome), alternating the
insomnia can be idiopathic, start at an early age, and be associated with sleep schedule (rotating work shifts) involving 3 hours or more in sleep
drug or alcohol abuse, chronic pain disorders, chronic depression, the time, or changing the total sleep time from day to day. These changes
use of certain drugs, obesity, and aging.60 desynchronize circadian rhythm, which can depress the degree of vigi-
Sleep disordered breathing and hypersomnia. Obstructive sleep lance, performance of psychomotor tasks, and arousal.66
apnea syndrome (OSAS) generally results from upper airway obstruc-
tion recurring during sleep with excessive snoring and multiple apneic Common Parasomnias
episodes that last 10 seconds or longer. The periodic breathing eventu- Parasomnias are unusual behaviors occurring during sleep.67 These
ally produces arousal, which interrupts the sleep cycle, reducing total behaviors include sleepwalking, night terrors, rearranging furniture,
sleep time and producing sleep and REM deprivation. Associated con- eating food, violent behavior, and restless leg syndrome.
ditions include obesity, decreased sensitivity to carbon dioxide and Two dysfunctions of sleep (somnambulism and night terrors) are
oxygen tensions, and upper airway obstruction. Sleep apnea produces common in children and may be related to central nervous system
hypercapnia and low oxygen saturation and eventually leads to polycy- immaturity. Somnambulism (sleepwalking) is a disorder primarily of
themia, pulmonary hypertension, systemic hypertension, stroke, right- childhood and appears to resolve within a few years. Sleepwalking is
sided congestive heart failure, dysrhythmias, liver congestion, cyanosis, therefore not associated with dreaming, and the child has no memory
and peripheral edema.61 Hypersomnia (excessive daytime sleepiness) is of the event on awakening. Sleepwalking in adults is often associated
associated with OSAS. Individuals may fall asleep while driving a car, with sleep disordered breathing.68 Night terrors are characterized by
working, or even while conversing, with significant concerns for safety.62 sudden apparent arousals in which the child expresses intense fear
Treatments for OSAS include use of nasal continuous positive air- or emotion. However, the child is not awake and can be difficult to
way pressure and dental devices, surgery of the upper airway and jaw arouse. Once awakened, the child has no memory of the night terror
in selected individuals, and management of obesity.63 Adenotonsillar event. Night terrors are not associated with dreams. Although this
hypertrophy is the major cause of obstructive sleep apnea in children problem occurs most often in children, adults also may experience it
and obesity increases risk. Tonsillectomy and adenoidectomy are the with corresponding daytime anxiety.
treatments of choice.64 Restless leg syndrome (RLS) is a common sensorimotor disorder
Narcolepsy is a primary hypersomnia of central origin character- associated with unpleasant sensations (prickling, tingling, crawling)
ized by hallucinations, sleep paralysis, and, rarely, cataplexy (brief that occurs at rest and is worse in the evening or at night. There is a
 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function 335

compelling urge to move the legs for relief with a significant effect on Lateral to each optic disc is the macula lutea, the area of most distinct
sleep and quality of life. The disorder is more common in women, the vision, and in the center is the fovea centralis that contains only cones
elderly, and individuals with iron deficiency. RLS has a familial tendency and provides the greatest visual acuity (see Figure 13-6).
and is associated with a circadian fluctuation of dopamine in the sub- As shown in Figure 13-10 (p. 330), nerve impulses pass through
stantia nigra. Iron is a cofactor in dopamine production and some indi- the optic nerves to the optic chiasm. The nerves from the inner (nasal)
viduals respond to iron administration as well as dopamine agonists.69 halves of the retinas cross to the opposite side and join fibers from
the outer (temporal) halves of the retinas to form the optic tracts. The
4 QUICK CHECK 13-3 fibers of the optic tracts synapse in the dorsal lateral geniculate nucleus
and pass by way of the optic radiation (or geniculocalcarine tract) to
1. Describe REM and non-REM sleep.
2. What is the major difference between the dyssomnias and parasomnias? the primary visual cortex in the occipital lobe of the brain.70 Light
entering the eye is focused on the retina by the lens—a flexible, bicon-
vex, crystal-like structure. The lens divides the anterior chamber into
THE SPECIAL SENSES (1) the aqueous chamber and (2) the vitreous chamber. Aqueous
humor fills the aqueous chamber and helps maintain pressure inside
Vision the eye, as well as provide nutrients to the lens and cornea. Aqueous
The eyes are complex sense organs responsible for vision. Within a humor is secreted by the ciliary processes and reabsorbed into the
protective casing, each eye has receptors, a lens system for focusing canal of Schlemm. If drainage is blocked, intraocular pressure increases
light on the receptors, and a system of nerves for conducting impulses (causing glaucoma). The vitreous chamber is filled with a gel-like sub-
from the receptors to the brain. Visual dysfunction may be caused by stance called vitreous humor. Vitreous humor helps to prevent the
abnormal ocular movements or alterations in visual acuity, refraction, eyeball from collapsing inward.
color vision, or accommodation. Visual dysfunction also may be the The central retinal artery provides blood to the inner retinal sur-
secondary effect of another neurologic disorder. face, and the choroid supplies nutrients to the outer surface of the
retina. Six extrinsic eye muscles allow gross eye movements and permit
The Eye and Its External Structures eyes to follow a moving object (Figure 13-7).
The wall of the eye consists of three layers: (1) sclera, (2) choroid, and The external structures protecting the eye include the eyelids (pal-
(3) retina (Figure 13-6). The sclera is the thick, white, outermost layer. pebrae), conjunctiva, and lacrimal apparatus (Figure 13-8). The eye-
It becomes transparent at the cornea—the portion of the sclera in the lids are used to control the amount of light reaching the eyes, and the
central anterior region that allows light to enter the eye. The choroid is conjunctiva lines the eyelids. Tears released from the lacrimal appara-
the deeply pigmented middle layer that prevents light from scattering tus bathe the surface of the eye and prevent friction, maintain hydra-
inside the eye. The iris, part of the choroid, has a round opening, the tion, and wash out foreign bodies and other irritants.
pupil, through which light passes. Smooth muscle fibers control the
size of the pupil so that it adjusts to bright light or dim light and to Visual Dysfunction
close or distant vision. Alterations in ocular movements. Abnormal ocular movements
The retina is the innermost layer of the eye, and contains millions result from oculomotor, trochlear, or abducens cranial nerve dysfunc-
of rods and cones—special photoreceptors that convert light energy tion (see Table 12-6). The three types of eye movement disorders are
into nerve impulses. Rods mediate peripheral and dim light vision and (1) strabismus, (2) nystagmus, and (3) paralysis of individual extra-
are densest at the periphery. Cones, densest in the center of the retina, ocular muscles.
are color and detail receptors. There are no photoreceptors where the In strabismus, one eye deviates from the other when the person is
optic nerve leaves the eyeball; this creates the optic disc, or blind spot. looking at an object. This is caused by a weak or hypertonic muscle in

Visual axis Anterior chamber Superior oblique

Trochlea
Lacrimal Lens Cornea Suspensory Medial rectus
caruncle Pupil Iris ligament Superior rectus
Lacrimal Lower lid
Optic nerve
duct Lateral
canthus
Canal of
Schlemm Ciliary
Posterior body
chamber Retina
Medial
rectus Choroid
muscle Sclera
Optic Lateral
disc rectus Levator palpebrae
Fovea Posterior superioris (cut)
muscle
Optic nerve
Central artery cavity Lateral rectus
and vein Inferior oblique
FIGURE 13-6  Internal Anatomy of the Eye. (From Thibodeau GA, FIGURE 13-7  Extrinsic Muscles of the Right Eye. (From Thibodeau
Patton KT: Anatomy & physiology, ed 6, St Louis, 2007, Mosby.) GA, Patton KT: Anatomy & physiology, ed 6, St Louis, 2007, Mosby.)
336 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function

Lacrimal TABLE 13-6 CHANGES IN THE EYE

Caruncle gland
CAUSED BY AGING
Lacrimal
canals STRUCTURE CHANGE CONSEQUENCE
Cornea Thicker and less Increase in astigmatism
curved
Formation of gray Not detrimental to
Lacrimal ring at edge of vision
sac cornea (arcus
Lacrimal senilis)
Puncta ducts Anterior chamber Decrease in size and Occasionally exerts pressure
volume caused by on Schlemm canal and may
Nasolacrimal thickening of lens lead to increased intraocu-
duct lar pressure and glaucoma
Lens Increase in opacity Decrease in refraction with
increased light scattering
(blurring) and decreased
color vision (green and
blue); can lead to cataracts
Ciliary muscles Reduction in pupil Persistent constriction (senile
diameter, atrophy miosis); decrease in critical
of radial dilation flicker frequency*
FIGURE 13-8  Lacrimal Apparatus. Fluid produced by lacrimal muscles
glands (tears) streams across the eye surface, enters the canals,
Retina Reduction in number Increase in minimum amount
and then passes through the nasolacrimal duct to enter the nose.
of rods at periphery, of light necessary to see
(From Thibodeau GA, Patton KT: Anatomy & physiology, ed 6, St
Louis, 2007, Mosby.) loss of rods and as- an object
sociated nerve cells

*The rate at which consecutive visual stimuli can be presented and

one eye. The deviation may be upward, downward, inward (entropia), still be perceived as separate.
or outward (extropia). Strabismus in children requires early interven-
tion to prevent amblyopia (reduced vision in the affected eye caused
by cerebral blockage of the visual stimuli). The primary symptom of by intraocular pressures greater than 12 to 20 mm Hg with death of
strabismus is diplopia (double vision). Causes of strabismus include retinal ganglion cells and their axons.71 There are three primary types
neuromuscular disorder of the eye muscle, diseases involving the cere- of glaucoma71:
bral hemispheres, or thyroid disease. 1. Open angle. This type of glaucoma is characterized by outflow
Nystagmus is an involuntary unilateral or bilateral rhythmic move- obstruction of aqueous humor at the trabecular meshwork or canal
ment of the eyes. It may be present at rest or when the eye moves. of Schlemm even though there is adequate space for drainage; often
Pendular nystagmus is characterized by a regular back and forth this is an inherited disease and is a leading cause of blindness with
movement of the eyes. In jerk nystagmus, one phase of the eye move- few preliminary symptoms.
ment is faster than the other. Nystagmus may be caused by an imbal- 2. Angle closure. In this type of glaucoma there is displacement of the
anced reflex activity of the inner ear, vestibular nuclei, cerebellum, iris toward the cornea with obstruction of the trabecular meshwork
medial longitudinal fascicle, or nuclei of the oculomotor, trochlear, and obstruction of outflow of aqueous humor from the anterior
and abducens cranial nerves (see Table 12-6 and Figure 12-24). Drugs, chamber; it may occur acutely with a sudden rise in intraocular
retinal disease, and diseases involving the cervical cord also may pro- pressure, causing pain and visual disturbances.
duce nystagmus. 3. Congenital closure. This is a rare disease associated with congenital
Paralysis of specific extraocular muscles may cause limited abduc- malformations and other genetic anomalies.
tion, abnormal closure of the eyelid, ptosis (drooping of the eyelid), Both medical and surgical therapies are available.72
or diplopia (double vision) as a result of unopposed muscle activity. Age-related macular degeneration (AMD) is a severe and irrevers-
Trauma or pressure in the area of the cranial nerves or diseases such ible loss of vision and a major cause of blindness in older individuals.
as diabetes mellitus and myasthenia gravis also paralyze specific extra- Hypertension, cigarette smoking, diabetes mellitus and family history
ocular muscles. of AMD are risk factors. The degeneration usually occurs after the age
Alterations in visual acuity. Visual acuity is the ability to see objects of 60 years. There are two forms: atrophic (dry, nonexudative) and
in sharp detail. With advancing age, the lens of the eye becomes less neovascular (wet, exudative). The atrophic form is slowly progressive
flexible and adjusts slowly, and there is altered refraction of light with accumulation of drusen (waste products from photoreceptors)
by the cornea and lens. Thus, visual acuity declines with age. Table in the retina and may include limited night vision and difficulty read-
13-6 contains a summary of changes in the eye caused by aging. Spe- ing. The neovascular form includes accumulation of drusen, abnor-
cific causes of visual acuity changes are (1) amblyopia, (2) scotoma, mal choroidal blood vessel growth, leakage of blood or serum, retinal
(3) cataracts, (4) papilledema, (5) dark adaptation, (6) glaucoma, detachment, fibrovascular scarring, loss of photoreceptors, and more
(7) retinal detachment, and (8) macular degeneration (Table 13-7). severe loss of central vision. Both medical and surgical therapies are
Glaucoma is the second leading cause of blindness and is characterized available.73
 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function 337

TABLE 13-7 CAUSES OF VISUAL ACUITY

CHANGES
DISORDER DESCRIPTION A
Amblyopia Reduced or dimmed vision, cause unknown
Associated with strabismus
Accompanies such diseases as diabetes mellitus, renal
failure, and malaria and use of drugs such as alcohol
and tobacco B
Scotoma Circumscribed defect of central field of vision
Often associated with retrobulbar neuritis and multiple Vertical
sclerosis, compression of optic nerve by tumor, inflam- Horizontal
mation of optic nerve, pernicious anemia, methyl
alcohol poisoning, and use of tobacco
C Vertical
Cataract Cloudy or opaque area in ocular lens FIGURE 13-9  Alterations in Refraction. A, Myopic eye. Parallel
Incidence increases with age because most commonly a rays of light are brought to a focus in front of the retina. B, Hyper-
result of degeneration; other causes are congenital opic eye. Parallel rays of light come to a focus behind the retina
in the unaccommodative eye. C, Simple myopic astigmatism. The
Papilledema Edema and inflammation of optic nerve where it enters
vertical bundle of rays is focused on the retina; the horizontal rays
eyeball
are focused in front of the retina. (From Stein HA, Slatt BJ, Stein
Caused by obstruction of venous return from retina from RM: The ophthalmic assistant: fundamentals and clinical practice,
one of three main sources: increased intracranial pres- ed 5, St Louis, 1998, Mosby.)
sure, retrobulbar neuritis, or changes in retinal blood
vessels
Dark ­adaptation With age, eye does not adapt as readily to dark Alterations in color vision. Normal sensitivity to color diminishes
Also, changes in quantity and quality of rhodopsin are with age because of the progressive yellowing of the lens that occurs
causative; vitamin A deficiencies can produce this at with aging. All colors become less intense, although color discrimina-
any age tion for blue and green is greatly affected. Color vision deteriorates
Glaucoma Increased intraocular pressures (>12-20 mm Hg) more rapidly for individuals with diabetes mellitus than for the general
Loss of acuity results from pressure on optic nerve, population.
which blocks flow of nutrients to optic nerve fibers, Abnormal color vision also may be caused by color blindness, an
leading to their death; sixth leading cause of blindness inherited trait. Color blindness affects 8% of the male population and
Retinal Tear or break in retina with accumulation of fluid and 0.5% of the female population. Although many forms of color blind-
­detachment separation from underlying tissue; seen as floaters, ness exist, most commonly the affected individual cannot distinguish
flashes of light, or a curtain over visual field; risks red from green.76 In the most severe form individuals see only shades
include extreme myopia, diabetic retinopathy, sickle of gray, black, and white.
cell disease Neurologic disorders causing visual dysfunction. Vision may be
disrupted at many points along the visual pathway, causing various
defects in the visual field. Visual changes may cause defects or blind-
Alterations in accommodation. Accommodation refers to changes ness in the entire visual field or in half of a visual field (hemianopia).
in the thickness of the lens. Accommodation is needed for clear vision (Figure 13-10 illustrates the many areas along the visual pathway that
and is mediated through the oculomotor nerve. Pressure, inflamma- may be damaged and the associated visual changes.)
tion, age, and disease of the oculomotor nerve may alter accommoda- Injury to the optic nerve causes same-side blindness. Injury to the
tion, causing diplopia, blurred vision, and headache. optic chiasm (the X-shaped crossing of the optic nerves) can cause
Loss of accommodation with advancing age is termed presbyopia, various defects, depending on the location of the injury.
a condition in which the ocular lens becomes larger, firmer, and less
elastic. The major symptom is reduced near vision, causing the indi- External Eye Structure Disorders
vidual to hold reading material at arm’s length. Treatment includes Infection and inflammatory responses are the most common condi-
corrective forward, contact, and intraocular lenses or laser refractive tions affecting the supporting structures of the eyes. Blepharitis is an
surgery for monovision.74,75 inflammation of the eyelids caused by Staphylococcus or seborrheic
Alterations in refraction. Alterations in refraction are the most dermatitis. A hordeolum (stye) is an infection (usually staphylococcal)
common visual problem. Causes include irregularities of the corneal of the sebaceous glands of the eyelids usually centered near an eyelash.
curvature, the focusing power of the lens, and the length of the eye. A chalazion is a noninfectious lipogranuloma of the meibomian (oil-
The major symptoms of refraction alterations are blurred vision and secreting) gland that often occurs in association with a hordeolum and
headache. Three types of refraction are as follows (Figure 13-9): appears as a deep nodule within the eyelid. These conditions present
Myopia—nearsightedness: Light rays are focused in front of the retina with redness, swelling, and tenderness and are treated symptomatically.
when the person is looking at a distant object. Conjunctivitis is an inflammation of the conjunctiva caused by
Hyperopia—farsightedness: Light rays are focused behind the retina bacteria, viruses, allergies, or chemical irritants.77 Acute bacterial
when a person is looking at a near object. conjunctivitis (pinkeye) is highly contagious and often caused by
Astigmatism—unequal curvature of the cornea: Light rays are bent Staphylococcus, Haemophilus, Streptococcus pneumoniae, and Morax-
unevenly and do not come to a single focus on the retina. Astigma- ella catarrhalis, although other bacteria may be involved. In children
tism may coexist with myopia, hyperopia, or presbyopia. younger than 6 years, Haemophilus infection often leads to otitis media
338 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function

L R

Optic nerve
1. Lesion of right optic Visual area
nerve and right eye blindness of the thalamus
1
L R

2
Retina
Optic
2. Lesion in optic chiasm and chiasm 3
bitemporal hemianopia
Optic Visual
L R tract cortex

3. Left optic tract lesion and

bilateral right hemianopia
FIGURE 13-10  Visual Pathways and Defects. (Modified from Thompson JM et al: Mosby’s clinical
­nursing, ed 5, St Louis, 2002, Mosby.)

(conjunctivitis-otitis syndrome). Preventing spread of the microor- malleus [hammer], incus [anvil], and stapes [stirrup]) transmit
ganism with meticulous handwashing and use of separate towels is the vibration of the tympanic membrane to the inner ear. When the
important. The disease also is treated with antibiotics. tympanic membrane moves, the malleus moves with it and transfers
Viral conjunctivitis is caused by an adenovirus. Again, it is conta- the vibration to the incus, which passes it on to the stapes. The stapes
gious, with symptoms of watering, redness, and photophobia. Allergic presses against the oval window, a small membrane of the inner ear.
conjunctivitis is associated with a variety of antigens, including pol- The movement of the oval window sets the fluids of the inner ear in
lens. Chronic conjunctivitis results from any persistent conjunctivitis. motion (Figure 13-12).
Trachoma (chlamydial conjunctivitis) is caused by Chlamydia tracho- The eustachian (pharyngotympanic) tube connects the middle ear
matis and often is associated with poor hygiene. It is the leading cause with the thorax. Normally flat and closed, the eustachian tube opens
of preventable blindness in the world. briefly when a person swallows or yawns, and it equalizes the pressure
Keratitis is an infection of the cornea caused by bacteria or viruses. in the middle ear with atmospheric pressure. Equalized pressure per-
Bacterial infections cause corneal ulceration, and type 1 herpes simplex mits the tympanic membrane to vibrate freely. Through the eustachian
virus can involve both the cornea and the conjunctiva. Severe ulcer- tube the mucosa of the middle ear is continuous with the mucosal lin-
ations with residual scarring require corneal transplantation. ing of the throat.
The inner ear is a system of osseous labyrinths (bony, mazelike
Hearing chambers) filled with perilymph. The bony labyrinth is divided into
The external auditory canal is surrounded by the bones of the cra- the cochlea, the vestibule, and the semicircular canals (see Figure
nium. The opening (meatus) of the canal is just above the mastoid 13-11). Suspended in the perilymph is the endolymph-filled membra-
process. The air-filled sinuses, called mastoid air cells, of the mastoid nous labyrinth that basically follows the shape of the bony labyrinth.
process promote conductivity of sound between the external and the Within the cochlea is the organ of Corti, which contains hair cells
middle ear. (hearing receptors). Sound waves that reach the cochlea through vibra-
tions of the tympanic membrane, ossicles, and oval window set the
The Normal Ear cochlear fluids into motion. Receptor cells on the basilar membrane
The ear is divided into three areas: (1) the external ear, involved only are stimulated when their hairs are bent or pulled by fluid movement.
with hearing; (2) the middle ear, involved only with hearing; and Once stimulated, hair cells transmit impulses along the cochlear nerve
(3) the inner ear, involved with both hearing and equilibrium. (a division of the vestibulocochlear nerve) to the auditory cortex of the
The external ear is composed of the pinna (auricle), which is the temporal lobe in the brain (see Figure 13-12). This is where interpreta-
visible portion of the ear, and the external auditory canal, a tube that tion of the sound occurs.
leads to the middle ear (Figure 13-11). Sound waves entering the exter- The semicircular canals and vestibule of the inner ear contain equi-
nal auditory canal hit the tympanic membrane (eardrum) and cause it librium receptors. In the semicircular canals the dynamic equilibrium
to vibrate. The tympanic membrane separates the external ear from receptors respond to changes in direction of movement. Within each
the middle ear. semicircular canal is the crista ampullaris, a receptor region com-
The middle ear is composed of the tympanic cavity, a small cham- posed of a tuft of hair cells covered by a gelatinous cupula. When the
ber in the temporal bone. Three ossicles (small bones known as the head is rotated, the endolymph in the canal lags behind and moves
 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function 339

in the direction opposite to the head’s movement. The hair cells are otoliths (small pieces of calcium salts) move in a gel-like material in
stimulated, and impulses are transmitted through the vestibular nerve response to changes in the pull of gravity. The otoliths pull on the gel,
(a division of the vestibulocochlear nerve) to the cerebellum. which in turn pulls on the hair cells in the maculae. Nerve impulses
The vestibule in the inner ear contains maculae—receptors essen- in the hair cells are triggered and transmitted to the brain (see Figure
tial to the body’s sense of static equilibrium. As the head moves, 13-12). Thus the ear not only permits the hearing of a large range of

External ear Middle ear Inner ear

(Not to scale)
Auricle Temporal External Tympanic Semicircular
(pinna) bone auditory membrane canals
meatus
Oval window
Facial nerve
Vestibular
nerve Acoustic
Cochlear nerve (VIII)
nerve
Cochlea
Vestibule
Round window
Eustachian tube
Malleus Incus Stapes

Auditory
ossicles
FIGURE 13-11  The Ear. External, middle, and inner ears. (Anatomic structures are not drawn to scale.)
(From Thibodeau GA, Patton KT: Anatomy & physiology, ed 6, St Louis, 2007, Mosby.)

Semicircular
canals Perilymph Vestibular (Reissner’s) membrane
space
Endolymph
(within membrane) Scala
Ampulla vestibuli
Vestibular nerve
Cochlear
Modiolus duct
Cochlear nerve
Utricle
(in vestibule)
Saccule
(in vestibule)
Oval window Scala
tympani
Oval window Cochlea
Tectorial Basilar Hair Supporting
Cochlear membrane membrane cells cells
duct
A B Organ of Corti
FIGURE 13-12  The Inner Ear. A, The bony labyrinth (orange) is the hard outer wall of the entire inner
ear and includes the semicircular canals, vestibule, and cochlea. Within the bony labyrinth is the mem-
branous labyrinth (purple), which is surrounded by perilymph and filled with endolymph. Each ampulla
in the vestibule contains a crista ampullaris that detects changes in head position and sends sensory
impulses through the vestibular nerve to the brain. B, The inset shows a section of the membranous
cochlea. Hair cells in the organ of Corti detect sound and send the information through the cochlear
nerve. The vestibular and cochlear nerves join to form the eighth cranial nerve. (From Thibodeau GA,
Patton KT: Anatomy & physiology, ed 6, St Louis, 2007, Mosby.)
340 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function

sounds but also assists with maintaining balance through the sensitive loss may be caused by maternal rubella, ototoxic drugs, prematurity,
equilibrium receptors. traumatic delivery, erythroblastosis fetalis, and congenital hereditary
malfunction. Diagnosis often is made when delayed speech develop-
Auditory Dysfunction ment is noted.80
Between 5% and 10% of the general population have impaired hear- Presbycusis is the most common form of sensorineural hear-
ing, and it is the most common sensory defect. The major categories ing loss in elderly people. Its cause may be atrophy of the basal end
of auditory dysfunction are conductive hearing loss, sensorineural of the organ of Corti, loss of auditory receptors, changes in vascular-
hearing loss, mixed hearing loss, and functional hearing loss.78 Hear- ity, or stiffening of the basilar membranes. Drug ototoxicities (drugs
ing loss may range from mild to profound. Auditory changes caused that cause destruction of auditory function) have been observed after
by aging are common and incremental (see the Aging & Changes in exposure to various chemicals; for example, antibiotics such as strep-
Hearing box). tomycin, neomycin, gentamicin, and vancomycin; diuretics such
as ethacrynic acid and furosemide; and chemicals such as salicylate,
quinine, carbon monoxide, nitrogen mustard, arsenic, mercury, gold,
GERIATRIC CONSIDERATIONS tobacco, and alcohol. In most instances, the drugs and chemicals listed
Aging & Changes in Hearing initially cause tinnitus (ringing in the ear), followed by a progressive
high-tone sensorineural hearing loss that is permanent.
Hearing loss affects about 33% of older people. Mixed and functional hearing loss. A mixed hearing loss is caused
CHANGES by a combination of conductive and sensorineural losses. With func-
IN STRUCTURE CHANGES IN FUNCTION tional hearing loss, which is rare, the individual does not respond to
Cochlear hair cell ­ Inability to hear high-frequency sounds voice and appears not to hear. It is thought to be caused by emotional
degeneration (presbycusis, sensorineural loss); inter- or psychologic factors.
feres with understanding speech; hearing Ménière disease. Ménière disease is a disorder of the middle ear
may be lost in both ears at different times with an unknown etiology that can be unilateral or bilateral. There
Loss of auditory neurons in Inability to hear high-frequency sounds is excessive endolymph and pressure in the membranous labyrinth
spiral ganglia of organ of (presbycusis, sensorineural loss); inter- that disrupts both vestibular and hearing functions. Recurring symp-
Corti feres with understanding speech; hearing toms include profound vertigo, nausea and vomiting associated with
may be lost in both ears at different times deafness, and tinnitus (ringing in the ears). Treatment is symptom-
Degeneration of basilar (co- Inability to hear at all frequencies but atic with either medical management or minimally invasive surgical
chlear) conductive membrane more pronounced at higher frequencies management.81
of cochlea (cochlear conductive loss)
Ear Infections
Decreased vascularity of Equal loss of hearing at all frequencies
cochlea (strial loss); inability to disseminate Otitis externa. Otitis externa is the most common inflammation
localization of sound of the outer ear and may be acute or chronic, infectious or nonin-
Loss of cortical auditory Equal loss of hearing at all frequencies fectious. The most common origins of acute infections are bacterial
neurons (strial loss); inability to disseminate microorganisms including Pseudomonas, Escherichia coli, and Staphy-
localization of sound lococcus aureus. Fungal infections are less common. Infection usually
follows prolonged exposure to moisture (swimmer’s ear). The earliest
Data from Frisina RD: Age-related hearing loss: ear and brain mecha- symptoms are inflammation with pruritus, swelling, and clear drainage
nisms, Ann N Y Acad Sci 1170:708–717, 2009; Howarth A, Shone GR: progressing to purulent drainage with obstruction of the canal. Ten-
Ageing and the auditory system, Postgrad Med J 82(965):166–171, derness and pain with earlobe retraction accompany inflammation.
2009. Acidifying solutions are used for early treatment and topical antimi-
crobials usually provide effective treatment for later stages of disease.82
Chronic infections are more often related to allergy or skin disorders.
Conductive hearing loss. A conductive hearing loss occurs when Otitis media. Otitis media is a common infection of infants and
a change in the outer or middle ear impairs conduction of the sound children. Most children have one episode by 3 years of age. The most
from the outer to the inner ear. Conditions that commonly cause a common pathogens are Streptococcus pneumoniae, Haemophilus influ-
conductive hearing loss include impacted cerumen, foreign bodies enzae, and Moraxella catarrhalis. Predisposing factors include allergy,
lodged in the ear canal, benign tumors of the middle ear, carcinoma of sinusitis, submucosal cleft palate, adenoidal hypertrophy, eustachian
the external auditory canal or middle ear, eustachian tube dysfunction, tube dysfunction, and immune deficiency. Breast-feeding is a protective
otitis media, acute viral otitis media, chronic suppurative otitis media, factor. Recurrent acute otitis media may be genetically determined.83
cholesteatoma, and otosclerosis. Acute otitis media (AOM) is associated with ear pain, fever, irri-
Symptoms of conductive hearing loss include diminished hearing tability, inflamed tympanic membrane, and fluid in the middle ear.
and soft speaking voice. The voice is soft because often the individual The appearance of the tympanic membrane progresses from erythema
hears his or her voice, conducted by bone, as loud. to opaqueness with bulging as fluid accumulates. There is an increas-
Sensorineural hearing loss. A sensorineural hearing loss is caused ing prevalence of AOM caused by penicillin-resistant microorganisms.
by impairment of the organ of Corti or its central connections. The Otitis media with effusion (OME) is the presence of fluid in the mid-
loss may occur gradually or suddenly. Conditions causing sensori- dle ear without symptoms of acute infection.
neural loss include congenital and hereditary factors, noise exposure, Treatment includes symptom management, particularly of pain,
aging, Ménière disease, ototoxicity, systemic disease (syphilis, Paget with watchful waiting, antimicrobial therapy for severe illness, and
disease, collagen diseases, diabetes mellitus), neoplasms, and auto- placement of tympanotomy tubes when there is persistent bilat-
immune processes.79 Congenital and neonatal sensorineural hearing eral effusion and significant hearing loss.83 Complications include
 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function 341

Olfactory bulb 3. Olfactory hallucinations—smelling odors that are not really

Fibers of olfactory nerve
present
Cribriform plate of Frontal bone 4. Parosmia—abnormal or perverted sense of smell
ethmoid bone
The sense of taste can be impaired by injury. Altered taste may
Nasal cavity
Olfactory be attributed to impaired smell associated with injury near the
tract hippocampus.
Olfactory Hypogeusia is a decrease in taste sensation, whereas ageusia is
recess an absence of the sense of taste. These disorders result from cranial
nerve injuries and can be specific to the area of the tongue innervated.
Dysgeusia is a perversion of taste in which substances possess an
unpleasant flavor (i.e., metallic). Alterations in taste may compromise
adequate nutrition or cause anorexia.86
Palate
Nasopharynx 4 QUICK CHECK 13-4
FIGURE 13-13  Olfaction. Midsagittal section of the nasal area 1. List the major structures of the eye.
shows the location of major olfactory sensory structures. (From 2. Visual disorders fall into several categories; name them.
Thibodeau GA, Patton KT: Anatomy & physiology, ed 6, St Louis, 3. How does fluid accumulate in the middle ear during otitis media?
2007, Mosby.) 4. What factors are involved in the sensation of flavor?

mastoiditis, brain abscess, meningitis, and chronic otitis media with

hearing loss. Persistent middle ear effusions may affect speech, lan- SOMATOSENSORY FUNCTION
guage, and cognitive abilities. Multivalent vaccines for prevention of
otitis media are effective for reducing disease incidence.84 Touch
The sensation of touch involves four afferent fiber types that medi-
Olfaction and Taste ate tactile sensation and there may be an additional sensory nerve
Olfaction (smell) is a function of cranial nerve I. Taste (gustation) is a that transmits pleasurable touch.87 Receptors sensitive to touch are
function of multiple nerves in the tongue, soft palate, uvula, pharynx, present in the skin with high densities in the fingers and lips. Meiss-
and upper esophagus innervated by cranial nerves VII and IX. Both ner and pacinian corpuscles are fast adapting receptors and sense
of these cranial nerves are influenced by hormones within the sensory movement across the skin and vibration, respectively. The slowly
cells. Dysfunctions of smell and taste may occur separately or jointly. adapting Merkel disks sense sustained light touch, and Ruffini end-
The strong relationship between smell and taste creates the sensation ings respond to deep sustained pressure, stretch, and joint position.
of flavor. If either sensation is impaired, the perception of flavor is Specific sensory input is carried to the higher levels of the CNS by
altered. Olfactory structures are illustrated in Figure 13-13. the dorsal column of the spinal cord and the anterior spinothalamic
Olfactory cells, located in the olfactory epithelium, are the receptor tract.
cells for smell. Seven different primary classes of olfactory stimulants The cutaneous senses develop before birth, but structural growth
have been identified: (1) camphoraceous, (2) musky, (3) floral, (4) pep- continues into early adulthood. Then a gradual decline occurs, with
permint, (5) ethereal, (6) pungent, and (7) putrid. The primary sensa- loss in tactile sensitivity with advancing age.88
tions of taste are (1) sour, (2) salty, (3) sweet, (4) bitter, and (5) umami Abnormal tactile perception may be caused by alterations at any
(savoriness). Taste buds sensitive to each of the primary sensations are level of the nervous system, from the receptor to the cerebral cortex.
located in specific areas of the tongue.85 Factors that interrupt or impair reception, transmission, perception,
Sensitivity to odors declines steadily with aging. See the Aging & or interpretation of touch—including trauma, tumor, infection, meta-
Changes in Olfaction and Taste box for a summary of changes in olfac- bolic changes, vascular changes, and degenerative diseases—may cause
tion and taste with aging. tactile dysfunction. In addition, most tactile sensations evoke affective
responses that determine whether the sensation is unpleasant, pleas-
GERIATRIC CONSIDERATIONS ant, or neutral.
Aging & Changes in Olfaction and Taste Proprioception
Decline in sensitivity to odors, usually after age 80, occurs. Awareness of the position of the body and its parts depends on impulses
Loss of olfaction may diminish appetite, taste, and food selection and may from the inner ear and from receptors in joints and ligaments. Sen-
affect nutrition. sory data are transmitted to higher centers, primarily through the
Inability to smell toxic fumes or gases can pose a safety hazard. dorsal columns and the spinocerebellar tracts, with some data pass-
Decline in taste sensitivity is more gradual than decline in sense of smell. ing through the medial lemnisci and thalamic radiations to the cortex.
Higher concentrations of flavors required to stimulate taste. These stimuli are necessary for the coordination of movements, the
Taste may be influenced by decreased salivary secretion. grading of muscular contraction, and the maintenance of equilibrium.
A progressive loss of proprioception has been reported in elderly
persons.89 As with tactile dysfunction, any factor that interrupts or
Olfactory and Taste Dysfunctions impairs the reception, transmission, perception, or interpretation of
Olfactory dysfunctions include the following: proprioceptive stimuli also alters proprioception and increases risk for
1. Hyposmia—impaired sense of smell falls and injury. Two common causes are vestibular dysfunction and
2. Anosmia—complete loss of sense of smell neuropathy.
342 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function

Specific vestibular dysfunctions are vestibular nystagmus and ver- associated with renal disease and diabetes mellitus. Although the exact
tigo. Vestibular nystagmus is the constant, involuntary movement sequence of events is unknown, neuropathies cause a diminished or
of the eyeball and develops when the semicircular canal system is absent sense of body position or position of body parts. Gait changes
overstimulated. Vertigo is the sensation of spinning that occurs with often occur. (Neuropathies are discussed further in Chapter 14.)
inflammation of the semicircular canals in the ear. The individual may
feel either that he or she is moving in space or that the world is revolv-
ing. Vertigo often causes loss of balance, and nystagmus may occur.
Ménière disease can cause loss of proprioception during an acute
attack, so that standing or walking is impossible.
4 QUICK CHECK 13-5
1. How are different touch receptors distributed over the body?
Peripheral neuropathies also can cause proprioceptive dysfunc- 2. What are two causes of alterations in proprioception?
tion. They may be caused by several conditions and commonly are

DID YOU UNDERSTAND?

Pain 14. Neuropathic pain is increased sensitivity to painful stimuli and results from
1. Pain is a complex phenomenon composed of sensory experiences (time, abnormal processing of pain information in the peripheral or central ner-
space, intensity) and emotion, cognition, and motivation. vous system.
2. The specificity theory of pain proposes that the intensity of pain is directly 15. Pain threshold is the least experience of pain that a person can recognize.
related to the degree of associated tissue injury. According to the gate Pain tolerance is the greatest level of pain that an individual is prepared to
control theory, specialized cells within the substantia gelatinosa act as a tolerate. Both are subjective and influenced by many factors.
gate, opening and closing the afferent pathways to transmission of painful 16. Pain threshold in older individuals varies.
stimuli. The neuromatrix theory of pain proposes that chronic pain is related 17. Newborns and young children have the anatomic and functional ability to
to multidimensional inputs triggered from the periphery or originating inde- perceive pain.
pendently within the brain. 18. Older individuals tend to have a slightly higher pain threshold, probably
3. The portions of the nervous system responsible for the sensation and because of changes in the thickness of the skin and peripheral neuropathies.
­perception of pain may be divided into three areas: (a) the afferent fibers, 19. Women appear to be more sensitive to pain than are men in all age groups.
(b) the central nervous system, and (c) the efferent pathways.
4. The afferent system is composed of nociceptors (Aδ and C fibers), the dor- Temperature Regulation
sal horn of the spinal column, and afferent neurons in the spinothalamic 1. Temperature regulation is achieved through precise balancing of heat pro-
tract. duction, heat conservation, and heat loss. Body temperature is maintained
5. The thalamus, cortex, and postcentral gyrus perceive, describe, and localize in a range around 37° C (98.6° F).
pain. The reticular formation and limbic system control the emotional and 2. Temperature regulation is mediated by the hypothalamus through thermo-
affective response to pain. receptors in the skin, hypothalamus, spinal cord, and abdominal organs.
6. Efferent pathways from the ventromedial thalamus and periaqueductal 3. Heat is produced through chemical reactions of metabolism, skeletal mus-
gray are responsible for modulation or inhibition of afferent pain signals. cle contraction, and vasoconstriction.
7. Nociception is the processing of pain and includes four phases: transduc- 4. Heat is lost through radiation, conduction, convection, vasodilation,
tion, transmission, perception, and modulation. decreased muscle tone, evaporation of sweat, increased respiration, and
8. Neuromodulators of pain include substances that (a) stimulate pain voluntary mechanisms.
nociceptors (e.g., prostaglandins, bradykinins, lymphokines, substance 5. Heat conservation is accomplished through vasoconstriction and voluntary
P, glutamate) and (b) suppress pain (e.g., GABA, endorphins). Some sub- mechanisms.
stances excite peripheral nerves but inhibit central nerves (e.g., serotonin, 6. Infants do not conserve heat well because of their greater body surface/
norepinephrine). mass ratio and decreased amounts of subcutaneous fat. Elderly persons
9. Endogenous opioids include enkephalins, endorphins, dynorphins, and have poor responses to environmental temperature extremes as a result of
endodmorphins that inhibit pain transmission and are present in varying slowed blood circulation, structural and functional changes in the skin, and
concentrations in the neurons of the brain, spinal cord, and gastrointestinal overall decrease in heat-producing activities.
tract. 7. Fever is triggered by the release of exogenous pyrogens from bacteria
10. Classifications of pain include nociceptive pain (with a known physiologic or the release of endogenous pyrogens (cytokines) from phagocytic cells.
cause), non-nociceptive pain (neurologic pain), acute pain (signal to the Fever is both a normal immunologic mechanism and a symptom of disease.
person of a harmful stimulus), and chronic pain (persistence of pain of 8. Fever involves the “resetting of the hypothalamic thermostat” to a higher
unknown cause or unusual response to therapy). level. When the fever breaks, the set point returns to normal.
11. Acute pain may be (a) somatic (superficial), (b) visceral (internal), or 9. Fever production aids responses to infectious processes. Higher tempera-
(c) referred (present in an area distant from its origin). The area of referred tures kill many microorganisms and decrease serum levels of iron, zinc, and
pain is supplied by the same spinal segment as the actual site of pain. copper that are needed for bacterial replication.
12. Chronic pain is pain lasting well beyond the expected normal healing time 10. Fever of unknown origin is a body temperature greater than 38.3° C (101° F)
and may be intermittent (e.g., low back pain) or persistent (e.g., migraine that remains undiagnosed.
headaches). 11. Hyperthermia (marked warming of core temperature) can produce nerve
13. Psychologic, behavioral, and physiologic responses to chronic pain include damage, coagulation of cell proteins, and death. Forms of accidental hyper-
depression, sleep disorders, preoccupation with pain, lifestyle changes, thermia include heat cramps, heat exhaustion, heat stroke, and malignant
and physiologic adaptation. hyperthermia. Heat stroke and malignant hyperthermia are potentially lethal.
 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function 343

DID YOU UNDERSTAND?—cont’d

12. Hypothermia (marked cooling of core temperature) slows the rate of chemi- 12. Conjunctivitis can be acute or chronic, bacterial, viral, or allergic. Redness,
cal reaction (tissue metabolism), increases the viscosity of the blood, slows edema, pain, and lacrimation are common symptoms. Chlamydial conjunc-
blood flow through the microcirculation, facilitates blood coagulation, and tivitis is the leading cause of blindness in the world and is associated with
stimulates profound vasoconstriction. Hypothermia may be accidental or poor sanitary conditions.
therapeutic. 13. Keratitis is a bacterial or viral infection of the cornea that can lead to cor-
neal ulceration. Photophobia, pain, and tearing are common symptoms.
Sleep 14. The ear is composed of external, middle, and inner structures. The exter-
1. Sleep is an active process and is divided into REM and non-REM stages, nal structures are the pinna, auditory canal, and tympanic membrane. The
each of which has its own series of stages. While asleep, an individual pro- tympanic cavity (containing three bones: the malleus, the incus, and the
gresses through REM and non-REM (slow wave) sleep in a predictable cycle. stapes), oval window, eustachian tube, and fluid compose the middle ear
2. REM sleep is controlled by mechanisms in the pons and mesencephalon. and transmit sound vibrations to the inner ear.
Non-REM sleep is controlled by release of inhibitory signals from the hypo- 15. The inner ear includes the bony and membranous labyrinths that transmit
thalamus and accounts for 75% to 80% of sleep time. sound waves through the cochlea to the acoustic division of the eighth
3. The sleep patterns of the newborn and young child vary from those of the cranial nerve. The semicircular canals and vestibule help maintain balance
adult in total sleep time, cycle length, and percentage of time spent in each through the equilibrium receptors.
sleep cycle. Elderly persons experience a total decrease in sleep time. 16. Approximately one third of all people older than 65 years have hearing loss.
4. The restorative, reparative, and growth processes occur during slow-wave 17. Hearing loss can be classified as conductive, sensorineural, mixed, or
(non-REM) sleep. Sleep deprivation can cause profound changes in personal- functional.
ity and functioning. 18. Conductive hearing loss occurs when sound waves cannot be conducted
5. Sleep disorders include (a) dyssomnias (disorders of initiating sleep [i.e., through the middle ear.
insomnia, sleep disordered breathing, hypersomnia, or disorders of the 19. Sensorineural hearing loss develops with impairment of the organ of Corti
sleep-wake schedule]) and (b) parasomnias (i.e., sleepwalking or night or its central connections. Presbycusis is the most common form of senso-
terrors). rineural hearing loss in elderly people.
6. Restless leg syndrome is associated with unpleasant sensations and a com- 20. A combination of conductive and sensorineural loss is a mixed hearing loss.
pelling urge to move the legs that disrupts sleep. 21. Loss of hearing with no known organic cause is a functional hearing loss.
22. Ménière disease is a disorder of the middle ear that affects hearing and
The Special Senses balance.
1. The wall of the eye has three layers: sclera, choroid, and retina. The retina 23. Otitis externa is an infection of the outer ear associated with prolonged
contains millions of baroreceptors known as rods and cones that receive exposure to moisture.
light through the lens and then convey signals to the optic nerve and subse- 24. Otitis media is an infection of the middle ear that is common in children.
quently to the visual cortex of the brain. Accumulation of fluid (effusion) behind the tympanic membrane is a com-
2. The eye is filled with vitreous and aqueous humor, which prevent it from mon finding.
collapsing. 25. The perception of flavor is altered if olfaction or taste dysfunctions occur.
3. The eyelids, conjunctiva, and lacrimal apparatus protect the eye. Infections Sensitivity to odor and taste decreases with aging.
are the most common disorders; they include blepharitis, conjunctivitis, 26. Hyposmia is a decrease in the sense of smell, and anosmia is the complete
chalazion, and hordeolum. loss of the sense of smell. Inflammation of the nasal mucosa and trauma or
4. Structural eye changes caused by aging result in decreased visual acuity. tumors of the olfactory nerve lead to a diminished sense of smell.
5. The major alterations in ocular movement include strabismus, nystagmus, 27. Hypogeusia is a decrease in taste sensation, and ageusia is the absence of
and paralysis of the extraocular muscles. the sense of taste. Loss of taste buds or trauma to the facial or glossopha-
6. Alterations in visual acuity can be caused by amblyopia, scotoma, cata- ryngeal nerves decreases taste sensation.
racts, papilledema, glaucoma, and macular degeneration.
7. Alterations in accommodation develop with increased intraocular pressure, Somatosensory Function
inflammation, and disease of the oculomotor nerve. Presbyopia is loss of 1. Tactile sensation is a function of receptors present in the skin (pacinian
accommodation caused by loss of elasticity of the lens with aging. corpuscles), and the sensory response is conducted to the brain through the
8. Alterations in refraction, including myopia, hyperopia, and astigmatism, are dorsal column and anterior spinothalamic tract.
the most common visual disorders. 2. Alterations in touch can result from disruption of skin receptors, sensory
9. Alterations in color vision can be related to yellowing of the lens with aging transmission, or central nervous system perception.
and color blindness, an inherited trait. 3. Proprioception is the position and location of the body and its parts. Pro-
10. Trauma or disease of the optic nerve pathways, or optic radiations, can prioceptors are located in the inner ear, joints, and ligaments. Propriocep-
cause blindness in the visual fields. Homonymous hemianopsia is caused tive stimuli are necessary for balance, coordinated movement, and grading
by damage of one optic tract. of muscular contraction.
11. Blepharitis is an inflammation of the eyelid; a hordeolum (stye) is an infec- 4. Disorders of proprioception can occur at any level of the nervous system
tion of the eyelid’s sebaceous gland; and chalazion is an infection of the and result in impaired balance and lack of coordinated movement.
eyelid’s meibomian gland.
344 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function

 KEY TERMS
• A -beta (Aβ) fiber  325 •  ovea centralis  335
F •  acinian corpuscle  341
P
• Accidental hyperthermia  332 • Functional hearing loss  340 • Pain modulation  326
• Acute bacterial conjunctivitis • Gate control theory (GCT)  325 • Pain perception  326
(pinkeye)  337 • Glaucoma  336 • Pain threshold  329
• Acute otitis media (AOM)  340 • Hair cell  338 • Pain tolerance  329
• Acute pain  327 • Heat cramp  332 • Pain transduction  325
• A-delta (Aδ) fiber  325 • Heat exhaustion  332 • Pain transmission  325
• Affective-motivational system  326 • Heat stroke  332 • Parasomnia  334
• Age-related macular degeneration • Hordeolum (stye)  337 • Parosmia  341
(AMD)  336 • Hyperopia  337 • Pattern theory  325
• Ageusia  341 • Hypersomnia  334 • Pendular nystagmus  336
• Allergic conjunctivitis  338 • Hyperthermia  331 • Perceptual dominance  329
• Amblyopia  336 • Hypogeusia  341 • Perilymph  338
• Anosmia  341 • Hyposmia  341 • Peripheral neuropathic pain  328
• Aqueous humor  335 • Hypothermia  333 • Peripheral sensitization  326
• Astigmatism  337 • Incus (anvil)  338 • Persistent pain  328
• Blepharitis  337 • Inhibitory neuromodulator  327 • Pinna  338
• Central neuropathic pain  328 • Insomnia  334 • Presbycusis  340
• Central sensitization  326 • Iris  335 • Presbyopia  337
• C fiber  325 • Jerk nystagmus  336 • Pupil  335
• Chalazion  337 • Keratitis  338 • Referred pain  328
• Choroid  335 • Lens  335 • REM (rapid eye movement) sleep  333
• Chronic conjunctivitis  338 • Macula lutea  335 • Restless leg syndrome (RLS)  334
• Chronic pain  328 • Maculae  339 • Retina  335
• Circadian rhythm  330 • Malignant hyperthermia  332 • Rod  335
• Cochlea  338 • Malleus (hammer)  338 • Ruffini ending  341
• Cognitive-evaluative system  326 • Mastoid air cell  338 • Sclera  335
• Color blindness  337 • Mastoid process  338 • Semicircular canal  338
• Conductive hearing loss  340 • Meissner corpuscle  341 • Sensorineural hearing loss  340
• Cone  335 • Ménière disease  340 • Sensory-discriminative system  326
• Conjunctivitis  337 • Merkel disk  341 • Sleep  333
• Cornea  335 • Mixed hearing loss  340 • Somatic pain  327
• Crista ampullaris  338 • Myopia  337 • Somnambulism (sleepwalking)  334
• Descending inhibitory pathway  327 • Narcolepsy  334 • Specificity theory of pain  324
• Diffuse noxious inhibitory control • Neuromatrix theory  325 • Stapes (stirrup)  338
(DNIC)  327 • Neuropathic pain  328 • Strabismus  335
• Diplopia  336 • Night terrors  334 • Suprachiasmatic nucleus (SCN)  333
• Dynorphin  327 • Nociception  325 • Temperature regulation
• Dysgeusia  341 • Nociceptor  325 (thermoregulation)  330
• Dyssomnia  334 • Non-REM sleep (NREM)  334 • Therapeutic hyperthermia  331
• Endogenous opioid  327 • Nystagmus  336 • Tinnitus  340
• Endogenous pyrogen  331 • Obstructive sleep apnea syndrome • Trachoma  338
• Endomorphin  327 (OSAS)  334 • Tympanic cavity  338
• Endorphin  327 • Olfactory hallucination  341 • Tympanic membrane  338
• Enkephalin  327 • Optic chiasm  337 • Vertigo  342
• Equilibrium receptor  338 • Optic disc  335 • Vestibular nystagmus  342
• Eustachian (pharyngotympanic) tube  338 • Organ of Corti  338 • Vestibule  338
• Excitatory neuromodulator  326 • Otitis externa  340 • Viral conjunctivitis  338
• Exogenous pyrogen  331 • Otitis media  340 • Visceral pain  327
• External auditory canal  338 • Otitis media with effusion (OME)  340 • Vitreous humor  335
• Fever  331 • Otolith  339
• Fever of unknown origin (FUO)  331 • Oval window  338
 CHAPTER 13  Pain, Temperature, Sleep, and Sensory Function 345

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 CHAPTER

14
Alterations in Cognitive Systems,
Cerebral Hemodynamics,
and Motor Function
Barbara J. Boss and Sue E. Huether

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Alterations in Cognitive Systems, 347 Alterations in Neuromotor Function, 364
Alterations in Arousal, 347 Alterations in Muscle Tone, 364
Alterations in Awareness, 353 Alterations in Movement, 365
Seizure Disorders, 354 Paresis/Paralysis, 365
Data Processing Deficits, 356 Hyperkinesia, 369
Alterations in Cerebral Hemodynamics, 361 Alterations in Complex Motor ­Performance, 372
Increased Intracranial Pressure, 361 Disorders of Posture (Stance), 372
Cerebral Edema, 362 Disorders of Gait, 372
Hydrocephalus, 363 Disorders of Expression, 373
Extrapyramidal Motor Syndromes, 373

A person achieves functional adequacy (competence) through com- responses. Any decrease in this state of awareness and varied responses
plex integrated processes. Three major neural systems account for is a decrease in consciousness.
this functional adequacy: cognitive systems, sensory systems, and Consciousness involves arousal and awareness (content of thought).
motor systems. Alterations in any or all of these affect functional ade- Arousal is an individual’s state of awakeness. Arousal is mediated by
quacy. The neural systems that are essential to cognitive function are the reticular activating system, which regulates aspects of attention and
(1) attentional systems that provide arousal and maintenance of atten- information processing and maintains consciousness. When a person
tion over time; (2) memory and language systems by which information loses cerebral function, the reticular activating system and brain stem
is communicated; and (3) affective or emotive systems that mediate can maintain a crude waking state known as a vegetative state (VS).
mood, emotion, and intention. These core systems are fundamental Cognitive cerebral functions, however, cannot occur without a func-
to the processes of abstract thinking and reasoning. The products of tioning reticular activating system.
abstraction and reasoning are organized and made operational through
the executive attentional networks. The normal functioning of these Alterations in Arousal
networks manifests through the motor network in a behavioral array The cause of an altered level of arousal may be organic or functional.
viewed by others as appropriate to human activity and successful living. Further distinction is then made between structural, metabolic, or psy-
chogenic arousal alterations.
Pathophysiology. Structural alterations in arousal are divided
ALTERATIONS IN COGNITIVE SYSTEMS according to whether the original location of the pathologic condition
Full consciousness is a state of awareness both of oneself and the envi- is above or below the tentorial plate. Structural causes include infec-
ronment and a set of responses to that environment. The fully con- tious, vascular, neoplastic, traumatic, congenital (developmental),
scious individual responds to external stimuli with a wide array of degenerative, polygenic, and metabolic causes.

347
348 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics

TABLE 14-1 CLINICAL MANIFESTATIONS OF METABOLIC AND STRUCTURAL CAUSES

OF ALTERED AROUSAL
MANIFESTATIONS METABOLICALLY INDUCED STRUCTURALLY INDUCED
Blink to threat (cranial nerves II, VII) Equal Asymmetric
Optic discs (cranial nerve II) Flat, good pulsation Papilledema
Extraocular movement Roving eye movements; normal doll’s eyes Gaze paresis, nerve palsy
(cranial nerves III, IV, VI) and calorics
Pupils (cranial nerves II, III) Equal and reactive; may be dilated (e.g., atropine), Asymmetric or nonreactive; may be midposition (midbrain
pinpoint (e.g., opiates), or midposition and fixed injury), pinpoint (pons injury), large (tectal injury)
(e.g., glutethimide [Doriden])
Corneal reflex (cranial nerves V, VII) Symmetric response Asymmetric response
Grimace to pain (cranial nerve VII) Symmetric response Asymmetric response
Motor function movement Symmetric Asymmetric
Muscle tone Symmetric Paratonic (rigid), spastic, flaccid, especially if asymmetric
Posture Symmetric Decorticate, especially if symmetric; decerebrate, espe-
cially if asymmetric (see Figure 14-6)
Deep tendon reflexes Symmetric Asymmetric
Babinski sign Absent or symmetric response Present
Sensation Symmetric Asymmetric

Disorders above the tentorial plate (supratentorial) produce changes

TABLE 14-2 DIFFERENTIAL CHARAC­TERIS­
in arousal by either diffuse or localized dysfunction. Diffuse dysfunc-
tion may be caused by disease processes (e.g., encephalitis) and may
TICS OF STATES CAUSING
affect the cerebral cortex or the underlying subcortical white matter. ALTERED AROUSAL
Disorders outside the brain but within the cranial vault can produce MECHANISM MANIFESTATIONS
diffuse dysfunction. Examples include neoplasms, closed-head trauma Supratentorial mass Initiating signs usually of focal cerebral dysfunc-
with subsequent subdural bleeding, and accumulation of pus in the ­lesions compressing or tion: vomiting, headache, hemiparesis, ocular
subdural space. Localized dysfunction generally is caused by masses displacing diencepha- signs, seizures, coma
that directly impinge on deep diencephalic structures (i.e., thalamus lon or brain stem Signs of dysfunction progress rostral to caudal
and hypothalamus) or that secondarily compress these structures in Neurologic signs at any given time point to one
the process of herniation. Disorders within the brain substance— anatomic area (e.g., diencephalon, mesen-
bleeding, infarcts, emboli, and tumors—function primarily as masses. cephalon, medulla)
Such localized destructive processes directly impair function of the Motor signs often asymmetric
thalamic or hypothalamic activating systems. Infratentorial mass of History of preceding brain stem dysfunction or
Disorders below the tentorial plate (infratentorial) produce a decline destruction causing sudden onset of coma
in arousal by direct destruction of the reticular activating system and its coma Localizing brain stem signs precede or
pathways or of the entire brain stem either by direct invasion or by indi- ­accompany onset of coma and always
rect impairment of its blood supply. In addition, decreased arousal may include oculovestibular abnormality
result from compression of the reticular activating system by a disease Cranial nerve palsies usually manifest
process. This compression may result from direct pressure or compres- “bizarre” respiratory patterns that appear at
sion as structures either expand or herniate. Causes include accumula- Metabolic coma onset
tions of blood or pus, neoplasms, and demyelinating disorders. Confusion and stupor commonly precede motor
Metabolic alterations in arousal include hypoxia, electrolyte dis- signs
turbances, hypoglycemia, drugs, and toxins (both endogenous and Psychiatric Motor signs usually are symmetric
exogenous). All the systemic diseases that eventually produce nervous ­unresponsiveness Pupillary reactions usually are preserved
system dysfunction are part of this metabolic category. Alterations in Asterixis, myoclonus, tremor, and seizures are
arousal range from slight drowsiness to coma. common
Psychogenic alterations in arousal (unresponsiveness), although Acid-base imbalance with hyperventilation or
uncommon, may signal general psychiatric disorders. Despite appar- hypoventilation is common
ent unconsciousness, the person actually is physiologically awake. Lids close actively
Clinical manifestations and evaluation. Patterns of clinical mani- Pupils reactive or dilated (cycloplegics)
festations help in determining the extent of brain dysfunction and Oculocephalic reflexes are unpredictable;
serve as indexes for identifying increasing or decreasing central ner- ­oculovestibular reflexes are physiologic (nys-
vous system (CNS) function. Distinctions are made between meta- tagmus is present)
bolic and structurally induced manifestations (Table 14-1). The types Motor tone is inconsistent or normal
of manifestations suggest the cause of the altered arousal state (Table Eupnea or hyperventilation is usual
14-2). Five categories of neurologic function are critical to the evalu- No pathologic reflexes are present
ation process: (1) level of consciousness, (2) pattern of breathing, (3) Electroencephalogram (EEG) is normal
pupillary reaction, (4) oculomotor responses, and (5) motor responses.
 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics 349

Level of consciousness is the most critical clinical index of ner- Oculomotor responses (resting, spontaneous, and reflexive eye
vous system function, with changes indicating either improvement or movements) change at various levels of brain dysfunction in coma-
deterioration of the individual’s condition. A person who is alert and tose individuals. Persons with metabolically induced coma, except
oriented to self, others, place, and time is considered to be function- with barbiturate-hypnotic and phenytoin poisoning, generally retain
ing at the highest level of consciousness, which implies full use of all ocular reflexes even when other signs of brain stem damage are pres-
the person’s cognitive capacities. From this normal alert state, levels ent. Destructive or compressive injury to the brain stem causes spe-
of consciousness diminish in stages from confusion to coma, each of cific abnormalities of the oculocephalic and oculovestibular reflexes
which is clinically defined (Table 14-3).
Patterns of breathing help evaluate the level of brain dysfunction
and coma (Figure 14-1). Rate, rhythm, and pattern should be evalu-
TABLE 14-3 LEVELS OF ALTERED
ated. Breathing patterns can be categorized as hemispheric or brain CONSCIOUSNESS
stem patterns (Table 14-4). STATE DEFINITION
With normal breathing, a neural center in the forebrain (cerebrum) Confusion Loss of ability to think rapidly and clearly; impaired judg-
produces a rhythmic pattern. When consciousness decreases, lower ment and decision making
brain stem centers regulate the breathing pattern by responding only Disorientation Beginning loss of consciousness; disorientation to time
to changes in Paco2 levels; this is called posthyperventilation apnea. followed by disorientation to place and impaired
Cheyne-Stokes respirations are an abnormal pattern of ventilation with memory; lost last is recognition of self
alternating periods of tachypnea and apnea (crescendo-decrescendo Lethargy Limited spontaneous movement or speech; easy arousal
pattern). Increases in Paco2 levels lead to tachypnea. The Paco2 level with normal speech or touch; may or may not be ori-
then decreases to below normal and breathing stops (apnea) until the ented to time, place, or person
carbon dioxide reaccumulates and again stimulates tachypnea (see Obtundation Mild to moderate reduction in arousal (awakeness) with
Figure 14-1). With opiate or sedative drug overdose, the respiratory limited response to environment; falls asleep unless
center is depressed so the rate of breathing gradually decreases until stimulated verbally or tactilely; answers questions with
respiratory failure occurs. minimal response
Pupillary changes indicate the presence and level of brain stem Stupor Condition of deep sleep or unresponsiveness from which
dysfunction because brain stem areas that control arousal are adjacent person may be aroused or caused to open eyes only by
to areas that control the pupils (Figure 14-2). For example, severe isch- vigorous and repeated stimulation; response is often
emia and hypoxia usually produce dilated, fixed pupils. Hypothermia withdrawal or grabbing at stimulus
may cause fixed pupils. Coma No verbal response to external environment or to any
Some drugs affect pupils and must be considered in evaluating stimuli; noxious stimuli such as deep pain or suctioning
individuals in comatose states. Large concentrations of atropine and do not yield motor movement
scopolamine fully dilate and fix pupils. Doses of sedatives (e.g., glu- Light coma Associated with purposeful movement on stimulation
tethimide) may be sufficient to produce a coma, causing the pupils to Coma Associated with nonpurposeful movement only on stimulation
become midposition or moderately dilated, unequal, and commonly Deep coma Associated with unresponsiveness or no response to any
fixed to light. Opiates cause pinpoint pupils. Severe barbiturate intoxi- stimulus
cation may produce fixed pupils.

Cheyne-Stokes
breathing

Central neurogenic
hyperventilation

Apneusis

Cluster breathing

Ataxic breathing

One minute

FIGURE 14-1  Abnormal Respiratory Patterns With Corresponding Level of Central Nervous
­System Activity. (From Urden LD, Davie JK, Lough ME: Thelan’s critical care nursing: diagnosis and
management, ed 5, St Louis, 2006, Mosby.)
350 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics

TABLE 14-4 PATTERNS OF BREATHING

BREATHING PATTERN DESCRIPTION LOCATION OF INJURY
Hemispheric Breathing Patterns
Normal After a period of hyperventilation that lowers arterial carbon dioxide Response of nervous system to an external stressor—not
pressure (Paco2), individual continues to breathe regularly but with associated with injury to CNS
reduced depth.
Posthyperventilation apnea Respirations stop after hyperventilation has lowered Pco2 level below Associated with diffuse bilateral metabolic or structural
normal. disease of cerebrum
Rhythmic breathing returns when Pco2 level returns to normal.
Cheyne-Stokes respirations Breathing pattern has a smooth increase (crescendo) in rate and depth Bilateral dysfunction of deep cerebral or diencephalic
of breathing (hyperpnea), which peaks and is followed by a gradual structures; seen with supratentorial injury and metaboli-
smooth decrease (decrescendo) in rate and depth of breathing to cally induced coma states
point of apnea, when cycle repeats itself. Hyperpneic phase lasts
longer than apneic phase.

Brain Stem Breathing Patterns

Central neurogenic A sustained, deep, rapid, but regular pattern (hyperpnea) occurs, May result from CNS damage or disease that involves
­hyperventilation with a decreased Paco2 and a corresponding increase in pH and Po2. midbrain and upper pons; seen after increased intracra-
nial pressure and blunt head trauma
Apneusis A prolonged inspiratory cramp (a pause at full inspiration) occurs; Indicates damage to respiratory control mechanism lo-
a common variant of this is a brief end-inspiratory pause of 2 or 3 cated at pontine level; most commonly associated with
sec, often alternating with an end-expiratory pause. pontine infarction but documented with hypoglycemia,
anoxia, and meningitis
Cluster breathing A cluster of breaths has a disordered sequence with irregular pauses Dysfunction in lower pontine and high medullary areas
between breaths.
Ataxic breathing Completely irregular breathing occurs, with random shallow and deep Originates from a primary dysfunction of medullary neu-
breaths and irregular pauses. Rate is often slow. rons controlling breathing
Gasping breathing pattern A pattern of deep “all-or-none” breaths is accompanied by a slow Indicative of a failing medullary respiratory center
(agonal gasps) respiratory rate.

CNS, Central nervous system.

Metabolic imbalance

Small, reactive, and regular

Diencephalic dysfunction Dysfunction of tectum (roof)

Small and reactive of the midbrain
Large “fixed” hippus

Dysfunction of third cranial nerve Pontine dysfunction

Sluggish, dilated, and fixed Pinpoint

Midbrain dysfunction
Midposition and fixed
FIGURE 14-2  Pupils at Different Levels of Consciousness.
 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics 351

(Figures 14-3 and 14-4). Those that involve an oculomotor nucleus or response noted may be (1) purposeful; (2) inappropriate, generalized
nerve cause the involved eye to deviate outward, producing a resting motor movement; or (3) not present. Motor signs indicating loss of
dysconjugate lateral position of the eye. cortical inhibition that are commonly associated with decreased con-
Motor responses help evaluate the level of brain dysfunction and sciousness include reflex grasping, reflex sucking, snout reflex, palmo-
determine the most severely damaged side of the brain. The pattern of mental reflex, and rigidity (paratonia) (Figure 14-5). Abnormal flexor
and extensor responses in the upper and lower extremities are defined
in Table 14-5 and illustrated in Figure 14-6 (also see p. 372).
Vomiting, yawning, and hiccups are complex reflex-like motor
responses that are integrated by neural mechanisms in the lower brain
stem. These responses may be produced by compression or diseases
involving tissues of the medulla oblongata (e.g., infection, neoplasm,
infarct) but also occur relative to other more benign stimuli to the
vagal nerve. Most CNS disorders produce nausea and vomiting. Vom-
iting without nausea indicates direct involvement of the central neural
mechanism (or pyloric obstruction; see Chapters 33 and 34. Vomiting
A often accompanies CNS injuries that (1) involve the vestibular nuclei
or its immediate projections, particularly when double vision (diplo-
pia) also is present; (2) impinge directly on the floor of the fourth ven-
tricle; or (3) produce brain stem compression secondary to increased
intracranial pressure.

4 QUICK CHECK 14-1

1. Why are structural as well as metabolic factors capable of producing
coma?
2. Why is level of consciousness the most critical index of central nervous
B system function?
3. Why do Cheyne-Stokes respirations appear in coma?
4. Why are oculomotor changes associated with levels of brain injury?

Outcomes of Alterations in Arousal

Outcomes of alterations in arousal fall into two categories: extent of
disability (morbidity) and mortality. Outcomes depend on the cause
and extent of brain damage and the duration of coma. Some indi-
viduals may recover consciousness and an original level of function,
some may have permanent disability, and some may never regain con-
sciousness and experience neurologic death. Two forms of neurologic
C
death—brain death and cerebral death—result from severe pathologic
FIGURE 14-3  Test for Oculocephalic Reflex Response (Doll’s conditions and are associated with irreversible coma. Other possible
Eyes Phenomenon). A, Normal response—eyes turn together to
outcomes are a vegetative state, a minimally conscious state, or locked-
side opposite from turn of head. B, Abnormal response—eyes do not
turn in conjugate manner. C, Absent response—eyes move in direc- in syndrome. The extent of disability has four subcategories: recovery
tion of head movement (brain stem injury). (From Rudy EB: Advanced of consciousness, residual cognitive function, psychologic function,
neurological and neurosurgical nursing, St Louis, 1984, Mosby.) and vocational function.

A B C
FIGURE 14-4  Test for Oculovestibular Reflex (Caloric Ice Water Test). A, Ice water is injected into
the ear canal. Normal response—conjugate eye movements. B, Abnormal response—dysconjugate or
asymmetric eye movements. C, Absent response—no eye movements.
352 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics

1 2 1

A
A B
1 2
B

C D
C
FIGURE 14-5  Pathologic Reflexes. A, Grasp reflex. B, Snout
reflex. C, Palmomental reflex. D, Suck reflex. FIGURE 14-6  Decorticate and Decerebrate Responses. A, Decor-
ticate response. Flexion of arms, wrists, and fingers with adduction
in upper extremities. Extension, internal rotation, and plantar flexion
in lower extremities. Both sides. B, Decerebrate response. All four
TABLE 14-5 ABNORMAL MOTOR extremities in rigid extension, with hyperpronation of forearms and
RESPONSES plantar extension of feet. C, Decorticate response on right side of
WITH DECREASED body and decerebrate response on left side of body. (From Rudy
RESPONSIVENESS EB: Advanced neurological and neurosurgical nursing, St Louis,
1984, Mosby.)
MOTOR LOCATION
RESPONSE DESCRIPTION OF INJURY
Abnormal motor Slowly developing flexion Suggest hemi- BOX 14-1 CRITERIA FOR BRAIN DEATH
responses, upper of arm, wrist, and fingers spheric damage 1. Completion of all appropriate diagnostic and therapeutic procedures with
extremity flexion with adduction in the up- above midbrain no possibility of brain function recovery
with or without per extremity and exten- 2. Unresponsive coma (no motor or reflex movements)
extensor responses sion, internal rotation, and 3. No spontaneous respiration (apnea)
in lower extremities plantar flexion of lower 4. No brain stem functions (ocular responses to head turning or caloric stimu-
­(decorticate rigidity) extremity lation; dilated, fixed pupils; no gag or corneal reflex)
Extensor responses Opisthotonos (hyperexten- Associated with 5. Isoelectric (flat) EEG (electrocerebral silence)
in upper and sion of vertebral column) severe damage 6. Persistence of these signs for an appropriate observation period
lower ­extremities with clenching of teeth; involving caudal
­(decerebrate extension, abduction, and diencephalon or Summarized from Wijdicks EF, Varelas PN, Gronseth GS et al:
­posturing, hyperpronation of arms; midbrain American Academy of Neurology. Evidence-based guideline update:
­decerebrate rigidity) and extension of lower determining brain death in adults: report of the Quality Standards
extremities Subcommittee of the American Academy of Neurology, Neurology
74(23):1911–1918, 2010.
In acute brain injury, shiver- Acute injury
ing and hyperpnea may often causes limb
accompany unelicited extension regard- abnormality of brain function must result from structural or known
recurrent decerebrate less of location metabolic disease and must not be caused by a depressant drug, alco-
spasms hol poisoning, or hypothermia. An isoelectric, or flat, electroencepha-
Extensor responses in Indicates pontine logram (EEG) (electrocerebral silence) for 6 to 12 hours in a person
upper extremities ac- level dysfunction who is not hypothermic and has not ingested depressant drugs indi-
companied by flexion cates brain death. The clinical criteria used to determine brain death
in lower extremities are noted in Box 14-1. A task force for determination of brain death
Flaccid state with little Damage to lower in children recommended the same criteria as for adults, but with a
or no motor response pons and upper longer observation period.2
to stimuli myelencephalon Cerebral death, or irreversible coma, is death of the cerebral hemi-
spheres exclusive of the brain stem and cerebellum. Brain damage is
permanent, and the individual is forever unable to respond behavior-
Brain death (total brain death) occurs when the brain is dam- ally in any significant way to the environment. The brain stem may
aged so completely that it can never recover and cannot maintain the continue to maintain internal homeostasis (i.e., body temperature,
body’s internal homeostasis. State laws define brain death as irrevers- cardiovascular functions, respirations, and metabolic functions). The
ible cessation of function of the entire brain including the brain stem survivor of cerebral death may remain in a coma or emerge into a per-
and cerebellum. On postmortem examination, the brain is autolyzing sistent vegetative state (VS) or a minimally conscious state (MCS). In
(self-digesting) or already autolyzed. Brain death has occurred when coma, the eyes are usually closed with no eye opening. The person does
there is no evidence of brain function for an extended period.1 The not follow commands, speak, or have voluntary movement.3
 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics 353

In a persistent vegetative state there is complete unawareness of

HEALTH ALERT
the self or surrounding environment and complete loss of cognitive
function. The individual does not speak any comprehensible words Attention-Deficit/Hyperactivity Disorder (ADHD):
or follow commands. Sleep-wake cycles are present, eyes open spon- Not Just a Childhood Disorder
taneously, and blood pressure and breathing are maintained without
Initially ADHD was viewed as a developmental disorder of childhood. It is
support. Brain stem reflexes (pupillary, oculocephalic, chewing, swal-
now recognized that 50% to 75% of persons diagnosed in childhood have
lowing) are intact but cerebral function is lost. There is bowel and
continuing symptoms into adulthood. Often the diagnosis is first made in ado-
bladder incontinence. Recovery is unlikely if the state persists for 12
lescence or young adulthood when behavioral control and self-organization
months. In a minimally conscious state (MCS) individuals may fol-
are expected of the person. The ability to function at work, at home, and in
low simple commands, manipulate objects, gesture or give yes/no
social situations is often impaired because of inattentiveness, hyperactivity,
responses, have intelligible speech, and have movements such as blink-
and impulsivity. Continued treatment including medications for symptomatic
ing or smiling.3 In locked-in syndrome there is complete paralysis of
adults is supported; substance abuse, which is more common in persons with
voluntary muscles with the exception of eye movement. Content of
ADHD, is reduced with continued treatment. The multifactorial patterns of
thought and level of arousal are intact, but the efferent pathways are
inheritance and gene-environment interactions are under investigation as are
disrupted (injury at the base of the pons with the reticular formation
the pathogenesis and pathophysiology of this disorder. Hopefully new findings
intact, often caused by basilar artery occlusion). Thus, the individual
will lead to improved prevention, diagnosis, and treatment options.
cannot communicate through speech or body movement but is fully
conscious, with intact cognitive function. Vertical eye movement and Data from Cubillo A, Rubia K: Structural and functional brain imaging
blinking are a means of communication.4 in adult attention-deficit/hyperactivity disorder, Expert Rev Neurother
10(4):603–620, 2010; Ficks CA, Waldman ID: Gene-environment
Alterations in Awareness interactions in attention-deficit/hyperactivity disorder, Curr Psychiatr
Awareness (content of thought) encompasses all cognitive functions, Rep 11(5):387–392, 2009; Schmidt S, Petermann F: Developmental
including awareness of self, environment, and affective states (i.e., psychopathology: attention deficit hyperactivity disorder (ADHD),  
BMC Psychiatr 9:58, 2009.
moods). Awareness is mediated by all of the core networks (selective
attention and memory) under the guidance of executive attention net-
works (i.e., the networks that involve abstract reasoning, planning,
decision making, judgment, error correction, and self-control). Each Pathophysiology. Very generally, the primary pathophysiologic
attentional function is localized not in a single brain area, but as a net- mechanisms that operate in disorders of awareness are (1) direct
work of interconnected brain areas. destruction caused by ischemia and hypoxia or indirect destruction
Selective attention (orienting) refers to the ability to select spe- resulting from compression and (2) the effects of toxins and chemicals.
cific information to be processed from available environmental and Disorders of selective attention, at least as they relate to visual orienting
internal stimuli. Certain midbrain and thalamic structures contrib- behavior, are produced by disease that involves portions of the mid-
ute to selective attention, so the etiologic factors for coma potentially brain. Disease affecting the superior colliculi manifests as a slowness in
can alter selective attention. Selective attention also is mediated by orienting attention. Parietal lobe disease may produce disengagement
the right parietal lobe. An isolated (pure) selective attention deficit from a stimulus or unilateral neglect syndrome. Sensory inattentive-
rarely occurs clinically. Causes of temporary, permanent, or progres- ness is a form of neglect. The person is able to recognize individual
sive attention deficits include seizure activity, parietal lobe contusions, sensory input from the dysfunctional side when asked but ignores the
subdural hematomas, stroke, gliomas or metastatic tumor, and late sensory input from the dysfunctional side when stimulated from both
Alzheimer and frontotemporal dementia (see pp. 357-359). sides (extinction). The entire complex of denial of dysfunction, loss
Memory is the ability of the brain to store and retrieve information. of recognition of one’s own body parts, and extinction sometimes is
Amnesia is the loss of memory and can be mild or severe. Two types referred to as the neglect syndrome. A disorder in vigilance may be
of memory disorders are retrograde amnesia (loss of past personal produced by disease in the prefrontal areas. Right dysfunction in the
history memories or past factual memories) and anterograde amnesia anterior cingulate gyrus and basal ganglia may cause detection prob-
(retention of memory of events in the distant past but unable to form lems, whereas problems with working memory may be produced with
new personal or factual memories). Image processing is a higher level left lateral frontal injury. Anterograde amnesia originates from patho-
of memory function and includes the ability to use sensory data and logic conditions in the hippocampus and related temporal lobe struc-
language to form concepts, assign meaning, and make abstractions. tures; the diencephalic region including the thalamus; and the basal
Alterations in image processing include an inability to form concepts forebrain. Retrograde amnesia and higher level memory deficits origi-
and generalizations or to reason. Thinking is very concrete. These nate from pathologic conditions in the widely distributed association
memory disorders may be temporary (e.g., after a seizure) or perma- areas of the cerebral cortex (see Figure 12-6, C). Executive attention
nent (e.g., after severe head injury or in Alzheimer disease). There may deficits are associated with alterations in the frontal and prefrontal cor-
be only the memory disorder, or the memory disorder may be associ- tex including the anterior cingulate gyrus, supplementary motor area,
ated with other cognitive disorders. and portions of the basal ganglia.
Executive attention deficits include the inability to maintain sus- Clinical manifestations. Clinical manifestations of selective atten-
tained attention (an inability to set goals and recognize when an object tion deficits, memory deficits, and executive attention function deficits
meets a goal), and a working memory deficit (an inability to remem- are presented in Table 14-6.
ber instructions and information needed to guide behavior). Executive Evaluation and treatment. Immediate medical management is
attention deficits may be temporary, progressive, or permanent. Atten- directed at diagnosing the cause and treating reversible factors. Reha-
tion-deficit/hyperactivity disorder (ADHD) is a common disorder of bilitative measures generally focus on compensatory or restorative
childhood that can continue through adulthood (see Health Alert). activities and recently have been greatly facilitated by computer tech-
Table 14-6 summarizes alterations in memory and attention. nology and other electronic devices.
354 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics

TABLE 14-6 CLINICAL MANIFESTATIONS OF ALTERATIONS IN ATTENTION AND MEMORY

DEFICIT CLINICAL SIGNS SYMPTOMS
Attention
Selective attention Inability to focus attention; decreased eye, head, and body movements Person reports inability to focus attention, failure to per-
­(orienting) associated with focusing on stimuli; decreased search and scanning; ceive objects and other stimuli (history of injuries, falls,
faulty orientation to stimuli, causing safety problems safety problems)

Memory
Antegrade amnesia Left hemisphere: disorientation to time, situation, place, name, person Person reports disorientation, confusion, “not listening,”
­(inability to form new (verbal identification); impaired language memory (e.g., names of “not remembering;” reports by others of person being
memories) objects); impaired semantic memory disoriented, not able to remember, not able to learn new
information
Right hemisphere: disorientation to self, person (visual), place (visual); im-
paired episodic memory (personal history); impaired emotional memory
Either or both hemispheres: confusion; behavioral change
Retrograde amnesia Left hemisphere: inability to retrieve personal history, past medical his- Person reports remote memory problems; others report that
(loss of past memories) tory; unaware of recent current events person cannot recall formerly known information
Right hemisphere: inability to recognize persons, places, objects, music,
and so on from past
Image processing Inability to categorize (identify similarities and differences) or sort; in- Reports by others of frequent misinterpretation of data,
ability to form concepts; inability to analyze relationships; misinterpre- failure to conceptualize or generalize information
tations; inability to interpret proverbs
Inability to perform deductive reasoning (convergent reasoning); inability Reports by others of predominantly concrete thinking;
to perform inductive reasoning (divergent reasoning); inability to lack of understanding of everyday situations, healthcare
abstract; concrete reasoning demonstrated; delusions regimens, and such; delusional thinking

Executive Attention Deficits

Vigilance Failure to stay alert and orient to stimuli Person reports decreased alertness or ability to orient
Detection Lack of initiative (anergy); lack of ambition; lack of motivation; flat affect; Reports by others of laziness or apathy, flat affect or lack
no awareness of feelings; appears depressed, apathetic, and emotion- of emotional expression; failing to exhibit or be aware of
less; fails to appreciate deficit; disinterested in appearance; lacks feelings
concern about childish or crude behavior
Mild Responds to immediate environment but no new ideas; grooming and Reports by others of lack of ambition, motivation, or initia-
social graces are lacking tive; failure to carry out adult tasks; lack of social graces
and new ideas
Severe Motionless; lack of response to even internal cues; does not respond to Reports by others of failure to groom or toilet self, un-
physical needs; does not interact with surroundings awareness of surroundings and own physical needs
Inability to use feedback regarding behavior; failure to recognize omis- Reports by others of not changing behavior when re-
sions and errors in self-care, speech, writing, and arithmetic; impaired quested; unawareness of limitations; does not recognize
cue utilization; overestimation of performance and correct errors in dressing, grooming, toileting, eating,
and such; fails to recognize speech and arithmetic errors;
careless speech
Failure to shift response set; failure to change behavior when conditions Reports by others of failure to use feedback; inability to incor-
change; cue utilization may be impaired porate feedback (does not correct when feedback is given)
Working memory Inability to set goals or form goals; indecisiveness Reports by others of failure to set goals, indecisiveness
Failure to make plans; inability to produce a complete line of reasoning; Reports by others of failure to plan, impulsiveness, “does
inability to make up a story; appears impulsive not think things through”
Failure to initiate behavior; failure to maintain behavior; failure to discon- Reports by others of not knowing where to begin, inability
tinue behavior; slowness to alternate response for the next step; motor to carry out sequential acts (maintain a behavior), inabil-
perseveration ity to cease a behavior

Selective attention deficits and executive attention deficits can be transient alteration in brain function, usually involving motor, sen-
confused with symptoms of other cognitive deficits. Differential diag- sory, autonomic, or psychic clinical manifestations and a temporary
nosis is difficult but essential for effective treatment. altered level of arousal. A seizure produces a brief disruption in the
brain’s electrical functions.5 Convulsion, a term sometimes applied
Seizure Disorders to seizures, refers to the jerky, contract-relax (tonic-clonic) move-
Seizure disorders represent a syndrome and not a specific ­disease ment associated with some seizures. Epilepsy is seizure activity for
entity. A seizure results from a sudden, explosive, disorderly dis- which no underlying correctable cause for the seizure can be found;
charge of cerebral neurons and is characterized by a sudden, therefore seizure activity recurs without treatment. In the United
 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics 355

States 2.5 million people have epilepsy with about 200,000 new cases
TABLE 14-7 CAUSES OF RECURRENT
diagnosed per year.6
SEIZURES IN DIFFERENT AGE
Conditions Associated With Seizure Disorders GROUPS
Any disorder that alters the neuronal environment may cause seizure AGE AT ONSET PROBABLE CAUSE
activity; therefore, theoretically, anyone may experience a seizure. The Neonates (<1 month) Acute CNS infection (sepsis, meningitis,
seizure threshold of some persons, however, is genetically lower. encephalitis)
Diseases or other processes that involve the nervous system can Cortical malformation
produce a seizure disorder. The onset may indicate the presence of Drug withdrawal or toxicity
an ongoing primary neurologic disease. Etiologic factors in seizures Genetic disorders
generally include (1) cerebral lesions, (2) biochemical disorders, (3) Intracranial hemorrhage and trauma
cerebral trauma, and (4) epilepsy, which can result from the following Kernicterus
conditions: Metabolic disturbances (hypoglycemia, hypocal-
• Metabolic defects cemia, hypomagnesemia, pyridoxine deficiency)
• Congenital malformation Perinatal hypoxic and ischemic encephalopathy
• Genetic predisposition Infants and children Degenerative disorders (i.e., tuberous sclerosis,
• Perinatal injury (1 month to 12 yr) neurofibromatosis, Tay-Sachs disease)
• Postnatal trauma Febrile seizures
• Myoclonic syndromes Genetic disorders (metabolic, degenerative,
• Infection primary epilepsy syndromes)
• Brain tumor Idiopathic
• Vascular disease Infantile spasms
• Fever Trauma
• Drug or alcohol abuse Adolescents (12 to Acute CNS infection (sepsis, meningitis,
Causes of recurrent seizures are age-related (Table 14-7). The cause 18 yr) encephalitis)
of seizures is often unknown. Brain tumor
Seizures may be precipitated by hypoglycemia, fatigue or lack of Genetic disorders
sleep, emotional or physical stress, febrile illness, large amounts of Idiopathic
water ingestion, constipation, use of stimulant drugs, withdrawal from Illicit drug use (i.e., cocaine, amphetamine)
depressant drugs (including alcohol), hyperventilation (respiratory Trauma
alkalosis), and some environmental stimuli, such as blinking lights, a Young adults (18 to Alcohol or drug withdrawal (i.e., barbiturates,
poorly adjusted television screen, loud noises, certain music, certain 35 yr) benzodiazepines)
odors, or merely being startled. Women may have increased seizure Brain tumor
activity immediately before or during menses. Idiopathic
Types of seizure disorders. Seizures are classified in different ways: Illicit drug use (i.e., cocaine, amphetamine)
by clinical manifestations, site of origin, EEG correlates, or response Trauma
to therapy. A simplified version of the International Classification of Older adults (>35 yr) Alcohol or drug withdrawal (i.e., barbiturates,
Epileptic Seizures is presented in Table 14-8. Terms used to describe benzodiazepines)
seizure activity are defined in Table 14-9. Brain tumor
Epilepsy now is considered to be the result of the interaction of com- Cerebrovascular disease (i.e., stroke, aneurysm,
plex genetic mutations with environmental effects that cause abnor- arteriovenous malformations)
malities in brain wiring, an imbalance in the brain’s neurotransmitters, CNS degenerative diseases (i.e., Alzheimer
or the development of abnormal nerve connections after injury.7 disease, multiple sclerosis)
A group of neurons may exhibit a paroxysmal depolarization shift and Idiopathic
function as an epileptogenic focus. These neurons are hypersensitive Metabolic disorders (i.e., uremia, hepatic failure,
and are more easily activated by hyperthermia, hypoxia, hypoglycemia, electrolyte abnormalities, hypoglycemia)
hyponatremia, repeated sensory stimulation, and certain sleep phases.
Epileptogenic neurons fire more frequently and with greater ampli- Data from Goetz CG, editor: Textbook of clinical neurology, ed 3,
tude. When the intensity reaches a threshold point, cortical excitation Philadelphia, 2007, Saunders; Nabbout R, Dulac O: Curr Opin Neurol
spreads. Excitation of the subcortical, thalamic, and brain stem areas 21(2):161–166, 2008; Waterhouse E, Towne A: Cleve Clin J Med
corresponds to the tonic phase (muscle contraction with increased 72(suppl 3):S26–S37, 2005.
CNS, Central nervous system.
muscle tone) and is associated with loss of consciousness.
The clonic phase (alternating contraction and relaxation of mus-
cles) begins when inhibitory neurons in the cortex, anterior thala- in brain tissue. Continued, severe seizure activity has the potential for
mus, and basal ganglia react to the cortical excitation. The seizure progressive brain injury and irreversible damage. In addition, if a sei-
discharge is interrupted, producing intermittent muscle contractions zure focus in the brain is active for a prolonged period, a mirror focus
that gradually decrease and finally cease. The epileptogenic neurons may develop in contralateral normal tissue.
are exhausted. Clinical manifestations. The clinical manifestations associated
During seizure activity, oxygen is consumed at a high rate—about with seizure depend on its type (see Table 14-8). Two types of symp-
60% greater than normal. Although cerebral blood flow also increases, toms signal a generalized tonic-clonic seizure: an aura, a partial sei-
oxygen is rapidly depleted, along with glucose, and lactate accumulates zure that immediately precedes the onset of a generalized tonic-clonic
356 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics

TABLE 14-8 INTERNATIONAL TABLE 14-9 TERMINOLOGY APPLIED

CLASSIFICATION OF TO A SEIZURE DISORDER
EPILEPTIC SEIZURES TERM DEFINITION
TRADITIONAL Aura A partial seizure experienced as a peculiar sensa-
TERMINOLOGY NEW NOMENCLATURE tion preceding onset of generalized seizure that
Focal motor; jacksonian I. Partial seizures (seizures beginning locally) may take the form of gustatory, visual, or auditory
seizures (occasionally A. Simple (without impairment of con- experience or a feeling of dizziness, numbness, or
become secondarily sciousness) just “a funny feeling”
generalized) 1. With motor signs Prodroma Early clinical manifestations, such as malaise,
2. With special sensory or somatosen- headache, or sense of depression, that may occur
sory symptoms hours to a few days before onset of a seizure
3. With autonomic symptoms or signs Tonic phase A state of muscle contraction in which there is
4. With psychic symptoms excessive muscle tone
Temporal lobe or psy- B. Complex (with impairment of conscious- Clonic phase A state of alternating contraction and relaxation of
chomotor seizures ness) muscles
1. Simple partial onset followed by Postictal phase Time period immediately following cessation of
impaired consciousness seizure activity
2. Impaired consciousness at onset—
with or without automatisms
C. Secondarily generalized (partial onset
Selective attention:
evolving to generalized tonic-clonic Vigilance
disengage component
seizures) Frontal lobe
II. Generalized seizures (bilaterally symmetric Parietal lobe
and without local onset) Working
Petit mal A. Absence memory
1. Typical
2. Atypical
Occipital
B. Myoclonic lobe
C. Clonic
D. Tonic
Grand mal E. Tonic-clonic
Drop attack F. Atonic (astatic, akinetic)
III. Unclassified epileptic seizures
Temporal lobe
Pulvinar nucleus Superior colliculus
of thalamus: of midbrain:
seizure; and a prodroma, early manifestations occurring hours to days engagement of move component of
before a seizure. Both may become familiar to the person experiencing selective attention selective attention
recurrent generalized seizures and may enable the person to prevent FIGURE 14-7  Right Cortical, Subcortical, and Brain Stem Areas
injuries during the seizure. of the Brain Mediating Cognitive Function. (From Boss GJ, Wilk-
Evaluation and treatment. The health history, physical examina- erson R: Communication: language and pragmatics. In Hoeman SP,
tion, and laboratory tests of blood and urine (concentrations of blood editor: Rehabilitation nursing; prevention, intervention & outcomes,
glucose, serum calcium, blood urea nitrogen, and urine sodium; and ed 4, p 508, St Louis, 2008, Mosby.)
creatinine clearance time) can identify systemic diseases known to
promote seizures. Radiographic studies and cerebrospinal fluid (CSF)
examination help identify neurologic diseases associated with seizures. Data Processing Deficits
The EEG is used to assess the type of seizure and determine its focus. Data processing deficits are problems associated with recognizing and
Treatment involves correcting or controlling the cause and, if none processing sensory information and include agnosia, dysphasia, and
is identified, administering antiseizure medications to suppress seizure acute confusional states.
activity. Counseling also may be of value. Preventing and predicting
epilepsy is a major area of research.8 Agnosia
Agnosia is a defect of pattern recognition—a failure to recognize the
form and nature of objects. Agnosia can be tactile, visual, or auditory,
4 QUICK CHECK 14-2 but generally only one sense is affected. For example, an individual
may be unable to identify a safety pin by touching it with a hand but
1. Why is irreversible coma different from brain death?
2. Why is a seizure different from epilepsy? is able to name it when looking at it. Agnosia may be as minimal as a
3. Why can so many conditions precipitate seizures? finger agnosia (failure to identify by name the fingers of one’s hand) or
4. Why is continued seizing dangerous? How does an epileptogenic focus more extensive, such as a color agnosia. Although agnosia is associated
­differ from a mirror focus? most commonly with cerebrovascular accidents, it may arise from any
pathologic process that injures specific areas of the brain.
 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics 357

The onset of an ACS usually is abrupt. The first clinical manifes-

Dysphasia tations are difficulty in concentration, restlessness, irritability, tremu-
Dysphasia is impairment of comprehension or production of language lousness, insomnia, and poor appetite. Later there are misperceptions,
with impaired communication. Comprehension or use of symbols, illusions, hallucinations, and delirium. Obsessions, compulsive behav-
in either written or verbal language, is disturbed or lost. Aphasia is a ior, and rituals may be evident.
more severe form of dysphasia and an inability to communicate. Often Delirium is associated with autonomic nervous system overactiv-
the terms dysphasia and aphasia are used interchangeably. The term ity; it typically develops over 2 to 3 days and most commonly occurs
dysphasia is used here. Dysphasias usually are associated with cere- in critical care units, following surgery, or during withdrawal from
brovascular accident involving the middle cerebral artery or one of its central nervous system depressants (i.e., alcohol or narcotic agents).
many branches. Language disorders, however, may arise from a variety Delirium initially manifests as difficulty in concentrating, restlessness,
of injuries and diseases—vascular, neoplastic, traumatic, degenerative, irritability, insomnia, tremulousness, and poor appetite. Some persons
metabolic, or infectious causes. Dysphasia results from dysfunction in experience seizures. Unpleasant, even terrifying, dreams or hallucina-
the left cerebral hemisphere, usually the frontotemporal region (see tions may occur. In a fully developed delirium state, the individual is
Figures 14-7 and 12-6). Most language disorders result from acute pro- completely inattentive and perceptions are grossly altered, with exten-
cesses or a chronic residual deficit of the acute process. Some progres- sive misperception and misinterpretation. The person appears dis-
sive language disorders are the result of degenerative disorders. tressed and often perplexed; conversation is incoherent. Frank tremor
Dysphasias have been classified both anatomically and functionally. and high levels of restless movement are common. Violent behavior
Other classifications describe fluency, volume, or quantity of speech, may be present. The individual cannot sleep, is flushed, and has dilated
although pure forms of any language dysfunction are rare. Expressive pupils, a rapid pulse rate (tachycardia), elevated temperature, and
dysphasias involve primarily expression deficits, but verbal compre- profuse sweating (diaphoresis). Delirium typically abates suddenly or
hension deficit also may be present. Receptive dysphasias may have gradually in 2 to 3 days, although occasionally delirium states persist
expressive deficits. (Table 14-10 compares types of dysphasias; Table for weeks.
14-11 illustrates some of the language disturbances.) Hypokinetic acute confusional states are associated with under-
Some dysphasias are referred to as transcortical dysphasias and activity and may occur in individuals who have fevers or metabolic
involve the ability to repeat (echolalia) and to recite. Speech is fluent but disorders (i.e., chronic liver or kidney failure), or who are under the
the words make no sense. The individual cannot read or write and has influence of central nervous system depressants. The individual exhib-
impaired comprehension. These dysphasias are caused by hypoxia or other its decreases in mental function, specifically alertness, attention span,
mechanisms that destroy the border zone between the cerebral arteries accurate perception, interpretation of the environment, and reaction
(see Figure 12-19). The sensory and motor speech areas are functional, but to the environment. Forgetfulness is prominent, and the individual
connections with other sensory or motor areas are impaired. Information dozes frequently.
cannot be transmitted to Wernicke area and transformed into language. Evaluation and treatment. The initial goals are to (1) establish that
the individual is confused and (2) determine the cause of the confusion
Acute Confusional States (organic or functional) (Table 14-12). The next step is to differentiate
Acute confusional states (ACS) are transient disorders of awareness whether the confusion is delirium, a hypokinetic confusional state, or
that result from cerebral dysfunction secondary to drug intoxication, an underlying dementia. A complete history and physical examination
metabolic disorders, nervous system disease, trauma, or surgery. With- as well as laboratory tests (electrocardiogram and blood, urine, cere-
drawal from alcohol, barbiturate, or other sedative drug ingestion is a brospinal fluid, and radiologic studies) are needed. Once the cause is
common cause. Acute confusional states may begin either suddenly or established, treatment is directed at controlling the primary disorder,
gradually, depending on the amount of exposure to the toxin. These with supportive measures used as appropriate. Delirium is preventable
states often occur with febrile illnesses, systemic diseases (e.g., heart in some individuals.10,10a Table 14-13 contains a comparison of the fea-
failure), head injury, anesthesia use, or certain focal cerebral lesions tures differentiating delirium and dementia.
and are seen postnatally.
Pathophysiology. Acute confusional states arise from disruption of
a widely distributed neural network involving the reticular activating 4 QUICK CHECK 14-3
system of the upper brain stem and its projections into the thalamus, 1. Why are there so many cognitive disorders?
basal ganglion, and specific association areas of the cortex and limbic 2. Why can so many disorders cause dysphasia?
areas. Delirium (hyperkinetic confusional state) is an acute state of 3. Why is impaired detection the most common feature of acute confusional
brain dysfunction associated with right-upper middle-temporal gyrus states (ACS)?
or left temporal-occipital junction disruption and several neurotrans- 4. How is an ACS different from dementia?
mitters are involved.9
Hypokinetic confusional states (hypoactive delirium) are
more likely to be associated with right-sided frontal-basal ganglion Dementia
disruption. Dementia is a progressive failure of many cerebral functions that often
Most metabolic disturbances that produce an acute confusional includes a decrease in orienting, memory, language, judgment, and
state interfere with neuronal metabolism or synaptic transmission. decision making. Because of declining intellectual ability, the individ-
Many drugs and toxins also interfere with neurotransmission function ual exhibits alterations in behavior.
at the synapse. Pathophysiology. Mechanisms leading to dementia include neuron
Clinical manifestations. The predominant feature of an acute con- degeneration, compression, atherosclerosis, and trauma. Genetic pre-
fusional state is impaired or lost detection. The person is highly dis- disposition is associated with the neurodegenerative diseases, including
tractible and unable to concentrate on incoming sensory information Alzheimer and Huntington diseases. CNS infections, including the human
or on any one particular mental or motor task. immunodeficiency virus (HIV) and slow-growing viruses associated with
358 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics

TABLE 14-10 MAJOR TYPES OF DYSPHASIA

VERBAL
TYPE EXPRESSION COMPREHENSION REPETITION
Expressive
Broca dysphasia, motor Nonfluent; cannot find words, difficulty writing Relatively intact Impaired

Receptive
Wernicke dysphasia, Fluent; can produce verbal language but it is meaningless, with in- Impaired (disturbance in understanding Impaired
sensory appropriate words, similar sounds or meaning substituted for cor- all language)
rect words, and neologisms that may be so extensive that speech
is incomprehensible; unable to monitor language for correctness,
so errors are not recognized Intonation, accent, cadence, rhythm,
and articulation normal

Others
Global, conductive, ano- Ranges from nonfluent and producing little speech to fluent with Can be relatively intact, impaired, or Can be intact or impaired
mia, transcortical motor, paraphrasia or impaired ability for naming completely lost with an inability to
or transcortical sensory repeat

Creutzfeldt-Jakob disease, are associated with dementia in addition to to identify underlying conditions that may be treatable. Unfortunately,
changes in motor function (i.e., ataxia, rigidity, and shuffling gait). Pro- no specific cure exists for most progressive dementias. Therapy is
gressive dementias produce nerve cell degeneration and brain atrophy. directed at maintaining and maximizing use of the remaining capaci-
Clinical manifestations. Clinical manifestations of the major ties, restoring functions if possible, and accommodating to lost abili-
dementias are presented in Table 14-14. ties. Helping the family to understand the process and to learn ways to
Evaluation and treatment. Establishing the cause for dementia may assist the individual is essential.
be complicated, but individuals with clinical manifestations of demen-
tia should be evaluated with laboratory and neuropsychologic testing
TABLE 14-12 DIFFERENCES BETWEEN
ORGANIC AND FUNCTIONAL
TABLE 14-11 EXAMPLES OF LANGUAGE CONFUSION
DISTURBANCES ORGANIC FUNCTIONAL
DISORDER EXAMPLE FACTOR CONFUSION CONFUSION
Verbal paraphrasia Question: What did the car do? Memory Recent more impaired than No consistent difference be-
Patient: The car would spit sweetly down the ­impairment remote tween recent and remote
road. (The car sped swiftly down the road.) Disorientation
Literal paraphrasia Request: Say “persistence is essential to Time Within own lifetime or May not be related to
­success.” reasonably near future person’s lifetime
Patient: Mesastence is instans to success. Place Familiar place or one where Bizarre or unfamiliar
Neologism Question: What do you call this? (Pointing to a person might easily be found places
plant.) Person Sense of identity usually Sense of identity
Patient: It’s a logper. preserved ­diminished
Circumlocution Question: What do you call this? (Pointing to a Misidentification of others as Misidentification of
plant.) familiar ­others based on
Patient: Something that grows. ­delusion system
Anomia Patient: It’s… Hallucinations Visual, vivid Auditory more frequent
Or Animals and insects common Bizarre and symbolic
Question: What did you do this morning? Illusions Common Not prominent
Patient: Reading. Delusions Concern everyday occur- Bizarre and symbolic
Question: Were you reading a book or newspa- rences and people
per? Confused Spotty confusion More consistent
Patient: One of those. Clear intervals mixed with No tendency to become
Telegraphic style Question: Where is your daughter? confused episodes worse at night
Patient: New Orleans…home…Monday. Worse at night
From Boss BJ: Dysphasia, dyspraxia, and dysarthria: distinguishing From Morris M, Rhodes M: Guidelines for the care of confused
features (part I), J Neurosurg Nurs 16(3):151–160, 1984. patients, Am J Nurs 72(9):1632, 1972.
 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics 359

READING
COMPREHENSION WRITING LOCATION OF LESION CAUSE OF LESION

Variable Impaired Left posteroinferior frontal lobe (Broca area) Occlusion of one or several branches of left middle
cerebral artery supplying inferior frontal gyrus

Impaired Impaired Left posterosuperior temporal lobe (Wernicke area) Occlusion of inferior division of left middle
cerebral artery

Variable; may be impaired or Variable or impaired Various areas including frontotemporal lobe; arcuate Occlusion of left middle cerebral artery of left in-
completely lost fasciculus, supramarginal gyrus, bundle of fibers from ternal carotid artery, tumors, other mass lesions,
temporal lobe that project anteriorly to premotor area; hemorrhage, embolic occlusion of ascending
angular gyrus and anterior or posterior presylvian parietal or posterior temporal branch of middle
fissures cerebral artery

Alzheimer Disease The three forms of AD are early-onset AD (very rare), early-onset famil-
Alzheimer disease (AD) (dementia of Alzheimer type [DAT], senile ial AD (FAD), and the most common (90%) form—late-onset AD.
disease complex) is one of the most common causes of severe cogni- Pathophysiology. The exact cause of Alzheimer disease is unknown.
tive dysfunction in older persons and the leading cause of dementia.10b Early-onset FAD has been linked to three genes with mutations on
chromosome 21 (abnormal amyloid precursor protein 14 [APP14],
abnormal presenilin 1 [PSEN1], and abnormal presenilin 2 [PSEN2]).
Late-onset AD may be related to the involvement of chromosome 19
TABLE 14-13 COMPARISON OF DELIRIUM with the apolipoprotein E gene-allele 4 (APOE4).11 Pathologic altera-
AND DEMENTIA tions in the brain include formation of neuritic plaques containing a
core of amyloid-beta protein, creation of neurofibrillary tangles, and
FEATURE DELIRIUM DEMENTIA
degeneration of basal forebrain cholinergic neurons with loss of ace-
Age Usually older Usually older tylcholine. Failure to process and clear amyloid precursor protein
Onset Acute—common during Usually insidious; acute results in the accumulation of toxic fragments of amyloid-beta pro-
hospitalization in some cases of tein that leads to formation of diffuse neuritic plaques, disruption of
strokes/trauma nerve impulse transmission, and death of neurons. The tau protein,
Associated Urinary tract infection, May have no other a microtubule-binding protein, in neurons detaches and forms an
conditions thyroid disorders, hypoxia, conditions insoluble filament called a neurofibrillary tangle, contributing to neu-
hypoglycemia, toxicity, Brain trauma ronal death (Figure 14-8). Senile plaques and neurofibrillary tangles
fluid-electrolyte imbalance, are more concentrated in the cerebral cortex and hippocampus. The
renal insufficiency, trauma loss of neurons results in brain atrophy with widening of sulci and
Course Fluctuating Chronic slow decline shrinkage of gyri (see Figure 14-8). Loss of acetylcholine and other
Duration Hours to weeks Months to years neurotransmitters contributes to the decline of memory and attention
Attention Impaired Intact early; often and the loss of other cognitive functions associated with AD.11a
impaired late Clinical manifestations. Initial clinical manifestations are insidi-
Sleep-wake cycle Disrupted Usually normal ous and often attributed to forgetfulness, emotional upset, or other
Alertness Impaired Normal illness. The individual becomes progressively more forgetful over time,
Orientation Impaired Intact early; impaired particularly in relation to recent events. Memory loss increases as the
late disorder advances, and the person becomes disoriented and confused
Behavior Agitated, withdrawn/de- Intact early and loses the ability to concentrate. Abstraction, problem solving, and
pressed judgment gradually deteriorate, with failure in mathematic calcula-
Speech Incoherent, rapid/slowed Word-finding problems tion ability, language, and visuospatial orientation. Dyspraxia may
Thoughts Disorganized, delusions Impoverished appear. The mental status changes induce behavioral changes, includ-
Perceptions Hallucinations/illusions Usually intact early ing irritability, agitation, and restlessness. Mood changes also result
Adapted from Caplan JP, Rabinowitz T: An approach to the patient from the deterioration in cognition. The person may become anxious,
with cognitive impairment: delirium and dementia, Med Clin North Am depressed, hostile, emotionally labile, and prone to mood swings.
94(6):1103–1116, ix, 2010. Motor changes may occur if the posterior frontal lobes are involved,
360 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics

TABLE 14-14 CLINICAL MANIFESTATIONS OF THE MAJOR DEGENERATIVE DEMENTIAS

NEUROLOGIC
DISEASE FIRST SYMPTOM MENTAL STATUS NEUROBEHAVIOR EXAMINATION
Alzheimer disease Memory loss; impaired learning Episodic memory loss Initially normal, progressive Initially normal
cognitive impairment
Creutzfeldt-Jakob Dementia, mood, anxiety, movement Variable, frontal/executive, Depression, anxiety Myoclonus, rigidity,
disease disorders focal cortical, memory ­parkinsonism
Dementia with Lewy Visual hallucinations, REM sleep dis- Drawing and frontal/executive; Visual hallucinations, Parkinsonism
body order, delirium; Capgras syndrome, spares memory; delirium depression, sleep disorder,
parkinsonism prone delusions
Frontotemporal Apathy; poor judgment/reasoning, Frontal/executive, language; Apathy, decline in person or Due to PSP/CBD overlap; verti-
dementia speech/language; hyperorality spares drawing social conduct, hyperorality, cal gaze palsy, axial rigidity,
euphoria, depression dystonia, alien hand
Vascular dementia Often but not always sudden, usually Frontal/executive, cognitive Apathy, delusions, anxiety Usually motor slowing, spas-
within 3 months of a stroke; variable; slowing; memory can be ticity; can be normal
apathy, falls, focal weakness intact

Adapted from Bird TD, Miller BL: Dementia. In Fauci AS et al, editors: Harrison’s principles of internal medicine, ed 15, p 2538, New York, 2008,
McGraw-Hill.
CBD, cortical basal degeneration; PSP, progressive supranuclear palsy; REM, rapid eye movement.

Healthy Brain Alzheimer Brain causing rigidity (paratonia, gegenhalten), with flexion posturing, pro-
pulsion, and retropulsion. Great variability in age of onset, intensity
and sequence of symptoms, and location and extent of brain abnor-
malities is common. Stages for the progression of Alzheimer disease
are summarized in Table 14-15.
Evaluation and treatment. The diagnosis of Alzheimer disease is
made by ruling out other causes; clinical criteria have been developed
to assist diagnosis.12 The history, including mental status examinations
(mini–mental status examination, clock drawing, and geriatric depres-
Brain cross-sections sion scale) and the course of the illness (which may span 5 years or
more), is used to assess progression of the disease. Efforts are in prog-
Sulcus Sulcus ress to identify imaging and biochemical markers for early diagnosis
and progression of Alzheimer type and other neurodegenerative causes
Gyrus Gyrus
of dementia (see Health Alert).13,14
Ventricle
Ventricle
Language Language
HEALTH ALERT
Biomarkers and Neurodegenerative Dementia
Memory Memory
Neurodegenerative disease processes that lead to dementia begin many years
before clinical manifestations are evident for Alzheimer disease, Huntington
Normal Brain (left) Alzheimer Brain (left) disease, and Parkinson disease. Efforts are underway to identify neuroimaging
techniques and predictive biomarkers in the brain, spinal fluid, and blood that
Neurofibrillary will guide a more comprehensive understanding of the etiology and biologic
tangles
pathways that mediate neurodegeneration. Identification and profiling of such
molecules will promote early identification of risk factors, enhance preventive
and protective measures, provide alerts for progression from mild to advanced
stages, and accelerate development of presymptomatic treatment for these
diseases.
Neuron Amyloid
plaques Data from Seelaar H et al: Clinical, genetic, and pathological hetero-
geneity of frontotemporal dementia: a review, J Neurol Neurosurg Psy-
chiatr 82(5):476–486, 2011; Patel B, Markus HS: Magnetic resonance
imaging in cerebral small vessel disease and its use as a surrogate
disease marker, Int J Stroke 6(1):47–59, 2011; Humpel C: Identifying
Normal Brain Alzheimer Brain and validating biomarkers for Alzheimer’s disease, Trends Biotechnol
29(1):26–32, 2011; Forlenza OV, Diniz BS, Gattaz WF: Diagnosis and
FIGURE 14-8  Common Pathologic Findings in Alzheimer Disease. biomarkers of predementia in Alzheimer’s disease, BMC Med 8:89,
The middle panel represents coronal slices through the left brain. 2010.
 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics 361

TABLE 14-15 PROGRESSION OF ALZHEIMER DISEASE

MILD COGNITIVE
STAGE IMPAIRMENT EARLY STAGE MIDDLE STAGE LATE STAGE END-STAGE
Cognitive Mild memory loss Measurable short-term memory Moderate to severe cognitive Little cognitive ability; No significant cognitive
loss; other cognition problems problems language not clear function
Functional Possibly depression (vs. Mild IADL problems IADL-dependent; some ADL ADL-dependent; Nonambulatory/ bed-
apathy); mild anxiety problems ­incontinent bound; unable to eat

Adapted from National Conference of Gerontological Nurse Practitioners and the National Gerontological Nursing Association: Counseling Points
1(1):6, 2008.
ADL, (Basic) activities of daily living; IADL, instrumental activities of daily living.

Treatment is directed at using devices to compensate for the In stage 1 of intracranial hypertension, vasoconstriction and exter-
impaired cognitive function, such as memory aids; maintaining unim- nal compression of the venous system occur in an attempt to further
paired cognitive functions; and maintaining or improving the gen- decrease the intracranial pressure. Thus, during the first stage of intra-
eral state of hygiene, nutrition, and health. Cholinesterase inhibitors cranial hypertension, ICP may not change because of the effective
have shown a modest effect on cognitive function in mild to moderate compensatory mechanisms, and there may be few symptoms (Figure
Alzheimer disease. An N-methyl-d-aspartate (NMDA) receptor antag- 14-9). Small increases in volume, however, cause an increase in pres-
onist blocks glutamate activity and may slow progression of disease in sure, and the pressure may take longer to return to baseline. This can
moderate to severe AD.15,16 be detected with ICP monitoring.
In stage 2 of intracranial hypertension, there is continued expansion
Frontotemporal Dementia of intracranial content. The resulting increase in ICP may exceed the
Frontotemporal dementia (FTD), previously known as Pick disease, brain’s compensatory capacity to adjust. The pressure begins to com-
is a rare, severe degenerative disease of the frontal and anterior frontal promise neuronal oxygenation, and systemic arterial vasoconstriction
lobes that produces death of tissue and dementia. There is a familial occurs in an attempt to elevate the systemic blood pressure sufficiently
association and an age of onset less than 60 years. The majority of cases to overcome the IICP. Clinical manifestations at this stage usually are
involve mutations of genes encoding tau protein. The disease is difficult subtle and transient, including episodes of confusion, restlessness,
to distinguish clinically and pathologically from Alzheimer disease.17 drowsiness, and slight pupillary and breathing changes (see Figure
14-9).
In stage 3 of intracranial hypertension, ICP begins to approach arte-
ALTERATIONS IN CEREBRAL HEMODYNAMICS rial pressure, the brain tissues begin to experience hypoxia and hyper-
An injured brain reacts with structural, chemical, and pathophysi- capnia, and the individual’s condition rapidly deteriorates. Clinical
ologic changes that are called secondary brain injuries. Critical features manifestations include decreasing levels of arousal or central neu-
of these changes include alterations in cerebral blood flow, intracranial rogenic hyperventilation, widened pulse pressure, bradycardia, and
pressure, and oxygen delivery (also see Chapter 15). small, sluggish pupils (see Figure 14-9).
Cerebral blood flow (CBF) to the brain is normally maintained at Dramatic sustained rises in ICP are not seen until all compensatory
a rate that matches local metabolic needs of the brain. Cerebral perfu- mechanisms have been exhausted. Then dramatic rises in ICP occur
sion pressure (CPP) (70-90 mm Hg) is the pressure required to per- over a very short period. Autoregulation, the compensatory alteration
fuse the cells of the brain, whereas cerebral blood volume (CBV) is in the diameter of the intracranial blood vessels designed to maintain
the amount of blood in the intracranial vault at a given time. Cerebral a constant blood flow during changes in cerebral perfusion pressure,
oxygenation is the critical factor and is measured by oxygen saturation is lost with progressively increased ICP. Accumulating carbon diox-
in the internal jugular vein. ide may still cause vasodilation locally, but without autoregulation this
Alterations in cerebral blood flow may be related to three injury vasodilation causes the hydrostatic (blood) pressure in the vessels to
states: inadequate cerebral perfusion (cerebral oligemia), normal drop and the blood volume to increase. The brain volume is thus fur-
cerebral perfusion with an elevated intracranial pressure, and exces- ther enhanced, and ICP continues to rise. Small increases in volume
sive cerebral blood volume (cerebral hyperemia). Treatments for these cause dramatic increases in ICP, and the pressure takes much longer
injury states are directed at improving or maintaining CPP, as well as to return to baseline. As the ICP begins to approach systemic blood
controlling intracranial pressure. An injured brain requires a CPP of pressure, cerebral perfusion pressure falls and cerebral perfusion slows
greater than 70 mm Hg. Intracranial pressure (ICP) normally is 1 to dramatically. The brain tissues experience severe hypoxia, hypercap-
15 mm Hg, or 60 to 180 cm H2O. nea, and acidosis.
In stage 4 of intracranial hypertension, brain tissue shifts (herniates)
Increased Intracranial Pressure from the compartment of greater pressure to a compartment of lesser
Increased intracranial pressure (IICP) may result from an increase pressure and IICP in one compartment of the cranial vault is not evenly
in intracranial content (as occurs with tumor growth), edema, excess distributed throughout the other vault compartments (see Figures 14-9
CSF, or hemorrhage. It necessitates an equal reduction in volume and 14-10). With this shift in brain tissue, the herniating brain tissue’s
of the other cranial contents. The most readily displaced content is blood supply is compromised, causing further ischemia and hypoxia
CSF. If intracranial pressure remains high after CSF displacement in the herniating tissues. The volume of content within the lower pres-
out of the cranial vault, cerebral blood volume and blood flow are sure compartment increases, exerting pressure on the brain tissue that
altered. normally occupies that compartment and impairing its blood supply.
362 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics

STAGES OF BEGINNING DECOMPENSATION

COMPENSATION DECOMPENSATION (HERNIATION)
STAGE 1 STAGE 2 STAGE 3 STAGE 4 DEATH
Mental Awake and Episodes of Beginning inability to
status alert confusion stay awake continuing on to progressively deeper coma
Restlessness
Lethargy Small, reactive pupils
Pupils Equal and Equal and progressing to slowing of response to light Bilateral
reactive reactive Ipsilateral dilation dilation and
and fixation fixation
Breathing Normal Normal Normal, may slow some then progressing to
(eupnea) (eupnea) Cheyne-Stokes breathing
Central neurogenic hyperventilation
apneustic or
ataxic breathing
160 Systolic
Blood 120
Pulse pressure
pressure 80 Diastolic

160
120
Pulse Slight
80
Full and bounding irregularity

Temperature Patterns vary

Surgical or medical Surgical or medical Surgical or medical intervention
intervention best here intervention needed here usually futile here

FIGURE 14-9  Clinical Correlates of Compensated and Uncompensated Phases of Intracranial

Hypertension. (From Beare PG, Myers JL: Principles and practice of adult health nursing, ed 3, St
Louis, 1998, Mosby.)

Cerebral Edema
Cerebral edema is an increase in the fluid content of brain tissue
­(Figure 14-11). The result is increased extracellular or intracellular tis-
3 sue volume. It occurs after brain insult from trauma, infection, hem-
orrhage, tumor, ischemia, infarct, or hypoxia. The harmful effects of
4 2 cerebral edema are caused by distortion of blood vessels, displacement
of brain tissues, and eventual herniation of brain tissue to a different
1
brain compartment.
Tentorial
membrane Three types of cerebral edema are (1) vasogenic edema, (2) cyto-
5
toxic (metabolic) edema, and (3) interstitial edema. Vasogenic edema
6 is clinically the most important type and is caused by the increased
permeability of the capillary endothelium of the brain after injury to
the vascular structure. The blood-brain barrier (selective permeabil-
ity of brain capillaries) is disrupted, and plasma proteins leak into the
extracellular spaces, drawing water to them and increasing the water
content of the brain parenchyma. Vasogenic edema starts in the area
of injury and spreads, with fluid accumulating in the white matter of
the ipsilateral side because the parallel myelinated fibers separate more
FIGURE 14-10  Herniation. Herniations can occur both above and
below the tentorial membrane. Suprateneorial: 1, uncal (trans-
easily. Edema promotes more edema because of ischemia from the
tentorial); 2, central 3, cinculate 4, transcalvarial; infratentorial: increasing pressure.
5, upward, 6, cerebellar tonsillar. Clinical manifestations of vasogenic edema include focal neuro-
logic deficits, disturbances of consciousness, and a severe increase in
ICP. Vasogenic edema resolves by slow diffusion.
In cytotoxic (metabolic) edema, toxic factors directly affect the cel-
Small hemorrhages often develop in the involved brain tissue. Obstruc- lular elements of the brain parenchyma (neuronal, glial, and endothe-
tive hydrocephalus may develop. The herniation process markedly and lial cells), causing failure of the active transport systems. The cells lose
rapidly increases intracranial pressure. Mean systolic arterial pressure their potassium and gain larger amounts of sodium. Water follows by
soon equals ICP, and cerebral blood flow ceases at this point. The types osmosis into the cells, so that the cells swell. Cytotoxic edema occurs
of herniation syndromes are outlined in Box 14-2. principally in the gray matter and may increase vasogenic edema.
 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics 363

BOX 14-2 HERNIATION SYNDROME

Supratentorial Herniation
1. Uncal herniation. Occurs when the uncus or hippocampal gyrus, or both,
shifts from the middle fossa through the tentorial notch into the posterior
fossa, compressing the ipsilateral third cranial nerve, the contralateral
third cranial nerve, and the mesencephalon. Uncal herniation generally
is caused by an expanding mass in the lateral region of the middle fossa.
The classic manifestations of uncal herniation are a decreasing level of
consciousness, pupils that become sluggish before fixing and dilating (first
the ipsilateral, then the contralateral pupil), Cheyne-Stokes respirations
(which later shift to central neurogenic hyperventilation), and the appear-
ance of decorticate and then decerebrate posturing.
2. Central herniation. The straight downward shift of the diencephalon
through the tentorial notch. It may be caused by injuries or masses located
around the outer perimeter of the frontal, parietal, or occipital lobes; extra-
cerebral injuries around the central apex (top) of the cranium; bilaterally
positioned injuries or masses; and unilateral cingulate gyrus herniation.
The individual rapidly becomes unconscious; moves from Cheyne-Stokes
respirations to apnea; develops small, reactive pupils and then dilated,
fixed pupils; and passes from decortication to decerebration.
3. Cingulate gyrus herniation. Occurs when the cingulate gyrus shifts under
FIGURE 14-11  Brain Edema. Intercellular lakes of high protein
the falx cerebri. Little is known about its clinical manifestations.
content fluid. (Hematoxylin-eosin stain; ×90.) (From Kissane JM,
editor: Anderson’s pathology, ed 9, St Louis, 1993, Mosby.)
Infratentorial Herniation
In the most common syndrome the cerebellar tonsil shifts through the foramen
magnum because of increased pressure within the posterior fossa. The clini-
cal manifestations are an arched stiff neck, paresthesias in the shoulder area, TABLE 14-16 TYPES OF HYDROCEPHALUS
decreased consciousness, respiratory abnormalities, and pulse rate variations.
TYPE MECHANISM CAUSE
Occasionally the force produces an upward transtentorial herniation of a cer-
ebellar tonsil or the lower brain stem. No specific set of clinical manifestations Noncommunicating Obstruction of CSF flow between Congenital
is associated with infratentorial herniation (see Figure 14-10). ventricles abnormality
Aqueduct stenosis
Arnold-Chiari malformation (brain
extension through foramen
Interstitial edema is seen most often with noncommunicating
magnum)
hydrocephalus. The edema is caused by transependymal movement
Compression by tumor
of CSF from the ventricles into the extracellular spaces of the brain
Communicating Impaired absorption of CSF within Infection with
tissues. The brain fluid volume increases predominantly around the
subarachnoid space inflammatory
ventricles, with increased hydrostatic pressure within the white matter.
­adhesions
The size of the white matter is reduced because of the rapid disappear-
Compression of subarachnoid space
ance of myelin lipids.
by a tumor
Hydrocephalus High venous pressure in sagittal
sinus
The term hydrocephalus refers to various conditions characterized
Head injury
by excess fluid in the cerebral ventricles, subarachnoid space, or both.
Congenital malformation
Hydrocephalus occurs because of interference with CSF flow caused
Increased CSF secretion by choroid Secreting
by increased fluid production, obstruction within the ventricular sys-
plexus tumor
tem, or defective reabsorption of the fluid. A tumor of the choroid
plexus may, in rare instances, cause overproduction of CSF. The types CSF, Cerebrospinal fluid.
of hydrocephalus are reviewed in Table 14-16.
Hydrocephalus may develop from infancy through adulthood.
Congenital hydrocephalus (i.e., ventricular enlargement before birth) Pathophysiology. The obstruction of CSF flow associated with
is rare. Noncommunicating hydrocephalus (internal hydrocephalus, hydrocephalus produces increased pressure and dilation of the ven-
intraventricular hydrocephalus)—obstruction within the ventricular tricles proximal to the obstruction. The increased pressure and dila-
system—is seen more often in children, and communicating hydro- tion cause atrophy of the cerebral cortex and degeneration of the white
cephalus—defective resorption of CSF from the cerebral subarach- matter tracts. Selective preservation of gray matter occurs. When
noid space—is found more often in adults. excess CSF fills a defect caused by atrophy, a degenerative disorder, or
Most cases of hydrocephalus develop gradually and insidiously a surgical excision, this fluid is not under pressure; therefore atrophy
over time. Acute hydrocephalus, however, may develop in a couple of and degenerative changes are not induced.
hours in persons who have sustained head injuries. Acute hydrocepha- Clinical manifestations. Acute hydrocephalus presents with signs
lus contributes significantly to IICP. of rapidly developing IICP. The person quickly deteriorates into a
364 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics

deep coma if not promptly treated. Normal-pressure hydrocepha-

ALTERATIONS IN NEUROMOTOR FUNCTION
lus (dilation of the ventricles without increased pressure) develops
slowly, with the individual or family noting declining memory and Movements are complex patterns of activity controlled by the CNS.
cognitive function. The triad symptoms of an unsteady, broad- They are influenced by the cerebral cortex, the pyramidal system, the
based gait with a history of falling; incontinence; and dementia is extrapyramidal system, and the motor units. Dysfunction in any of
common.17a these areas can cause motor dysfunction. General neuromotor dys-
Evaluation and treatment. The diagnosis is based on physical functions may produce changes in muscle tone, movement, and com-
examination, computed tomography (CT) scan, and magnetic reso- plex motor performance.
nance imaging (MRI). A radioisotopic cisternogram may be per-
formed to diagnose normal-pressure hydrocephalus. Hydrocephalus Alterations in Muscle Tone
can be treated by surgery to resect cysts, neoplasms, or hematomas Normal muscle tone involves a slight resistance to passive movement.
or by ventricular bypass into the normal intracranial channel or into Throughout the range of motion, the resistance is smooth, constant,
an extracranial compartment using a shunting procedure, one of the and even. The alterations of muscle tone and their characteristics and
three most common neurosurgical procedures. Excision or coagula- causes are presented in Table 14-17.
tion of the choroid plexus occasionally is needed when a papilloma
is present. In normal-pressure hydrocephalus, reduction in CSF is Hypotonia
achieved through diuresis or placement of a ventriculoperitoneal In hypotonia (decreased muscle tone), passive movement of a muscle
shunt. occurs with little or no resistance. Causes include pure pyramidal tract
damage (a rare occurrence) and cerebellar damage. A pure pyramidal
tract injury produces hypotonia and weakness. The hypotonia contrib-
4 QUICK CHECK 14-4 utes to the ataxia and intention tremor in cerebellar damage and mani-
fests with minimal weakness and normal or slightly exaggerated reflexes.
1. What are the four stages of intracranial hypertension (increased intracra-
nial pressure)? Hypotonia or flaccidity (a state in which the muscle may be moved rap-
2. How does supratentorial herniation differ from infratentorial herniation? idly without resistance) occurs when the nerve impulses needed for mus-
3. What are the four different types of cerebral edema? cle tone are lost, such as in spinal cord injury or cerebrovascular accident.
4. How is communicating hydrocephalus different from noncommunicating Individuals with hypotonia tire easily (asthenia) or are weak. They
hydrocephalus? may have difficulty rising from a sitting position, sitting down with-
out using arm support, and walking up and down stairs, as well as an

TABLE 14-17 ALTERATIONS IN MUSCLE TONE

ALTERATIONS CHARACTERISTICS CAUSE
Hypotonia Passive movement of a muscle mass with little or no resistance Thought to be caused by decreased muscle spindle activity
as a result of decreased excitability of neurons
Muscles may be moved rapidly without resistance
Flaccidity Associated with limp, atrophied muscles, and paralysis Occurs typically when nerve impulses necessary for muscle
tone are lost
Hypertonia Increased muscle resistance to passive movement Results when lower motor unit reflex arc continues to func-
May be associated with paralysis tion but is not mediated or regulated by higher centers
May be accompanied by muscle hypertrophy
Spasticity A gradual increase in tone causing increased resistance until tone ­ Exact mechanism unclear; appears to arise from an increased
suddenly diminishes, which results in clasp-knife phenomenon; excitability of alpha motor neurons to any input because of
increased deep tendon reflexes (hyperreflexia); clonus (spread of reflexes) absence of descending inhibition of pyramidal systems
Gegenhalten Resistance to passive movement, which varies in direct proportion to force Exact mechanism unclear; associated with frontal lobe
(paratonia) applied injury
Dystonia Sustained involuntary twisting movement Produced by slow muscular contraction; lack of reciprocal
inhibition of muscle
Rigidity Muscle resistance to passive movement of a rigid limb that is uniform Occurs as a result of constant, involuntary contraction of
in both flexion and extension throughout the motion muscle
Plastic, or lead pipe Increased muscular tone relatively independent of degree of force used Associated with basal ganglion damage
in passive movement; does not vary throughout the passive movement
Cogwheel Uniform resistance may be interrupted by a series of brief jerks, resulting Associated with basal ganglion damage
in movements much like a ratchet, “cogwheel” phenomenon
Gamma Characterized by extensor posturing (decerebrate rigidity) Loss of excitation of extensor inhibitory areas by cerebral
cortex decreasing inhibition of alpha and gamma motor
neurons
Alpha Impaired relaxation characterized by extensor rigidity of skeletal muscle Loss of cerebellum input to lateral vestibular nuclei
after contraction
 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics 365

inability to stand on their toes. Because of their weakness, accidents whereas others (e.g., chorea, ballism, tardive dyskinesia) result from
during ambulatory and self-care activities are common. The joints too much dopaminergic activity. Still others are not primarily related
become hyperflexible, so persons with hypotonia may be able to to dopamine function. Movement disorders are not necessarily associ-
assume positions that require extreme joint mobility. The joints may ated with mass, strength, or tone but are neurologic dysfunctions with
appear loose, and the knee jerks are pendulous. either insufficient or excessive movement. Muscle strength is quantita-
The muscle mass atrophies because of decreased input entering the tively evaluated on a scale of 0 to 4+ or 5+, in which 4+ or 5+ is normal
motor unit, and muscles appear flabby and flat. Muscle cells are gradu- and 0 indicates an inability to move against gravity.
ally replaced by connective tissue and fat. Fasciculations may be pres-
ent in some cases. Paresis/Paralysis
Paresis (weakness) is partial paralysis with incomplete loss of mus-
Hypertonia cle power. Paralysis is loss of motor function so that a muscle group
In hypertonia (increased muscle tone), passive movement of a mus- is unable to overcome gravity. Two subtypes of paresis/paralysis are
cle occurs with resistance. The four types of hypertonia are spastic- described: upper motor neuron paresis/paralysis and lower motor
ity (Figure 14-12), gegenhalten (paratonia), dystonia (Figures 14-13 neuron paresis/paralysis (Table 14-18).
and 14-14), and rigidity. Four types of rigidity are described: plastic or
lead-pipe, cogwheel, gamma, and alpha (see Table 14-17).
Individuals with hypertonia tire easily (asthenia) or are weak. Pas-
sive and active movement is affected equally, except in paratonia, in
which more active than passive movement is possible. As a result of
hypertonia and weakness, accidents occur during ambulatory and self-
care activities.
The muscles may atrophy because of decreased use. However,
hypertrophy occasionally occurs as a result of the overstimulation of
muscle fibers. Overstimulation occurs when the motor unit reflex arc
remains intact and functioning but is not inhibited by higher centers.
This causes continual muscle contraction, resulting in enlargement of
the muscle mass and the development of firm muscles.

Alterations in Movement
Movement requires a change in the contractile state of muscles. Abnor-
mal movements occur when CNS dysfunctions alter muscle innerva-
tion. Currently, neuropharmacology and experimental therapeutics
provide the knowledge base for movement disorders. Researchers
have found that dopamine functions in several movement disorders.
Some (e.g., the akinesias) result from too little dopaminergic activity,

FIGURE 14-13  Dystonic Posturing of the Hand and Foot. (From

Perkin GD: Mosby’s color atlas and text of neurology, ed 2, London,
2002, Mosby.)

FIGURE 14-12  Paroxysm of Left-Sided Hemifacial Spasm. FIGURE 14-14  Spasmodic Torticollis. A characteristic head pos-
(From Perkin GD: Mosby’s color atlas and text of neurology, ed 2, ture. (From Perkin GD: Mosby’s color atlas and text of neurology,
London, 2002, Mosby.) ed 2, London, 2002, Mosby.)
366 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics

TABLE 14-18 UPPER AND LOWER MOTOR Upper Motor Neuron Syndromes

NEURON SIGNS AND Upper motor neuron paresis/paralysis is known also as spastic pare-
SYMPTOMS sis/paralysis, and different terms are used to describe the specific dis-
LOWER MOTOR NEURON orders. Hemiparesis/hemiplegia is paresis/paralysis of the upper and
UPPER MOTOR (VENTRAL HORN [SPINAL lower extremities on one side. Diplegia is paralysis of corresponding
NEURON (PYRAMIDAL CORD], MOTOR NUCLEI parts of both sides of the body as a result of cerebral hemisphere inju-
CELLS [MOTOR CORTEX]) [BRAIN STEM]) ries. Paraparesis/paraplegia refers to weakness/paralysis of the lower
Muscle groups are affected Individual muscles may be affected extremities. Quadriparesis/quadriplegia refers to paresis/paralysis of
all four extremities. Both paraparesis/paraplegia and quadriparesis/
Mild weakness Mild weakness quadriplegia may be caused by dysfunction of the spinal cord. Upper
Minimal disuse muscle atrophy Marked muscle atrophy cord damage results in quadriparesis/quadriplegia, and lower cord
No fasciculations Fasciculations damage preserves upper extremity function and causes paraparesis/
Increased muscle stretch reflexes Decreased muscle stretch reflexes paraplegia. (Spinal cord injury is discussed in Chapter 15.)
­(clasp-knife spasticity; resistance Upper motor neuron paresis/paralysis is associated with a pyrami-
to passive flexion that releases dal motor syndrome, which involves a series of motor dysfunctions
abruptly to allow easy flexion) resulting from interruption of the pyramidal system (Figures 14-15
Clonus may be present Clonus not present and 14-16). The injury may be in the cerebral cortex, the subcortical
Hypertonia, spasticity Hypotonia, flaccidity white matter, the internal capsule, the brain stem, or the spinal cord.
Hyporeflexia The clinical manifestations reflect muscle overactivity and include
Pathologic reflexes (Babinski and No Babinski sign excessive movements, such as clonus and spasms, occurring regu-
Hoffmann signs, loss of abdomi- larly as a result of loss of higher motor center control. There is great
nal reflexes) variation depending on the suddenness of onset and the age of the
Often initial impairment of only Asymmetric and may involve one limb individual.
skilled movements only in beginning to become gener- Spinal shock is the complete cessation of spinal cord func-
alized as disease progresses tions below the lesion (below the level of the pons). It is character-
ized by complete flaccid paralysis, absence of reflexes, and marked

Motor cortex
1. Birth injuries
(cerebral palsies
of childhood)
2. Neoplasms
3. Trauma
4. Inflammations
Internal capsule
Bulbar 1. Vascular lesions
1. Bulbar palsies (CVA, thrombosis, embolism, UPPER MOTOR NEURON
hemorrhage, aneurysms)
Anterior horn cell 2. Neoplasms
1. Poliomyelitis 3. Trauma
LOWER MOTOR NEURON

2. Motor system disease 4. Inflammations

3. Polyneuritis (varied locations)
Brain stem
1. Demyelinating diseases
Primary muscle (multiple sclerosis)
1. Muscular dystrophies 2. Vascular lesions
2. Myasthenia gravis 3. Neoplasms
3. Polymyositis 4. Trauma
5. Inflammations
6. Degenerative diseases
(Parkinson disease)
Muscle Peripheral
spindle nerve Spinal cord
(sensory) 1. Demyelinating diseases
2. Neoplasms
Motor end- 3. Trauma
plate Myoneural junction
1. Myasthenia gravis 4. Inflammations
(varied locations)
FIGURE 14-15  Motor Function Syndromes. Disturbances in motor function are classified pathologi-
cally along upper and lower motor neuron structures. It should be noted that the same pathologic con-
dition occurs at more than one site in an upper motor neuron (above right). A few pathologic conditions
involve both upper and lower motor neuron structures, as in amyotrophic lateral sclerosis, for example.
Other lesion sites include myoneural junction and primary muscle, making it possible to classify condi-
tions as neuromuscular and muscular, respectively.
 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics 367

MOTOR CORTEX
(PRECENTRAL GYRUS)

INTERNAL CAPSULE

Corticobulbar tract
Cranial nerve III
motor nucleus CEREBRAL PEDUNCLE

Cranial nerve V
PONS
Cranial nerve VII

Cranial nerve IX
Cranial nerve X
Cranial nerve XI
Cranial nerve XII SPINAL CORD

Crossed pyramidal tract

Decussation of
the pyramids
Ventral corticospinal tract
FIGURE 14-16  Structures of the Upper Motor Neuron, or Pyramidal, System. Pyramidal system
fibers are shown to originate primarily in cells in precentral gyrus of motor cortex; to converge at inter-
nal capsule; to descend to form central third of cerebral peduncle; to descend further through pons,
where small fibers supply cranial nerve motor nuclei along the way; to form pyramids at medulla,
where most of the fibers decussate; and then to continue to descend in lateral column of white matter
of spinal cord. A few fibers descend without crossing at medulla level (see Figure 12-8).

disturbances of bowel and bladder function. A major factor in spinal rigidity occasionally occurs. Most often, passive range-of-motion
shock is the sudden destruction of the efferent pathways. If destruction movements cause the “clasp-knife” phenomenon, probably by activat-
occurs more slowly, spinal shock may not develop (see Chapter 15). ing the stretch receptors in the muscle spindles and the Golgi tendon
If the pyramidal system is interrupted above the level of the pons, organ. (Muscle function is discussed in Chapter 36.) With pyramidal
the hand and arm muscles are greatly affected. Paralysis rarely involves motor syndrome, predominantly the flexors of the arms and extensors
all the muscles on one side of the body, even when the hemiplegia of the legs are affected.
results from complete damage to the internal capsule. Bilateral move-
ments, such as those of the eye, jaw, and larynx, as well as those of the Lower Motor Neuron Syndromes
trunk, are affected only slightly if at all. Predominantly the limbs are Lower (primary, alpha) motor neurons are the large motor neurons
influenced. in the anterior (or ventral) horn of the spinal cord, the motor nuclei
Paralysis associated with a pyramidal motor syndrome rarely of the brain stem, and the axons that originate from these nerve cell
remains flaccid for a prolonged time. After a few days or weeks, a grad- bodies (to course in the anterior spinal roots or in the cranial nerves
ual return of spinal reflexes marks the end of spinal shock. Reflexes to reach skeletal muscles) (Figure 14-17). Dysfunction in this motor
then become hyperactive, and muscle tone increases significantly, system impairs both voluntary and involuntary movement. The degree
particularly in antigravity muscles. Spasticity is common, although of paralysis or paresis is proportional to the number of lower motor
368 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics

Dorsal root ganglion

Afferent fiber

Ascending pathway

Anterior horn cell

(lower motor neuron)

Motor end-plate

Descending pathways
Gamma
afferent fiber Gamma efferent fiber

Alpha efferent fiber

Motor end-plate

Muscle spindle
FIGURE 14-17  Structures Composing Lower Motor Neuron, Including Motor (Efferent) and Sen-
sory (Afferent) Elements. (Top) Anterior horn cell (in anterior gray column of spinal cord and its axon),
terminating in motor end-plate as it innervates extrafusal muscle fibers in quadriceps muscle. (Detailed
enlargement) Sensory and motor elements of gamma loop system. Gamma efferent fibers shown
innervating the muscle spindle (sensory receptor of skeletal muscle). Contraction of muscle spindle
fibers stretches central portion of the spindle and causes the gamma afferent spindle fiber to transmit
impulse centrally to cord. Muscle spindle gamma afferent fibers in turn synapse on the anterior horn
cell and impulses are transmitted by way of alpha efferent fibers to skeletal (extrafusal) muscle, causing
it to contract. Muscle spindle discharge is interrupted by active contraction of skeletal muscle fibers.

neurons affected. If only some of the motor units that supply a muscle Amyotrophies. Lower motor neuron syndromes originating in the
are affected, only partial paralysis (or paresis) results. If all motor units anterior horn cells or the motor nuclei of the cranial nerves are called
are affected, a complete paralysis results. Other clinical manifestations amyotrophies. Paralytic poliomyelitis is a contagious viral disease that
also are proportional to the degree of dysfunction, but the precise involves a severe inflammatory reaction in motor neurons, some of
manifestations depend on the location of the dysfunction in the motor which do not survive, leaving an irreversible paralysis (1 in 200 infec-
unit and in the CNS. tions).18 It has been eradicated in most of the world by vaccines.
Small motor (gamma) neurons, which maintain muscle tone A virally induced or postinfectious/postvaccination inflammatory
and protect the muscle from injury, are needed for normal motor process may injure or destroy anterior horn cells or cranial nerve cell
movement. They depend on input from the muscle spindle (arriv- bodies. Most of these inflammatory processes are mild and are fol-
ing through an afferent limb rising to the cord). Dysfunction in this lowed by rapid cellular recovery.
motor system (the gamma loop) impairs tone and reduces tendon In the amyotrophies, muscle strength, muscle tone, and muscle
reflexes, causing hyporeflexia. The muscles become susceptible to bulk are affected in the muscles innervated by the involved motor neu-
damage from hyperextensibility. rons. The paresis and paralysis associated with anterior horn cell injury
Generally, the large and small motor neuron systems are equally are segmental, but because each muscle is supplied by two or more
affected. Therefore the muscle has reduced or absent tone and is roots, the segmental character may be difficult to see. When cranial
accompanied by hyporeflexia or areflexia (loss of tendon reflexes) and nerve motor nuclei are affected (these lack nerve roots and have only
flaccid paresis/paralysis. small rootlets near the point of exit from the brain stem), the distribu-
Denervated muscles (i.e., muscles that have lost their nervous sys- tion of the motor weakness follows that of the cranial nerve. The weak-
tem input) atrophy over weeks to months, mostly from disuse, and ness may involve distal muscles, proximal muscles, or the muscles of
demonstrate fasciculations (muscle rippling or quivering under the midline structures. Hypotonia and hyporeflexia/areflexia are present.
skin). Occasionally, denervated muscles cramp. Fibrillation (isolated The atrophy associated with amyotrophy is segmental when the
contraction of a single muscle fiber due to metabolic changes in dener- anterior horn cells of the spinal cord are involved and follows the
vated muscle not visible clinically). distribution of the cranial nerve when the motor nuclei of the cranial
 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics 369

nerves are affected. It may be in distal, proximal, or midline muscles. stimuli); and (3) paroxysmal excessive activity, including cataplexy
Fasciculations are associated particularly with primary motor neu- and excessive startle reaction.
ron injury, and muscle cramps and mild fatigue are common. If the
pathologic process is limited to the primary motor neuron, no sensory Huntington Disease
changes are evident. Huntington disease (HD), also known as chorea, is a relatively rare,
Several brain stem syndromes, called nuclear palsies, involve dam- hereditary, degenerative hyperkinetic movement disorder diffusely
age to one or more of the cranial nerve nuclei. Causes include vascular involving the basal ganglia and cerebral cortex. The onset of Hunting-
occlusion, tumor, aneurysm, tuberculosis, and hemorrhage. ton disease is usually between 25 and 45 years of age, when the trait
The anterior horn cells and the motor nuclei of the cranial nerves may already have been passed to the person’s children. The disorder
may be secondarily affected in many severe pathologic processes has a prevalence rate of approximately 3 to 7 per 100,000 persons and
involving primarily the cranial nerves. The condition may extend occurs in all races.19
proximally to affect the nerve roots or rootlets and the motor neurons
themselves, a process commonly seen, for example, in Guillain-Barré
syndrome. If enough motor neurons are destroyed, permanent loss HEALTH ALERT
of motor function results because regeneration of the damaged axons Tourette Syndrome
requires a living neuronal cell body.
In progressive spinal muscular atrophy, the anterior horn cells There is growing evidence that Tourette syndrome (TS) occurs worldwide
of the spinal cord are affected. This disorder occurs in adults and and has common features across all races and cultures. The hallmark of TS is
closely resembles the familial progressive muscular atrophies that the presence of multiple motor and vocal tics. The tics may be either simple,
occur in infants and children and are considered inherited meta- involving only an individual muscle group (e.g., eye blinking or grunting), or
bolic disorders (see Chapter 38). If the motor nuclei of the cranial complex, requiring coordinated movement of muscle groups (e.g., head bang-
nerves are affected instead of the anterior horn cells, the disorder ing or repeating of another person’s words). Sensory tics involve unpleasant
is called a progressive bulbar palsy, so named because the myel- sensations in the face, head, and neck areas. Probably underdiagnosed, the
encephalon originally was called the bulb and a degenerative pro- onset of TS is typically between the ages of 2 and 15 years, with the tics less-
cess causes a progressively more serious condition. When any lower ening in adulthood. The syndrome has a complex multifactorial etiology with
motor neuron syndrome involves the cranial nerves that arise from undetermined genetic, environmental, immune, and hormonal factors. The
the bulb (i.e., cranial nerves IX, X, XII), the dysfunction is called a pathophysiology of TS is unclear and currently under study. There is evidence
bulbar palsy. of frontal-striatal-thalamic dysfunction and, in some cases, altered dopami-
The clinical manifestations of bulbar palsy include paresis or nergic neurotransmission. TS is often diagnosed in association with anxiety,
paralysis of the jaw, face, pharynx, and tongue musculature. Articu- depression, attention-deficit/hyperactivity disorder (ADHD), and obsessive-
lation is affected, especially articulation of the lingual (r, n, l), labial compulsive disorder.
(b, m, p, f), dental (d, t), and palatal (k, g) consonants. Modulation is
Data from Robertson MM: Gilles de la Tourette syndrome: the complexi-
impaired, making the voice rasping or nasal. Pharyngeal reflexes are
ties of phenotype and treatment, Br J Hosp Med (Lond) 72(2):100–117,
diminished or lost, palate and vocal cord movement during phona- 2011; Worbe Y et al: Distinct structural changes underpin clinical
tion is impaired, and chewing and swallowing are affected. The facial phenotypes in patients with Gilles de la Tourette syndrome, Brain 133(Pt
muscles are weak, and the face appears to droop, with decreased jaw 12):3649–3660, 2010; Worbe Y et al: Repetitive behaviours in patients
jerk. Atrophy and fasciculations eventually occur. All these mani- with Gilles de la Tourette syndrome: tics, compulsions, or both? PLoS
festations become progressively worse, leading to aspiration, mal- One 5(9):e12959, 2010; Jankovic J, Gelineau-Kattner R, Davidson A:
nutrition, possible dehydration, and an inability to communicate Tourette’s syndrome in adults, Mov Disord 25(13):2171–2175, 2010.
verbally.

Hyperkinesia Pathophysiology. Huntington disease (HD) is inherited from both

Hyperkinesia (excessive movements) represents the second broad cat- mothers and/or fathers who have the autosomal dominant trait with
egory of abnormal movements. Within this category are a number of high penetrance. The Huntingtin gene (HTT) is located on the short
specific dysfunctions including tremors (Table 14-19). Also included arm of chromosome 4. Mutated forms of the HD gene contain abnor-
under the general category of hyperkinesias are dyskinesias—abnor- mally repeated segments of deoxyribonucleic acid (DNA), called CAG
mal involuntary movements. trinucleotide repeats. These repeated segments result in the synthesis
Paroxysmal dyskinesias are abnormal, involuntary movements of huntingtin proteins. CAG repeat allele lengths are defined as fully
that occur as spasms. The type of dyskinesia varies depending on the penetrant at ≥40, reduced penetrance at 36 to 39, high normal at 27
specific disorder. to 35, and normal at ≤26. Fathers, but not mothers, with high normal
Tardive dyskinesia is the involuntary movement of the face, trunk, alleles do not develop HD but are at risk of transmitting potentially
and extremities. Although the condition occurs occasionally in indi- penetrant HD alleles (≥36) to their offspring, who can develop HD.20
viduals with Parkinson disease, it usually occurs as a side effect of pro- The principal pathologic feature of Huntington disease is severe degen-
longed phenothiazine drug therapy. The most common symptom of eration of the basal ganglia, particularly the caudate nucleus. Tangles of
tardive dyskinesia is rapid, repetitive, stereotypic movements. Most protein (huntingtin protein) collect in the brain cells and chains of gluta-
characteristic is continual chewing with intermittent protrusions of mine on the abnormal molecules stick to each other and contribute to neu-
the tongue, lip smacking, and facial grimacing. ronal loss.21 Basal ganglia and nigral depletion of gamma-aminobutyric
Other movement disorders in this category are (1) complex repeti- acid (GABA), an inhibitory neurotransmitter, is the principal biochemi-
tive movements, including automatism, stereotype, complex tics, cal alteration in Huntington disease. It alters the integration of motor and
e.g., Tourette syndrome (see Health Alert), compulsions, persevera- mental function.22 Frontal cerebral atrophy occurs late in the disease. The
tions, and mannerisms; (2) positivism (excessive reactions to certain triggers and timing of pathogenesis are not clearly understood.
370 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics

TABLE 14-19 TYPES OF HYPERKINESIA AND TREMOR

TYPE CHARACTERISTICS CAUSES
Hyperkinesia
Chorea* Nonrepetitive muscular contractions, usually of extremities of face; random Associated with excess concentration of or supersensi-
pattern of irregular, involuntary rapid contractions of groups of muscles; disap- tivity to dopamine within basal ganglia
pears with sleep, decreases with resting; increases with emotional stress and
attempted voluntary movement
Athetosis* Disorder of distal muscle postural fixation; slow, sinuous, irregular movements Occurs most commonly as result of injury to putamen of
most obvious in distal extremities, more rhythmic than choreiform movements basal ganglion; exact pathophysiologic mechanism is
and always much slower; movements accompany characteristic hand posture; not known
slowly fluctuating grimaces
Ballism Disorder of proximal muscle postural fixation with wild flinging movement of limbs; Results from injury to subthalamic nucleus (one of
movement is severe and stereotyped, usually lateral; does not lessen with sleep; nuclei that comprise basal ganglia); thought to be
ballism is most common on one side of body, a condition termed hemiballism caused by reduced inhibitory influence in nucleus, a
release phenomenon; hemiballism results from injury
to contralateral subthalamic nucleus
Hyperactivity State of prolonged, generalized, increased activity that is largely involuntary but May be caused by frontal and reticular activating
may be subject to some voluntary control; not highly stereotyped but rather man- system injury
ifests as continuous changes in total body posture or in excessive performance
of some simple activity, such as pacing under inappropriate circumstances
Wandering Tendency to wander without regard for environment “Release phenomenon” associated with bilateral injury
to globus pallidus or putamen
Akathisia Special type of hyperactivity; mild compulsion to move (usually more localized Dopaminergic transmission may be involved
to legs); severe, frenzied motion possible; movements are partly voluntary and
may be transiently suppressed; carrying out movement brings sense of relief;
frequent complication of antipsychotic drugs

Tremor at Rest
Parkinsonian tremor Rhythmic, oscillating movement affecting one or more body parts Caused by regular contraction of opposing groups of
muscles
Regular, rhythmic, slower flexion-extension contraction; involves principally meta- Loss of inhibitory influence of dopamine in the basal
carpophalangeal and wrist joints; alternating movements between thumb and ganglia, causing instability of basal ganglial feedback
index finger described as “pill rolling;” disappears during voluntary movement circuit within cerebral cortex

Postural Tremor
Asterixis (tremor of Irregular flapping movement of hands accentuated by outstretching arms Exact mechanisms responsible unknown; thought to be
hepatic encepha- related to accumulation of products normally detoxi-
lopathy) fied by liver, i.e., ammonia
Metabolic Rapid, rhythmic tremor affecting fingers, lips, and tongue; accentuated by Occurs in conditions associated with disturbed metabo-
­extending body part; enhanced physiologic tremor lism or toxicity, as in thyrotoxicosis (hyperthyroid-
ism), alcoholism, and chronic use of barbiturates,
amphetamines, lithium, or amitriptyline [Elavil]; exact
mechanism responsible unknown
Essential (familial) Tremor of fingers, hands, and feet; absent at rest but accentuated by extension Not associated with any other neurologic abnormalities;
of body part, prolonged muscular activity, and stress cause unknown

Intention Tremor
Cerebellar Tremor initiated by movement, maximal toward end of movement Occurs in disease of dentate nucleus (one of deep
cerebellar nuclei responsible for efferent output) and su-
perior cerebellar peduncle (stalklike structure connected
to pons); caused by errors in feedback from periphery
and errors in preprogramming goal-directed movement
Rubral Rhythmic tremor of limbs that originates proximally by movement Results from lesions involving dentatorubrothalamic
tract (a spinothalamic tract connecting red nucleus in
reticular formation and dentate nucleus in cerebellum)
Myoclonus Series of shocklike nonpatterned contractions of portion of a muscle, entire Associated with an irritable nervous system and sponta-
muscle, or group of muscles that cause throwing movements of a limb; usually neous discharge of neurons; structures associated
appear at random but frequently triggered by sudden startle; do not disappear with myoclonus include cerebral cortex, cerebellum,
during sleep reticular formation, and spinal cord

*Choreoathetosis involves both chorea and athetosis; precise pathophysiology unknown.

 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics 371

Clinical manifestations. Symptoms of Huntington disease progress excess of cholinergic (excitatory) activity in the feedback circuit are
slowly and include involuntary fragmentary movements, such as cho- manifested by hypertonia (tremor and rigidity) and akinesia, produc-
rea (irregular, uncontrolled, excessive movement), athetosis (writhing ing a syndrome of abnormal movement called parkinsonism (Parkin-
movements), and ballism (flinging movements). Chorea, the most son syndrome, parkinsonian syndrome, paralysis agitans) (Figure
common type of abnormal movement, begins in the face and arms, 14-18). Dementia may develop over decades with infiltration of Lewy
eventually affecting the entire body. There is progressive dysfunction bodies (accumulation of abnormal protein in nerve cells) and plaque
of intellectual and thought processes (dementia). Any one of these formation similar to Alzheimer disease.25
features may mark the onset of the disease. Cognitive deficits include Clinical manifestations. The classic manifestations of Parkinson
loss of working memory and reduced capacity to plan, organize, and disease are tremor at rest (resting tremor), rigidity (muscle stiffness),
sequence. Thinking is slow, and apathy is present. Restlessness, disin- bradykinesia/akinesia (poverty of movement), postural disturbance,
hibition, and irritability are common. Euphoria or depression may be dysarthria, and dysphagia. They may develop alone or in combina-
present. tion, but as the disease progresses, all are usually present. There is no
Evaluation and treatment. The diagnosis of Huntington disease is true paralysis. The symptoms are always bilateral but usually involve
based on family history and clinical presentation of the disorder. No one side early in the illness. Because the onset is insidious, the begin-
known treatment is effective in halting the degeneration or progression ning of symptoms is difficult to document. Early in the disease, reflex
of symptoms. Drug therapies are being explored.23 status, sensory status, and mental status usually are normal. Postural
abnormalities (flexed, forward leaning), difficulty walking, and weak-
Hypokinesia ness develop. Speech may be slurred. Autonomic-neuroendocrine
Hypokinesia (decreased movement) is loss of voluntary movement symptoms include inappropriate diaphoresis, orthostatic hypoten-
despite preserved consciousness and normal peripheral nerve and sion, drooling, gastric retention, constipation, and urinary retention.
muscle function. Types of hypokinesia include akinesia, bradykinesia, Depression is also prevalent.
and loss of associated movement. Disorders of equilibrium result from postural abnormalities
Akinesia and bradykinesia. Akinesia is a decrease in voluntary and ­(Figure 14-19). The person with Parkinson disease cannot make the
associated movements. It is related to dysfunction of the extrapyrami- appropriate postural adjustment to tilting or falling and falls like a
dal system and caused by either a deficiency of dopamine or a defect post when starting to tilt. The festinating gait (short, accelerating
of the postsynaptic dopamine receptors, which occurs in parkinson- steps) of the individual with Parkinson disease is an attempt to main-
ism. Bradykinesia is slowness of voluntary movements. All voluntary tain an upright position while walking. Individuals are also unable
movements become slow, labored, and deliberate, with difficulty in to right themselves when changing from a reclining or crouching
(1) initiating movements, (2) continuing movements smoothly, and position to a standing position and when rolling over from a supine
(3) performing synchronous (at the same time) and consecutive tasks. to a lateral or prone position. Sleep disorders and excessive day-
Both akinesia and bradykinesia involve a delay in the time it takes to time sleepiness are commonly experienced.26 Sensory disturbances
start to perform a movement. (pain and impaired smell and vision), difficulty concentrating, and
Loss of associated movement. In hypokinesia, the normal, habit- hallucinations are some of the nonmotor symptoms of Parkinson
ually associated movements that provide skill, grace, and balance to disease.27
voluntary movements are lost. Decreased associated movements
accompanying emotional expression cause an expressionless face, a
statue-like posture, absence of speech inflection, and absence of spon-
taneous gestures. Decreased associated movements accompanying Oxidative stress Genetic
locomotion cause reduction in arm and shoulder movements, in hip Mitochondrial dysfunction predisposition
swinging, and in rotary motion of the cervical spine. Loss of nerve growth factors

Parkinson Disease Lewy body formation

Parkinson disease (PD) is a commonly occurring disorder of move- Nigrostriatal dopaminergic in residual neurons
ment. Either primary Parkinson disease or secondary parkinsonism neurodegeneration in (proteins misfolding
may occur. Secondary parkinsonism is parkinsonism caused by basal ganglia and accumulation of
disorders other than Parkinson disease (i.e., head trauma, infection, alpha-synuclein)
neoplasm, atherosclerosis, toxins, drug intoxication). Drug-induced
parkinsonism, caused by neuroleptics, antiemetics, and antihyperten-
Dopamine deficiency
sives, is the most common secondary form and usually is reversible.
(loss of normal inhibition Lewy body dementia
Parkinson (primary) disease begins after the age of 40 years, with
of muscle tone) later in disease
the incidence increasing after 60 years. It is more prevalent in males
and a leading cause of neurologic disability in individuals older than
60 years. The prevalence is about 1 in 272 persons, with approximately Unopposed cholinergic
60,000 new cases diagnosed in the United States each year.24 activity (promotes
Pathophysiology. The pathogenesis of primary Parkinson disease muscle tone)
is unknown. Several genes have been identified. Epidemiologic data
also suggest viral and environmental toxins as possible causes. There is
Resting tremor
degeneration of the basal ganglia (see Figure 12-9) with dysfunctional
Rigidity
or misfolded α-synuclein protein and loss of dopamine-producing
Bradykinesia/akinesia
neurons in the substantia nigra and dorsal striatum. The resulting
depletion of dopamine, an inhibitory neurotransmitter, and relative FIGURE 14-18  Pathophysiology of Parkinson Disease.
372 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics

Dystonia has been associated with basal ganglia abnormality, but the
exact pathophysiologic mechanisms are unknown. One dystonic pos-
ture already discussed in this chapter is decorticate posture (striatal
posture or upper motor neuron dysfunction posture), which may be
unilateral or bilateral. Decorticate posture (also referred to as anti-
gravity posture or hemiplegic posture) is characterized by upper
extremities flexed at the elbows and held close to the body and by lower
extremities that are externally rotated and extended (see Figure 14-6).
Decorticate posture is thought to occur when the brain stem is not
inhibited by the cerebral cortex motor area. Upper motor neuron pos-
ture is more commonly described as the arm flexed at the elbow with
a wrist drop, the leg inadequately bent at the knee, the hip excessively
circumabducted, and the presence of footdrop.
Decerebrate posture refers to increased tone in extensor muscles
and trunk muscles, with active tonic neck reflexes. When the head is in
a neutral position, all four limbs are rigidly extended. The decerebrate
posture is caused by severe injury to the brain and brain stem, result-
ing in overstimulation of the postural righting and vestibular reflexes.
Basal ganglion posture refers to a stooped, hyperflexed posture
FIGURE 14-19  Stooped Posture of Parkinson Disease. (From with a narrow-based, short-stepped gait. This posture abnormality
Perkin DG: Mosby’s color atlas and text of neurology, ed 2, London, results from the loss of normal postural reflexes and not from defects
2002, Mosby.) in proprioceptive, labyrinthine, or visual function. Dysfunctional
equilibrium results when the individual loses stability and cannot
make the appropriate postural adjustment to tilting or loss of balance,
Progressive dementia is more common in persons older than 70 falling instead. Dysfunctional righting is the inability to right oneself
years. Mental status may be further compromised by the side effects of when changing from a lying or crouching to a standing position or
the medication taken to control symptoms. when rolling from the supine to the lateral or prone position. Dysfunc-
Evaluation and treatment. The diagnosis of Parkinson disease is tional postural fixation is the involuntary flexion of the head and neck,
based on the history and physical examination. Causes of second- causing the person difficulty in maintaining an upright trunk position
ary parkinsonism are first excluded. No specific diagnostic tests are while standing or walking. Basal ganglion dysfunction accounts for this
available, except positron emission tomography (PET). Treatment posture.
of Parkinson disease is symptomatic with drug therapy to decrease Senile posture is characterized by an increasingly flexed posture
akinesia. Because of troublesome side effects and loss of effective- similar to that caused by basal ganglion dysfunction. The posture is
ness, however, drug therapy may not be started until the symptoms associated with frontal lobe dysfunction, but the primary pathophysi-
become incapacitating. Deep brain stimulation is replacing surgery ology is not known.
to treat persons unresponsive to drug therapy. Implants of stem cells
and fetal cells as well as gene therapy hold promise for future treat- Disorders of Gait
ments.28,29 Dysphagia and general immobility are special problems of Four predominant types of gait are (1) upper motor neuron dys-
the individual with PD requiring interdisciplinary efforts to improve function gait, (2) cerebellar (ataxic) gait, (3) basal ganglion gait, and
functional status.30 (4) senile gait (pseudoparkinsonian gait). As with posture, equilibrium
and balance are affected with gait disturbances.
ALTERATIONS IN COMPLEX MOTOR Several upper motor neuron gaits exist. With mild forms, the indi-
vidual may have footdrop with fatigue and hip and leg pain. A spastic
­PERFORMANCE
gait, which is associated with unilateral injury, manifests by a shuf-
The alterations in complex motor performance include disorders of fling gait with the leg extended and held stiff, causing a scraping over
posture (stance), disorders of gait, and disorders of expression. the floor surface. The leg swings improperly around the body rather
than being appropriately lifted and placed. The foot may drag on
Disorders of Posture (Stance) the ground, and the person tends to fall to the affected side. A scis-
An inequality of tone in muscle groups, because of a loss of normal sors gait is associated with bilateral injury and spasticity. The legs are
postural reflexes, results in a posturing of limbs. Equilibrium and bal- adducted so they touch each other. As the person walks, the legs are
ance are disrupted. Many reflex systems govern tone and posture, but swung around the body but then cross in front of each other because
the most important factor in posture control is the stretch reflex, in of adduction. Injury to the pyramidal system accounts for these gaits.
which extensor (antigravity) muscle stretching causes increased exten- A cerebellar gait is wide-based with the feet apart and often turned
sor tone and inhibited flexor tone. Four types of disorders of postures outward or inward for greater stability. The pelvis is held stiff, and the
are (1) dystonic posture, (2) decerebrate posture, (3) basal ganglion individual staggers when walking. Cerebellar dysfunction accounts for
posture, and (4) senile posture. this particular gait.
Dystonia is the maintenance of an abnormal posture through mus- A basal ganglion gait and a senile gait are both broad-based gaits in
cular contractions. When muscular contractions are sustained for sev- which the person walks with small steps and a decreased arm swing. The
eral seconds, they are called dystonic movements; when contractions head and body are flexed and the arms semiflexed and abducted, whereas
last for longer periods, they are called dystonic postures. Dystonic the legs are flexed and rigid in more advanced states. Basal ganglion and
postures may last for weeks, causing permanent, fixed contractures. frontal lobe dysfunction, respectively, account for these two gaits.
 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics 373

Disorders of Expression Dyspraxia/apraxia is a disorder of learned motor skills with diffi-

Disorders of expression involve the motor aspects of communication culty planning and executing coordinated motor movements. It can be
and include (1) hypermimesis, (2) hypomimesis, and (3) dyspraxias/ developmental, beginning at birth (developmental dyspraxia), or asso-
apraxias. Hypermimesis commonly manifests as pathologic ­laughter ciated with vascular disorders (common in stroke), trauma, tumors,
or crying. Pathologic laughter is associated with right hemisphere degenerative disorders, infections, or metabolic disorders. People
injury, and pathologic crying is associated with left hemisphere injury. with dyspraxia have difficulty performing tasks requiring motor skills
The exact pathophysiology is not known. Hypomimesis manifests as including speaking, writing, using tools or utensils, playing sports, fol-
aprosody—the loss of emotional language. Receptive aprosody involves lowing instructions, and focusing.31
an inability to understand emotion in speech and facial expression. True dyspraxias occur when the connecting pathways between the
Expressive aprosody involves the inability to express emotion in speech left and right cortical areas are interrupted (Figure 14-20). Dysprax-
and facial expression. Aprosody is associated with right hemisphere ias may result from any pathologic process that disrupts the cortical
damage. areas necessary for the conceptualization and execution of a complex
motor act or the communication pathways within the left hemisphere
or between the hemispheres.

Premotor EXTRAPYRAMIDAL MOTOR SYNDROMES

area Corpus
callosum Because the extrapyramidal system encompasses all the motor path-
ways except the pyramidal system, two types of motor dysfunction
make up the extrapyramidal motor syndromes: (1) the basal ganglia
Insula motor syndromes and (2) the cerebellar motor syndromes. Unlike
pyramidal motor syndromes, both extrapyramidal motor syndromes
Wernicke result in movement or posture disturbance without significant paraly-
area sis, along with other distinctive symptoms (Table 14-20).
Basal ganglia motor syndromes are caused by an imbalance of
Supra- dopaminergic and cholinergic activity in the corpus striatum. A rela-
marginal tive excess of cholinergic activity produces akinesia and hypertonia.
gyrus A relative excess of dopaminergic activity produces hyperkinesia and
hypotonia. Symptoms associated with Parkinson and Huntington dis-
Visual Visual eases are exemplary of disorders of the basal ganglia. Cerebellar motor
association cortex syndromes are associated with ataxia and other symptoms affecting
area coordinated movement. Cerebellar disorders primarily influence the
FIGURE 14-20  Pathways Disrupted in Dyspraxias. Formulation same side of the body, so that damage to the right cerebellum generally
of the idea of the motor act is thought to originate in the region of causes symptoms on the right side of the body.
the supramarginal gyrus in the inferior left parietal lobe. This area is
connected via associational pathways to the left premotor cortex.
The left premotor cortex is connected through the corpus callosum 4 QUICK CHECK 14-5
to the right premotor and motor areas. An injury that interrupts the 1. Why are there so many causes of hypertonia?
pathways between the left supramarginal gyrus and the premotor 2. How is chorea different from athetosis?
region produces a dyspraxia that involves the entire body. An injury 3. Why is paresis/paralysis a type of hypokinesia?
that disrupts the callosal pathways produces a dyspraxia of the left 4. What structures are involved in alterations of complex motor performance?
side of the body only.

TABLE 14-20 PYRAMIDAL VS. EXTRAPYRAMIDAL MOTOR SYNDROME

MANIFESTATIONS PYRAMIDAL MOTOR SYNDROME EXTRAPYRAMIDAL MOTOR SYNDROME
Unilateral movement Paralysis of voluntary movement Little or no paralysis of voluntary movement
Tendon reflexes Increased tendon reflexes Normal or slightly increased tendon reflexes
Babinski sign Present Absent
Involuntary movements Absence of involuntary movements Presence of tremor, chorea, athetosis, or dystonia
Muscle tone Spasticity in muscles (e.g., clasp-knife phenomenon) Plastic (equal throughout movement) rigidity or intermit-
tent (generalized but predominantly in flexors of limbs
and trunk) rigidity (cogwheel rigidity)
Hypertonia present in flexors of arms and extensors of legs Hypotonia, weakness and gait disturbances in cerebellar
disease
374 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics

DID YOU UNDERSTAND?

Alterations in Cognitive Systems 4. Supratentorial herniation involves temporal lobe and hippocampal gyrus
1. Full consciousness is an awareness of oneself and the environment with an shifting from the middle fossa to posterior fossa; transtentorial herniation
ability to respond to external stimuli with a wide variety of responses. involves a downward shift of the diencephalon through the tentorial notch;
2. Consciousness has two components: arousal and awareness. and shifting of the cingulate gyrus can occur under the falx cerebri.
3. An altered level of arousal occurs by diffuse bilateral cortical dysfunction, 5. The most common infratentorial herniation is a shift of the cerebellar tonsils
bilateral subcortical (reticular formation, brain stem) dysfunction, and local- through the foramen magnum.
ized hemispheric dysfunction. 6. Hydrocephalus comprises a variety of disorders characterized by an excess
4. An alteration in breathing pattern and level of consciousness reflect the of fluid within the ventricles, subarachnoid space, or both. Hydrocephalus
level of brain dysfunction. occurs because of interference with cerebrospinal fluid flow caused by
5. Pupillary changes reflect changes in level of brain stem function, drug increased fluid production or obstruction within the ventricular system or by
action, and response to hypoxia and ischemia. defective reabsorption of the fluid.
6. Abnormal eye movements, including nystagmus and divergent gaze, reflect
alterations in brain stem function. Alterations in Neuromotor Function
7. Level of brain function manifests by changes in generalized motor responses 1. Motor dysfunction may be characterized as alterations of motor tone, move-
or no responses. ment, and complex motor performance.
8. Loss of cortical inhibition associated with decreased consciousness pro-
duces abnormal flexor and extensor movements. Alterations in Tone
9. Cerebral death or irreversible coma represents permanent brain damage, 1. Hypotonia and hypertonia are the main categories of altered tone.
with an ability to maintain cardiac, respiratory, and other vital functions. 2. The four types of hypertonia are spasticity, gegenhalten, dystonia, and rigidity.
10. Brain death results from irreversible brain damage, with an inability to
Alterations in Movement
maintain internal homeostasis.
1. Paresis, paraplegia, hyperkinesias, and hypokinesia are the main catego-
11. Arousal returns in vegetative states, but awareness is absent.
ries of altered movement.
12. With a deficit in selective attention, mediated by midbrain, thalamus, and
2. Two subtypes of paresis/paralysis are described: upper motor neuron spas-
parietal lobe structures, the individual cannot focus on selective stimuli and
tic paresis/paralysis and lower motor neuron flaccid paresis/paralysis.
thus neglects those stimuli.
3. An upper motor neuron syndrome is characterized by paresis/paralysis,
13. In amnesia, some past memories are lost and new memories cannot be
hypertonia, and hyperreflexia.
stored.
4. Interruption of the pyramidal tract below the pons results in spinal shock.
14. Frontal areas mediate vigilance, detection, and working memory.
5. Lower motor neuron syndromes manifest by impaired voluntary and invol-
15. With vigilance deficits, the person cannot maintain sustained concentration.
untary movements and flaccid paralysis.
16. With detection deficits, the person is unmotivated and unable to set goals
6. Partial paralysis occurs with only partial loss of alpha motor neurons, and
and plan.
total paralysis is complete loss of alpha motor neurons. Loss of gamma
17. Seizures represent a sudden, chaotic discharge of cerebral neurons, with
motor neurons impairs muscle tone and decreases tendon reflexes.
transient alterations in brain function. Seizures may be generalized or focal
7. Amyotrophy (e.g., poliomyelitis) is a lower motor neuron syndrome involv-
and can result from cerebral lesions, biochemical disorders, trauma, or
ing the anterior horn cells, with loss of muscle tone and strength resulting
epilepsy.
in segmental paresis and hyporeflexia.
18. Data processing deficits include agnosias, dysphasias, acute confusional
8. Nuclear palsies involve damage to the cranial nerve nuclei.
states, and dementias.
9. Bulbar palsies involve cranial nerves IX, X, and XII.
19. Agnosias are defects of recognition and may be tactile, visual, or auditory.
10. Included in the category of hyperkinesias are chorea, athetosis, ballism,
They are caused by dysfunction in the primary sensory area or the interpre-
akathisia, tremor, and myoclonus.
tive areas of the cerebral cortex.
11. Huntington disease (chorea) is a rare hereditary disease involving the basal
20. Dysphasia (aphasia) is an impairment of comprehension or production of
ganglia and cerebral cortex. It is inherited as an autosomal dominant trait
language. Dysphasia may be expressive or receptive.
and commonly manifests between 25 and 45 years of age with involuntary
21. Acute confusional states are characterized chiefly by a loss of detec-
fragmentary movements.
tion and, in the case of delirium, an intense autonomic nervous system
12. The major pathologic feature of Huntington disease is severe degeneration
hyperactivity.
of the basal ganglia and the frontal cerebral cortex. The basal ganglia and the
22. Alzheimer disease is a chronic irreversible dementia that is related to
substantia nigra exhibit a depletion of gamma-aminobutyric acid (an inhibi-
altered production or failure to clear amyloid from the brain.
tory neurotransmitter) secreting neurons. This depletion leads to an excess
23. Frontotemporal dementias are rare early-onset degenerative diseases simi-
of dopaminergic activity that causes involuntary, fragmentary movements.
lar to Alzheimer disease.
13. Types of hypokinesia include akinesia, bradykinesia, and loss of associated
Alterations in Cerebral Hemodynamics movements.
1. Increased intracranial pressure may result from edema, excess cerebrospinal 14. Parkinson disease is a commonly occurring degenerative disorder of the
fluid, hemorrhage, or tumor growth. When intracranial pressure approaches basal ganglia (corpus striatum) involving degeneration of the dopamine-
arterial pressure, hypoxia and hypercapnia produce brain damage. secreting nigrostriatal pathway. The pathogenesis of Parkinson disease is
2. Cerebral edema is an increase in the fluid content of the brain resulting from unknown, but researchers suggest genetic, viral, and environmental toxins
infection, hemorrhage, tumor, ischemia, infarct, or hypoxia. as possible causes.
3. The shifting or herniation of brain tissue from one compartment to another
disrupts the blood flow of both compartments and damages brain tissue.
 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics 375

DID YOU UNDERSTAND?—cont’d

15. Degeneration of the dopaminergic nigrostriatal pathway causes dopamine 4. D isorders of expression include hypermimesis, hypomimesis, and dyspraxia/
depletion in the basal ganglia and excess of cholinergic activity in the cor- apraxia.
tex, basal ganglia, and thalamus. Tremor and rigidity are caused by the 5. Dyspraxia is an impairment of the conceptualization or execution of a com-
excess cholinergic activity. Progressive dementia may be associated with plex motor act.
an advanced stage of the disease.
16. Treatment of Parkinson disease is symptomatic, involving levodopa Extrapyramidal Motor Syndromes
(l-dopa), a precursor of dopamine. 1. Extrapyramidal motor syndromes include basal ganglia and cerebellar motor
syndromes.
Alterations in Complex Motor Performance 2. Basal ganglia disorders manifest by alterations in muscle tone and posture,
1. Alterations in complex motor performance include disorders of posture including rigidity, involuntary movements, and loss of postural reflexes.
(stance), disorders of gait, and disorders of expression. 3. Cerebellar motor syndromes result in loss of muscle tone, difficulty with
2. Disorders of posture include dystonic posture, decerebrate posture, basal coordination, and disorders of equilibrium and gait.
ganglion posture, and senile posture.
3. Disorders of gait include upper motor neuron gait, cerebellar gait, basal gan-
glion gait, and senile gait.

 KEY TERMS
•  cute confusional state (ACS)  357
A • D elirium (hyperkinetic confusional •  ocked-in syndrome  353
L
• Acute hydrocephalus  363 state)  357 • Memory  353
• Agnosia  356 • Dementia  357 • Memory disorder  353
• Akinesia  371 • Diplegia  366 • Metabolic alteration in arousal  348
• Alzheimer disease (AD) (dementia of • Dysphasia  357 • Minimally conscious state (MCS)  353
Alzheimer type [DAT], senile disease • Dyspraxia  373 • Mirror focus  355
complex)  359 • Dystonia  365 • Motor response  351
• Amnesia  353 • Dystonic movement  372 • Neglect syndrome  353
• Amyotrophy  368 • Dystonic posture  372 • Neurofibrillary tangle  359
• Anterograde amnesia  353 • Echolalia  357 • Noncommunicating hydrocephalus
• Aphasia  357 • Epilepsy  354 (internal hydrocephalus, intraventricular
• Apraxia  373 • Epileptogenic focus  355 hydrocephalus)  363
• Areflexia  368 • Executive attention deficit  353 • Normal-pressure hydrocephalus  364
• Arousal  347 • Expressive dysphasia  357 • Nuclear palsy  369
• Aura  355 • Extinction  353 • Oculomotor response  349
• Autoregulation  361 • Extrapyramidal motor syndrome  373 • Paralysis  365
• Awareness (content of thought)  353 • Fibrillation  368 • Paraparesis  366
• Basal ganglia motor syndrome  373 • Flaccid paresis/paralysis  368 • Paraplegia  366
• Basal ganglion gait  372 • Frontotemporal dementia (FTD) (Pick • Paresis  365
• Basal ganglion posture  372 disease)  361 • Parkinson disease  371
• Bradykinesia  371 • Gegenhalten (paratonia)  365 • Parkinsonism (Parkinson syndrome,
• Brain death (total brain death)  352 • Guillain-Barré syndrome  369 parkinsonian syndrome, paralysis
• Bulbar palsy  369 • Hemiparesis  366 agitans)  371
• Cerebellar gait  372 • Hemiplegia  366 • Paroxysmal dyskinesia  368
• Cerebellar motor syndrome  373 • Hiccup  351 • Pattern of breathing  349
• Cerebral blood flow (CBF)  361 • Huntington disease (HD)  369 • Persistent vegetative state  353
• Cerebral blood volume (CBV)  361 • Hydrocephalus  363 • Poliomyelitis  368
• Cerebral death (irreversible coma)  352 • Hyperkinesia  369 • Prodroma  356
• Cerebral edema  362 • Hypermimesis  373 • Progressive bulbar palsy  369
• Cerebral oxygenation  361 • Hypertonia  365 • Progressive spinal muscular atrophy  369
• Cerebral perfusion pressure (CPP)  361 • Hypokinesia  371 • Psychogenic alteration in arousal
• Clonic phase  355 • Hypokinetic confusional state (hyperac- (unresponsiveness)  348
• Communicating hydrocephalus  363 tive delirium)  357 • Pupillary change  349
• Consciousness  347 • Hypomimesis  373 • Pyramidal motor syndrome  366
• Convulsion  354 • Hypotonia  364 • Quadriparesis  366
• Cytotoxic (metabolic) edema  362 • Image processing  353 • Quadriplegia  366
• Decerebrate posture  372 • Increased intracranial pressure • Receptive dysphasia  357
• Decorticate posture (antigravity posture, (IICP)  361 • Retrograde amnesia  353
hemiplegic posture)  372 • Interstitial edema  363 • Rigidity  365
• Level of consciousness  349 • Scissors gait  372
376 CHAPTER 14  Alterations in Cognitive Systems, Cerebral Hemodynamics

  K E Y T E R M S—cont’d
• S econdary parkinsonism  371 • S pastic gait  372 • U pper motor neuron gait  372
• Seizure  354 • Spasticity  365 • Upper motor neuron paresis/
• Selective attention  353 • Spinal shock  366 paralysis  366
• Selective attention deficit  353 • Structural alteration in arousal  347 • Vasogenic edema  362
• Senile gait  372 • Tardive dyskinesia  369 • Vegetative state (VS)  347
• Senile posture  372 • Tonic phase  355 • Vomiting  351
• Sensory inattentiveness  353 • Transcortical dysphasia  357 • Yawning  351

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 CHAPTER

15
Disorders of the Central and
Peripheral Nervous Systems
and Neuromuscular Junction
Barbara J. Boss and Sue E. Huether

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Central Nervous System Disorders, 377 Peripheral Nervous System and Neuromuscular Junction
Traumatic Brain and Spinal Cord Injury, 377 ­Disorders, 399
Degenerative Disorders of the Spine, 387 Peripheral Nervous System Disorders, 399
Cerebrovascular Disorders, 388 Neuromuscular Junction Disorders, 399
Headache, 392 Tumors of the Central Nervous System, 400
Infection and Inflammation of the Central Nervous System, 393 Cranial Tumors, 400
Demyelinating Degenerative Disorders, 397 Spinal Cord Tumors, 404

Alterations in central nervous system (CNS) function are caused by In recent years, individuals with traumatic brain injury have
traumatic injury, vascular disorders, tumor growth, infectious and improved survival outcomes mostly because of advancements in
inflammatory processes, metabolic derangements (including those safety measures (e.g., passive seat restraints, air bags, protective head
arising from nutritional deficiencies and drugs or chemicals), and gear), reduced transport time to hospitals or trauma centers, and
degenerative processes. Alterations in peripheral nervous system func- improved on-scene medical management. Prevention and manage-
tion involve the nerve roots, a nerve plexus or the nerves themselves, ment of secondary and tertiary brain injuries also have improved
or the neuromuscular junction. outcomes.
The damage from brain trauma can be focal, affecting one area of
CENTRAL NERVOUS SYSTEM DISORDERS the brain, or diffuse (diffuse axonal injury), involving more than one
area of the brain. Usually both types of injuries are associated with an
Traumatic Brain and Spinal Cord Injury event of primary brain injury.
Brain Trauma Head injuries can be caused by closed (blunt) trauma and open
Major head injury is traumatic insult to the brain capable of produc- (penetrating) trauma. Closed (blunt) trauma is more common and
ing physical, intellectual, emotional, social, and vocational changes. involves either the head striking a hard surface or a rapidly moving
Those at highest risk for traumatic brain injury (TBI) are children 4 object striking the head. The dura remains intact, and brain tissues are
years and younger, adolescents 15 to 19 years, and adults 65 years and not exposed to the environment. Blunt trauma may result in both focal
older. Males have the highest incidence in every age group. Traumatic brain injuries and diffuse axonal injuries (Table 15-2). Open trauma
brain injury is highest among blacks and in lower- and median-income occurs when a break in (penetration of) the dura results in exposure
families. Most traumatic brain injuries are caused by transportation- of the cranial contents to the environment. The most common type
related events, falls, sports-related events, and violence.1 The causative of blunt trauma is mild (75% to 90%) and causes mild concussion
mechanisms are summarized in Table 15-1. and classical cerebral concussion (Table 15-3). Focal brain injury and

377
378 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems

TABLE 15-1 CAUSES OF BRAIN INJURIES

TYPE OF INJURY MECHANISM
Focal Brain Injury Localized injury from direct impact
Blunt trauma Closed injury
Coup Injury is directly below site of forceful impact
Contrecoup Injury is on opposite side of brain from site of forceful impact
Extradural (epidural) hematoma Vehicular accidents, minor falls, sporting accidents
Subdural hematoma Vehicular accidents or falls, especially in elderly persons or persons with chronic alcohol abuse
Intracerebral hemorrhage; subarachnoid hemorrhage Contusions caused by forceful impact, usually vehicular accidents or long distance falls
Compound fracture Objects strike head with great force or head strikes object forcefully; temporal blows, occipital
blows, upward impact of cervical vertebrae (basilar skull fracture)
Penetrating trauma Open injury
Missiles (bullets) or sharp projectiles (knives, ice picks, axes, screwdrivers)
Diffuse Brain Injury (diffuse axonal injury) Traumatic shearing forces; tearing of axons from twisting and rotational forces with injury over
widespread area
Moving head strikes hard, unyielding surface or moving object strikes stationary head; vehicular
accidents (occupant or pedestrian); torsional head motion

TABLE 15-2 SEVERITY OF TRAUMA RELATED TO TRAUMA STATE INDUCED AND ONSET

AND PERSISTENCE OF CLINICAL MANIFESTATIONS
TRAUMA STATE INDUCED
PERSISTENCE
SEVERITY DIFFUSE AXONAL ONSET OF CLINICAL OF DAI CLINICAL
OF TRAUMA FOCAL INJURY INJURY (DAI) MANIFESTATIONS MANIFESTATIONS
Mild blunt trauma Mild concussion Immediate Hours to days
Moderate blunt trauma Classic cerebral concussion Immediate Up to 6 months or longer
Paraplegia (associated with injury to Immediate
top of head)
Blindness (associated with occipital Immediate
injury)
Delayed development of unrespon- Delayed
siveness (vasomotor or vasovagal
syncopal episode)
Severe blunt trauma Mild DAI Immediate Recovery in days to weeks
Moderate DAI Immediate Residual manifestation
Severe DAI Immediate Permanent severe
­disability
Acute epidural hemorrhage Immediate to delayed (2-3 hr)
Acute contusional swelling Delayed onset (few hours after
injury)
Acute subdural hematoma Delayed onset (few hours to 1
week after injury)
Subacute subdural hematoma* Delayed onset (1 to few weeks)
Subdural hygroma (fluid accumulation) Delayed onset
Traumatic cerebral hemorrhage* Delayed onset (as late as 1
week after injury)

*May be seen after moderate head injury, especially in elderly people.

diffuse axonal injury (DAI) each account for half of all injuries. Focal neural injury, primary glial injury, and vascular responses. Secondary
brain injury accounts for more than two thirds of head injury deaths; injury is an indirect consequence of the primary injury and includes
DAI accounts for fewer than one third. However, more severely dis- a cascade of cellular and molecular events (i.e., altered cerebral blood
abled survivors, including those in an unresponsive state or reduced flow, hypoxia, ischemia, inflammation, cerebral edema, increased
level of consciousness, have DAI. intracranial pressure, and herniation) that cause further neural injury
Three mechanisms produce brain damage: primary, secondary, and or death. Tertiary injury develops days or months later as a conse-
tertiary injury. Primary injury is caused by the impact and involves quence of primary and secondary injury and can result from systemic
 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems 379

1
TABLE 15-3 CATEGORIES OF DIFFUSE 2
BRAIN INJURY b

TYPE OF INJURY MECHANISM

Mild concussion Temporary axonal disturbance affecting at-
tentional and memory systems; consciousness a b a
not lost
Grade I Confusion and disorientation with amnesia c
(momentary)
Grade II Momentary confusion and retrograde amnesia
after 5-10 min
Grade III Confusion and retrograde amnesia from impact;
also anterograde amnesia
Classic cerebral Same as grade IV mild concussion—diffuse ce-
­concussion rebral disconnection from brain stem reticular
activating system; physiologic neurologic dys-
FIGURE 15-1  Coup and Contrecoup Head Injury After Blunt
function without substantial anatomic disrup-
Trauma. 1, Coup injury: impact against object; a, site of impact
tion; immediate loss of consciousness lasting and direct trauma to brain; b, shearing of subdural veins; c, trauma
less than 6 hr; retrograde and anterograde to base of brain. 2, Contrecoup injury: impact within skull; a, site
amnesia (post-traumatic); may be uncompli- of impact from brain hitting opposite side of skull; b, shearing forces
cated or complicated through brain. These injuries occur in one continuous motion—the
Diffuse axonal injury Prolonged traumatic coma (longer than 6 hr) head strikes the wall (coup) and then rebounds (contrecoup). (Modi-
(DAI) fied from Rudy EB: Advanced neurological and neurosurgical nurs-
Mild Post-traumatic coma lasts 6-24 hr; persistent ing, St Louis, 1984, Mosby.)
residual cognitive, psychologic, and sensorimo-
tor deficits; rare—only 8% of severe head
injuries; reversible memory loss, confusion, is concentrated into a smaller area. Brain edema forms around and
disorientation in damaged neural tissues, contributing to the increasing intracra-
Moderate Widespread physiologic impairment through- nial pressure (see Chapter 14). Within the contused areas, infarction,
out cerebral cortex and diencephalon; coma necrosis, multiple hemorrhages, and edema occur. The tissue has a
longer than 24 hr; tearing of axons in both pulpy quality. The maximal effects of these injuries peak 18 to 36 hours
hemispheres; prolonged incomplete recovery after severe head injury.
among survivors with headaches, nausea, and Contusions are found most commonly in the frontal lobes, particu-
memory difficulty; common—20% of severe larly at the poles and along the inferior orbital surfaces; in the temporal
head injuries lobes, especially at the anterior poles and along the inferior surface;
Severe Formerly called primary brain stem injury or and at the frontotemporal junction. They cause changes in attention,
brain stem contusion; prolonged coma—days memory, executive attention functions (see Chapter 14), affect, emo-
to months; irreversible coma or death; severe tion, and behavior. Less commonly, contusions occur in the parietal
mechanical disruption of axons in both hemi- and occipital lobes. Focal cerebral contusions are usually superficial,
spheres, diencephalon, and brain stem; 16% of involving just the gyri. Hemorrhagic contusions may coalesce into a
severe head injuries large confluent intracranial hematoma.
A contusion may be evidenced by immediate loss of consciousness
(generally accepted to last no longer than 5 minutes), loss of reflexes
(individual falls to the ground), transient cessation of respiration,
complications, such as pneumonia, fever, infections, and immobility, brief period of bradycardia, and decrease in blood pressure (lasting 30
that contribute to further brain injury. seconds to a few minutes). Increased cerebrospinal fluid (CSF) pres-
Primary brain injury sure and electrocardiogram (ECG) and electroencephalogram (EEG)
Focal brain injury. Focal brain injuries are specific, grossly changes occur on impact. Vital signs may stabilize to normal values in
observable brain lesions that occur in a precise location (e.g., corti- a few seconds; reflexes then return and the person regains conscious-
cal contusions, epidural hemorrhage, subdural hematoma, intracere- ness over minutes to days. Residual deficits may persist and some per-
bral hematoma, and open brain trauma). The force of impact typically sons never regain a full level of consciousness.
produces contusions (blood leaking from injured blood vessels) from Evaluation includes a complete history and physical examination.
injury to the vault, vessels, and supporting structures that, in turn, pro- Skull and spinal x-ray films are often taken and a computed tomog-
duce epidural hemorrhage and subdural and intracerebral hematomas. raphy (CT) scan or magnetic resonance imaging (MRI) may be per-
The mechanisms of injury are depicted in Figure 15-1. formed. Large contusions and lacerations with hemorrhage may be
Focal brain injury results from compression of the skull at the surgically excised. Treatment is otherwise directed at controlling intra-
point of impact and rebound effects. The injury may be coup or con- cranial pressure and managing symptoms.
trecoup (see Figure 15-1 and Table 15-1) and produces contusions Extradural hematomas (bleeding between the dura mater and
(brain bruising). The severity of contusion varies with the amount of the skull [i.e., epidural hematomas, epidural hemorrhages]) repre-
energy transmitted by the skull to underlying brain tissue. The smaller sent 1% to 2% of major head injuries and occur in all age groups, but
the area of impact, the greater the severity of injury because the force most commonly in those 20 to 40 years old. An artery is the source of
380 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems

Anterior hematoma, the existing subdural space gradually fills with blood.
A vascular membrane forms around the hematoma in approximately
2 weeks. Further enlargement may take place.
In acute, rapidly developing subdural hematomas, the expanding
Epidural Subdural clots directly compress the brain. As intracranial pressure rises, bleed-
hematoma hematoma ing veins are compressed. Thus, bleeding is self-limiting, although
cerebral compression and displacement of brain tissue can cause tem-
poral lobe herniation.
An acute subdural hematoma classically begins with headache,
drowsiness, restlessness or agitation, slowed cognition, and confu-
sion. These symptoms worsen over time and progress to loss of con-
sciousness, respiratory pattern changes, and pupillary dilation (i.e., the
symptoms of temporal lobe herniation). Homonymous hemianopia
(defective vision in either the right or the left field [see Figure 13-10]),
disconjugate gaze, and gaze palsies also may occur.
Of those individuals affected by chronic subdural hematomas,
80% have chronic headaches and tenderness over the hematoma on
palpation. Most persons appear to have a progressive dementia with
Intracerebral generalized rigidity (paratonia). Chronic subdural hematomas require
hematoma a craniotomy to evacuate the gelatinous blood. Percutaneous drain-
age for chronic subdural hematomas has proven successful. However,
Posterior reaccumulation often occurs unless the surrounding membrane is
FIGURE 15-2  Brain Hematomas. removed.
Intracerebral hematomas (bleeding within the brain) occur in 2%
to 3% of persons with head injuries, may be single or multiple, and are
bleeding in 85% of extradural hematomas; 15% result from injury to associated with contusions. Although most commonly located in the
the meningeal vein or dural sinus (Figure 15-2). The temporal fossa is frontal and temporal lobes, they may occur in the hemispheric deep
the most common site of extradural hematoma caused by injury to the white matter. Penetrating injury or shearing forces traumatize small
middle meningeal artery or vein. The temporal lobe shifts medially, blood vessels. The intracerebral hematoma then acts as an expanding
precipitating uncal (see Figure 14-10) and hippocampal gyrus hernia- mass, increasing intracranial pressure, compressing brain tissues, and
tion through the tentorial notch. Extradural hemorrhages are found causing edema (see Figure 15-2). Delayed intracerebral hematomas
occasionally in the subfrontal area, especially in the young and elderly may appear 3 to 10 days after the head injury.
populations, caused by injury to the anterior meningeal artery or a Intracerebral hematomas cause a decreasing level of consciousness.
venous sinus, and in the occipital-suboccipital area, resulting in her- Coma or a confusional state from other injuries, however, can make
niation of the posterior fossa contents through the foramen magnum. the cause of this increasing unresponsiveness difficult to detect. Con-
Individuals with classic temporal extradural hematomas lose con- tralateral hemiplegia also may occur and, as intracranial pressure rises,
sciousness at injury; one third of those affected then become lucid for temporal lobe herniation may appear. In delayed intracerebral hema-
a few minutes to a few days (if a vein is bleeding). As the hematoma toma, the presentation is similar to that of a hypertensive brain hem-
accumulates, a headache of increasing severity, vomiting, drowsiness, orrhage—sudden, rapidly progressive decreased level of consciousness
confusion, seizure, and hemiparesis may develop. Because temporal with pupillary dilation, breathing pattern changes, hemiplegia, and
lobe herniation occurs, the level of consciousness is rapidly lost, with bilateral positive Babinski reflexes.
ipsilateral pupillary dilation and contralateral hemiparesis. History and physical examination help to establish the diagnosis
A CT scan or MRI usually is needed to diagnose extradural hema- and CT scan, MRI, and cerebral angiography confirm it. Evacuation
toma. The prognosis is good if intervention is initiated before bilateral of a singular intracerebral hematoma has only occasionally been help-
dilation of the pupils occurs. Extradural hematomas are almost always ful, mostly for subcortical white matter hematomas. Otherwise, treat-
medical emergencies requiring surgical ligation of bleeding vessels. ment is directed at reducing the intracranial pressure and allowing the
Subdural hematomas (bleeding between the dura mater and the hematoma to reabsorb slowly.
brain) arise in 10% to 20% of persons with traumatic brain injury. Open (penetrating) brain trauma (trauma that penetrates the
Acute subdural hematomas develop rapidly, commonly within hours, dura mater) produces discrete (focal) injuries and includes compound
and usually are located at the top of the skull (the cerebral convexi- skull fractures and missile injuries. A compound skull fracture opens
ties). Bilateral hematomas occur in 15% to 20% of persons. Subacute a communication between the cranial contents and the environment
subdural hematomas develop more slowly, often over 48 hours to 2 and should be investigated whenever lacerations of the scalp, tympanic
weeks. Chronic subdural hematomas (commonly found in elderly per- membrane, sinuses, eye, or mucous membranes are present. Such frac-
sons and persons who abuse alcohol and have some degree of brain tures may involve the cranial vault or the base of the skull (basilar skull
atrophy with a subsequent increase in extradural space) develop over fracture). Bone fragments cause tangential injury (injury caused by
weeks to months. Bridging veins tear, causing both rapidly and sub- direct contact) and, occasionally, penetrating injuries. Cranial nerves
acutely developing subdural hematomas, although torn cortical veins may be damaged with a basilar skull fracture.
or venous sinuses and contused tissue also may be the source. These Missiles include bullets, rocks, shell fragments, knives, and blunt
subdural hematomas act like expanding masses, increasing intra- instruments. The mechanisms of injury are crush injury (lacera-
cranial pressure that eventually compresses the bleeding vessels (see tion and crushing of whatever the missile touches) and stretch injury
­Figure 15-2). Brain herniation can result. With a chronic subdural (blood vessels and nerves damaged without direct contact as a result
 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems 381

of stretching). The tangential injury is to the coverings and the brain several minutes, possibly with amnesia for events preceding the trauma
(scalp and brain lacerations) and may also include skull fractures and (retrograde amnesia). Anterograde amnesia (lack of memories) may
meningeal or cerebral lacerations. When driven into the brain sub- also exist transiently. Persons may experience head pain and complain
stance, projectiles and debris from scalp and skull injury produce a of nervousness and “not being themselves” for up to a few days.
penetrating brain injury. In classic cerebral concussion, consciousness is lost for up to 6
Most persons lose consciousness with open-head injury. The depth hours and reflexes fail, causing falls. Reflexes are regained as respon-
and duration of the coma are related to the location of injury, extent siveness returns. Transiently, breathing stops, bradycardia occurs, and
of damage, and amount of bleeding. Open-head injury often requires blood pressure falls. Vital signs quickly stabilize to within normal lim-
débridement of the traumatized tissues to prevent infection and to its. Retrograde and anterograde amnesia exist (see Chapter 14), along
remove blood clots, thereby reducing intracranial pressure. Intra- with a confusional state lasting for hours to days. Head pain, nausea,
cranial pressure also is managed with steroids, dehydrating agents, fatigue, attentional and memory system impairments (inability to con-
osmotic diuretics, or a combination of these drugs. Broad-spectrum centrate and forgetfulness), and mood and affect changes (nervous-
antibiotics are administered. ness, anxiety reactions, depression, irritability, fatigability, insomnia)
A compound fracture may be diagnosed through physical examina- occur. A postconcussive syndrome, including headache, nervousness
tion, skull x-ray films, or both. Basilar skull fracture is determined on or anxiety, irritability, insomnia, depression, inability to concentrate,
the basis of clinical findings. Skull x-rays often do not demonstrate the forgetfulness, and fatigability, may exist. Treatment entails reassurance
fracture, although intracranial air or air in the sinuses on x-ray film, and symptomatic relief in addition to 24 hours of close observation.
CT scan, or MRI is indirect evidence of a basilar skull fracture. In mild diffuse axonal injury, 30% of persons display decerebrate
Bed rest and close observation for meningitis and other complica- or decorticate posturing and may experience prolonged periods of stu-
tions are prescribed for a basilar skull fracture. Prophylactic antibiotics por or restlessness (see Figure 14-6).
are controversial and may or may not be given. In moderate diffuse axonal injury, the score on the Glasgow Coma
Diffuse brain injury. Diffuse brain injury (diffuse axonal injury Scale (GCS) is 4 to 8 initially and 6 to 8 by 24 hours. Thirty-five percent
[DAI]) involves widespread areas of the brain. Damage to delicate of victims have transitory decerebration or decortication, with uncon-
axonal fibers and white matter tracts that project to the cerebral cor- sciousness lasting days or weeks. On awakening, the person is confused
tex cause concussion. Mechanical effects from shaking (high levels of and suffers a long period of post-traumatic anterograde and retro-
acceleration and deceleration [whiplash]) and rotational and twisting grade amnesia. There is often permanent deficit in memory, attention,
movements are the primary mechanisms of injury, producing strains abstraction, reasoning, problem solving, executive functions, vision or
and distortions within the brain. The freely moving head is attached to perception, and language. Mood and affect changes range from mild
the neck, allowing rotational forces to trigger shearing forces on brain to severe.
tissues. The most severe axonal injuries are located more peripheral to In severe diffuse axonal injury, the person experiences immediate
the brain stem, causing extensive cognitive and affective impairments, autonomic dysfunction that disappears in a few weeks. Increased intra-
as seen in survivors of traumatic brain injury from vehicular crashes. cranial pressure appears 4 to 6 days after injury. Pulmonary complica-
Axonal damage reduces the speed of informational processing and tions occur often. Profound sensorimotor and cognitive system deficits
responding and disrupts the individual’s attention span. are present. Severely compromised coordinated movements and verbal
Pathophysiologically, axonal damage can be seen only with an elec- and written communication skills, inability to learn and reason, and
tron microscope and involves numerous axons, either alone or in con- failure to modulate behavior are found also.
junction with actual tissue tears. Areas where axons and small blood High-resolution CT scan and MRI assist in the diagnosis of focal
vessels are torn appear as small hemorrhages, particularly in the cor- and diffuse injuries. Medical management must address endocrine and
pus callosum and dorsolateral quadrant of the rostral brain stem at the metabolic derangements. Early and late seizures must be prevented
superior cerebellar peduncle. More and more damaged axons are vis- and controlled. Mortality associated with acute head injury is signifi-
ible 12 hours to several days after the injury (secondary brain injury). cantly higher in persons treated with corticosteroids within 8 hours of
The severity of diffuse injury correlates with how much shearing force the injury.2,3
was applied to the brain stem. DAI is not associated with intracranial Secondary brain trauma. Secondary brain trauma is the result of
hypertension immediately after injury; however, acute brain swelling both systemic and intracranial processes and is an indirect result of
caused by increased intravascular blood flow within the brain, vaso- primary brain trauma. Systemic hypotension, hypoxia, anemia, and
dilation, and increased cerebral blood volume is seen often and can hypercapnia and hypocapnia contribute to secondary brain insults.
result in death. Mechanisms of secondary injury include cerebral edema, increased
Several categories of diffuse brain injury exist: mild concussion, intracranial pressure (IICP), decreased cerebral perfusion pressure,
classic concussion, mild DAI, moderate DAI, and severe DAI (see ischemia, and brain herniation. Cellular and molecular brain damage
Table 15-2). DAI has the following consequences: from the effects of primary injury develops hours to days later. Astro-
1. Physical consequences: spastic paralysis, peripheral nerve injury, cyte swelling and proliferation alter the blood-brain barrier and cause
swallowing disorders, dysarthria, visual and hearing impairments, IICP. Release of excitatory neurotransmitters, such as glutamate and
taste and smell deficits aspartate, cause neuronal depolarization and alter postsynaptic recep-
2. Cognitive deficits: disorientation and confusion, short attention tor function. A hypermetabolic state, mitochondrial influx of calcium,
span, memory deficits, learning difficulties, dysphasia, poor judg- fluctuations in sodium and potassium levels, poor perfusion, influx of
ment, perceptual deficits inflammatory mediators, and mitochondrial failure all contribute to
3. Behavioral manifestations: agitation, impulsiveness, blunted affect, cytotoxic edema, axonal swelling, and neuronal death.4,5
social withdrawal, depression The management of secondary brain trauma is related to preven-
Mild concussion is characterized by immediate but transitory clini- tion and includes removal of hematomas and management of hypo-
cal manifestations. CSF pressure rises, and ECG and EEG changes occur tension, hypoxemia, anemia, intracranial pressure, replacement fluids,
without loss of consciousness. The initial confusional state lasts for 1 to body temperature, and ventilation. Research is in progress to find
382 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems

specific pharmacologic interventions and neuroprotective agents that ligaments, and joints of the vertebral column may be damaged through
limit the progression of secondary injury.6,7 fracture and compression of one or more elements, dislocation of ele-
ments, or both fracture and dislocation. Vertebral injuries can be classi-

4 QUICK CHECK 15-1

fied as (1) simple fracture—a single break usually affecting transverse or
spinous processes; (2) compressed (wedged) vertebral fracture—­vertebral
1. How is a concussion different from a contusion? body compressed anteriorly; (3) comminuted (burst) fracture—­vertebral
2. Why do extradural, subdural, and intracerebral hematomas act like expand- body shattered into several fragments; and (4) dislocation.
ing masses? The vertebrae fracture readily with both direct and indirect trauma.
3. Why is head motion the principal causative mechanism of diffuse brain When the supporting ligaments are torn, the vertebrae move out of
injury? alignment and dislocations occur. A horizontal force moves the ver-
tebrae straight forward; if the individual is in a flexed position at the
time of injury, the vertebrae are then angulated. Flexion and extension
Spinal Cord Trauma injuries may result in dislocations. (Bone, ligament, and joint injuries
Each year 12,000 persons experience serious spinal cord injury. Male are presented in Table 15-4.)
gender and ages 16 to 30 years are strong risk factors. Motor vehicle Vertebral injuries in adults occur most often at vertebrae C1 to C2
accidents are the leading cause of injury (41%); falls are the next most (cervical), C4 to C7, and T10 (thoracic) to L2 (lumbar) (see Figure
common cause (27%) followed by violence and sports activities.8 12-10), the most mobile portions of the vertebral column. The cord
Elderly people are particularly at risk for minor trauma that results in occupies most of the vertebral canal in the cervical and lumbar regions,
serious spinal cord injury because of preexisting degenerative vertebral so it is easily injured. (Injuries to the cord are summarized in Table 15-5.)
disorders.
Crushed vertebral
PATHOPHYSIOLOGY  Spinal cord injuries most commonly occur body with cord
because of vertebral injuries that result from acceleration, deceleration, or compression
deformation forces usually applied at a distance. These forces compress
the tissues, pull or exert traction (tension) on the tissues, or shear tissues
so that they slide into one another (Figures 15-3 to 15-6). The bones,

Compression
Osteophytes fracture
without cord
compression

Disruption of
Spinal cord
intervertebral
compression
disks

Ligament
compression
FIGURE 15-5  Axial Compression Injuries of the Spine. In axial
FIGURE 15-3  Hyperextension Injuries of the Spine. Hyperexten- compression injuries of the spine, the spinal cord is contused
sion injuries of the spine can result in fracture or nonfracture injuries directly by retropulsion of bone or disk material into the spinal canal.
with spinal cord damage.

Stretched
ligaments

Wedge
fracture

FIGURE 15-4  Flexion Injury of the Spine. Hyperflexion produces

translation (subluxation) of vertebrae that compromises the cen-
tral canal and compresses spinal cord parenchyma or vascular
structures. FIGURE 15-6  Flexion-Rotation Injuries of the Spine.
 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems 383

TABLE 15-4 MECHANISMS OF VERTEBRAL INJURY INVOLVING BONE, LIGAMENTS,

AND JOINTS
MECHANISM LOCATION
OF INJURY LOCATION OF VERTEBRAL INJURY FORCES OF INJURY OF INJURY
Hyperextension Fracture and dislocation of posterior elements, Results from forces of acceleration-deceleration and s­ udden Cervical area
such as spinous processes, transverse processes, reduction in anteroposterior diameter of spinal cord
laminae, pedicles, or posterior ligaments
Hyperflexion Fracture or dislocation of vertebral bodies, disks, or Results from sudden and excessive force that propels neck Cervical area
ligaments forward or causes an exaggerated lateral movement of neck
to one side
Vertical compression Shattering fractures Results from a force applied along an axis from top of cranium T12 to L2
(axial loading) through vertebral bodies
Rotational forces Rupture support ligaments in addition to producing Adds shearing force to acceleration forces Cervical area
(­flexion-rotation) fractures

TABLE 15-5 SPINAL CORD INJURIES

INJURY DESCRIPTION
Cord concussion Results in temporary disruption of cord-mediated functions
Cord contusion Bruising of neural tissue causes swelling and temporary loss of cord-mediated functions
Cord compression Pressure on cord causes ischemia to tissues; must be relieved (decompressed) to prevent permanent damage to spinal cord
Laceration Tearing of neural tissues of spinal cord; may be reversible if only slight damage sustained by neural tissues; may result in
permanent loss of cord-mediated functions if spinal tracts are disrupted
Transection Severing of spinal cord causes permanent loss of function
Complete All tracts in spinal cord are completely disrupted; all cord-mediated functions below transection are completely and
­permanently lost
Incomplete Some tracts in spinal cord remain intact, together with functions mediated by these tracts; has potential for recovery
although function is temporarily lost
Preserved sensation only Some demonstrable sensation below level of injury
Preserved motor nonfunctional Preserved motor function without useful purpose; sensory function may or may not be preserved
Preserved motor functional Preserved voluntary motor function that is functionally useful
Hemorrhage Bleeding into neural tissue as a result of blood vessel damage; usually no major loss of function
Damage or obstruction of spinal Causes local ischemia
blood supply

With injury, microscopic hemorrhages appear in the central gray CLINICAL MANIFESTATIONS  Normal activity of the spinal cord
matter and pia-arachnoid, increasing in size until the entire gray mat- cells at and below the level of injury ceases because of loss of the con-
ter is hemorrhagic and necrotic. Edema in the white matter occurs, tinuous tonic discharge from the brain or brain stem and inhibition
impairing the microcirculation of the cord. Localized hemorrhaging of suprasegmental impulses immediately after cord injury, thus caus-
and edema are followed by reduced vascular perfusion and develop- ing spinal shock. In spinal shock, reflex function is completely lost
ment of ischemic areas. Oxygen tension in the tissue at the injury site in all segments below the lesion. This condition involves all skeletal
is decreased. The microscopic hemorrhages and edema are maximal at muscles; bladder, bowel, and sexual function; and autonomic control.
the level of injury and two cord segments above and below it. Severe impairment below the level of the lesion is obvious; it includes
Cellular and subcellular alterations and tissue necrosis occur. Cord paralysis and flaccidity in muscles, absence of sensation, loss of bladder
swelling increases the individual’s degree of dysfunction, making it and rectal control, transient drop in blood pressure, and poor venous
hard to distinguish functions permanently lost from those temporar- circulation. The condition also results in disturbed thermal control
ily impaired. In the cervical region, cord swelling may be life-threat- because the sympathetic nervous system is damaged. The hypothala-
ening because it may impair the diaphragm function (phrenic nerves mus cannot regulate body heat through vasoconstriction and increased
exit at C3 to C5) and vegetative functions (mediated by the medulla metabolism; therefore the individual assumes the temperature of the
oblongata). air (poikilothermia).
Circulation in the white matter tracts of the spinal cord returns to Spinal shock generally lasts 7 to 20 days, with a range of a few days
normal in about 24 hours, but gray matter circulation remains altered. to 3 months. It terminates with the reappearance of reflex activity,
Phagocytes appear 36 to 48 hours after injury, and microglia proliferate hyperreflexia, spasticity, and reflex emptying of the bladder.
with altered astrocytes. Red blood cells then begin to disintegrate, and Loss of motor and sensory function depends on the level of injury.
resorption of hemorrhages begins. Degenerating axons are engulfed by All motor, sensory, reflex, and autonomic functions cease below any
macrophages in the first 10 days after injury. The traumatized cord is transected area and also may cease below concussive, contused, com-
replaced by acellular collagenous tissue, usually in 3 to 4 weeks. Menin- pressed, or ischemic areas. Table 15-6 summarizes the clinical manifes-
ges thicken as part of the scarring process. tations of spinal cord injury.
384 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems

TABLE 15-6 CLINICAL MANIFESTATIONS OF SPINAL CORD INJURY

STAGE MANIFESTATIONS
Spinal Shock Stage Loss of motor function
Complete spinal cord transection 1. Quadriplegia with injuries of cervical spinal cord
2. Paraplegia with injuries of thoracic spinal cord
Muscle flaccidity
Loss of all reflexes below level of injury
Loss of pain, temperature, touch, pressure, and proprioception below level of injury
Pain at site of injury caused by zone of hyperesthesia above injury
Atonic bladder and bowel
Paralytic ileus with distention
Loss of vasomotor tone in lower body parts; low and unstable blood pressure
Loss of perspiration below level of injury
Loss or extreme depression of genital reflexes such as penile erection and bulbocavernous reflex
Dry and pale skin; possible ulceration over bony prominences
Respiratory impairment
Partial spinal cord transection Asymmetric flaccid motor paralysis below level of injury
Asymmetric reflex loss
Preservation of some sensation below level of injury
Vasomotor instability less severe than that seen with complete cord transection
Bowel and bladder impairment less severe than that seen with complete cord transection
Preservation of ability to perspire in some portions of body below level of injury
Brown-Séquard syndrome (associated with penetrating injuries, hyperextension and flexion, locked facets, and compres-
sion fractures)
1. Ipsilateral paralysis or paresis below level of injury
2. Ipsilateral loss of touch, pressure, vibration, and position sense below level of injury
3. Contralateral loss of pain and temperature sensations below level of injury
Central cervical cord syndrome (acute cord compression between bony bars or spurs anteriorly and thickened ligamentum
flavum posteriorly associated with hyperextension)
1. Motor deficits in upper extremities, especially hands, more dense than in lower extremities
2. Varying degrees of bladder dysfunction
Burning hand syndrome (variant of central cord syndrome; in 50% of cases an underlying spine fracture/dislocation is
present)
1. Severe burning paresthesias and dysesthesias in the hands or feet
Anterior cord syndrome (compromise of anterior spinal artery by occlusion or pressure effect of disk)
1. Loss of motor function below level of injury
2. Loss of pain and temperature sensations below level of injury
3. Touch, pressure, position, and vibration senses intact
Posterior cord syndrome (associated with hyperextension injuries with fractures of vertebral arch)
1. Impaired light touch and proprioception
Conus medullaris syndrome (compression injury at T12 from disk herniation or burst fracture of body of T12)
1. Flaccid paralysis of legs
2. Flaccid paralysis of anal sphincter
3. Variable sensory deficits
Cauda equina syndrome (compression of nerve roots below L1 caused by fracture and dislocation of spine or large pos-
terocentral intervertebral disk herniation)
1. Lower extremity motor deficits
2. Variable sensorimotor dysfunction
3. Variable reflex dysfunction
4. Variable bladder, bowel, and sexual dysfunction
Syndrome of neuropraxia (postathletic injury, associated with congenital spinal stenosis)
1. Dramatic but transient neurologic deficits including quadriplegia
Horner syndrome (injury to preganglionic sympathetic trunk or postganglionic sympathetic neurons of superior cervical
ganglion)
1. Ipsilateral pupil smaller than contralateral pupil
2. Sunken ipsilateral eyeball
3. Ptosis of affected eyeball
4. Lack of perspiration on ipsilateral side of face
 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems 385

TABLE 15-6 CLINICAL MANIFESTATIONS OF SPINAL CORD INJURY—cont’d

STAGE MANIFESTATIONS
Heightened Reflex Activity Stage Emergence of Babinski reflexes, possibly progressing to a triple reflex; possible development of still later flexor spasms
Reappearance of ankle and knee reflexes, which become hyperactive
Contraction of reflex detrusor muscle leading to urinary incontinence
Appearance of reflex defecation
Mass reflex with flexion spasms, profuse sweating, piloerection, and bladder and occasional bowel emptying may be
evoked by autonomic stimulation of skin or from full bladder
Episodes of hypertension
Defective heat-induced sweating
Eventual development of extensor reflexes, first in muscles of hip and thigh, later in leg
Possible paresthesias below level of transection: dull, burning pain in lower back, abdomen, buttocks, and perineum

Autonomic hyperreflexia (dysreflexia) may occur after spinal paroxysmal hypertension (up to 300 mm Hg, systolic), a pounding
shock resolves. The syndrome is associated with a massive, uncom- headache, blurred vision, sweating above the level of the lesion with
pensated cardiovascular response to stimulation of the sympathetic flushing of the skin, nasal congestion, nausea, piloerection caused by
nervous system (Figure 15-7). The condition is life-threatening pilomotor spasm, and bradycardia (30 to 40 beats/min). The symp-
and requires immediate treatment. Individuals most likely to be toms may develop singly or in combination (syndrome) and often are
affected have lesions at the T6 level or above. Characteristics include associated with a distended bladder or rectum.

4 3
Corticospinal tracts Brain interprets sensory
carry motor impulses inputs; course of action
to appropriate muscles determined
Empty bladder
Remove painful stimulus, etc.

Spinal 2
ganglion Spinothalamic tracts
carry the impulses
Gray to brain
ramus

Splanchnic nerve
White
ramus Vagus nerve
Spinal
ganglion
1
Visceral distention
Bowel
STIMULUS Bladder
Abdomen
5 Pain receptors
Motor output Skin
Empty bladder Glans penis
Remove painful stimulus, etc. Uterus
Eliminates stimulus
to sensory nerve

A
FIGURE 15-7  Autonomic Hyperreflexia. A, Normal response pathway.
Continued
386 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems

5
Ninth cranial nerve stimulated by carotid;
receptors send message to vasomotor
center of medulla, vagus nerve
stimulated; impulse sent to SA node;
results in bradycardia

Carotid
sinuses 4
Glossopharyngeal Increased blood pressure
nerve (IX) stimulates carotid sinus
receptors

Medulla Carotid sinus

6 nerve
Autonomic response to Vagus nerve (X)
hypertension down to
level of cord lesion
SA node
Arterial dilation
Flushed skin
Headache
Sweating

3
Lesion Reflex stimulus to
major sympathetic
outflow resulting in:
Vasospasm
Hypertension
Pallor of skin
Pilomotor spasms
2
Spinothalamic tracts
carry sensory impulses
to level of lesion
(T6 and above)

1
Visceral distention
Bowel
STIMULUS Bladder
Abdomen
Pain receptors
Skin
Glans penis
Uterus
B

FIGURE 15-7, cont’d  B, Autonomic dysreflexia pathway. SA, Sinoatrial. (Modified from Rudy EB:
Advanced neurological and neurosurgical nursing, St Louis, 1984, Mosby.)

In autonomic hyperreflexia, sensory receptors below the level of or bowel emptying usually relieves the syndrome, and drugs such as
the cord lesion are stimulated. The intact autonomic nervous system phenoxybenzamine may facilitate this result.
reflexively responds with an arteriolar spasm that increases blood
pressure. Baroreceptors in the cerebral vessels, the carotid sinus, and EVALUATION AND TREATMENT  Diagnosis of spinal cord injury
the aorta sense the hypertension and stimulate the parasympathetic is based on physical examination, radiologic examination, CT scan,
system. The heart rate decreases, but the visceral and peripheral ves- MRI, and myelography. For a suspected or confirmed vertebral
sels do not dilate because efferent impulses cannot pass through the fracture or dislocation, regardless of the presence or absence of
cord. spinal cord injury, the immediate intervention is immobilization
The most common cause is a distended bladder or rectum, but any of the spine to prevent further injury. Decompression and surgical
sensory stimulation can elicit autonomic hyperreflexia. Stimulation of fixation may be necessary. Corticosteroids are given at the time of
the skin or pain receptors may cause autonomic hyperreflexia. Bladder injury to decrease secondary cord injury from inflammation and
 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems 387

thereafter for several days. Nutrition, lung function, skin integrity, Intervertebral
and bladder and bowel management must be addressed. Plans for disk
rehabilitation need early consideration.
In cases of autonomic hyperreflexia, intervention must be prompt Herniated
because cerebrovascular accident is possible. The head of the bed nucleus
should be elevated, and the stimulus should be found and removed. pulposus
Antihypertensive medications may be used if blood pressure remains
elevated.

Degenerative Disorders of the Spine

Degenerative Joint Disease (DJD)
Degenerative disk disease. Degenerative disk disease (DDD) is Compressed
common in individuals 30 years of age and older. It is, in part, a pro- spinal nerve
cess of normal aging and includes a genetic component, involving Vertebral Spinal
genes that code the cartilage intermediate layer protein (CILP), as lamina cord
well as environmental interactions that may increase susceptibility
to lumbar disk disease by disrupting normal building and mainte- FIGURE 15-8  Herniated Nucleus Pulposus. (Modified from
nance of cartilage.9 Causes include biochemical (e.g., inflammatory Thompson JM et al: Mosby’s clinical nursing, ed 5, St Louis, 2002,
mediators) and biomechanical alterations (e.g., mechanical load- Mosby.)
ing and compression) of the intervertebral disk tissue. Diminished
blood supply and loss of disk proteoglycans cause subsequent disk
dehydration, alterations in disk structure, and impaired disk func-
tion. The disk can herniate, pinching nerves or placing strain on motor deficits, such as tingling, numbness, and weakness in various
the spine. The pathologic findings in DDD include disk protrusion, parts of the leg and foot. The percentage of the population affected
spondylolysis and/or subluxation (spondylolisthesis), degenera- with low back pain at some point in their lives is 60% to 80%, and
tion of vertebrae, and spinal stenosis. Lumbar disk disease causes the annual prevalence is 5%. Men and women are equally affected.
one third of all back pain that affects 70% to 90% of adults at some Women report low back symptoms more often after 60 years of age.
point in their lives. However, only a small percentage of people with
degenerative disk disease have any functional incapacity because of PATHOGENESIS  Most cases of low back pain are idiopathic, and
pain. no precise diagnosis is possible. The local processes include tension
Spondylolysis. Spondylolysis is a structural defect (degenera- caused by tumors or disk prolapse, bursitis, synovitis, rising venous
tion or developmental defect) of the spine involving the lamina or and tissue pressures (found in degenerative joint disease), abnormal
neural arch of the vertebra. The lumbar spine is affected most often. bone pressures, spinal immobility, inflammation caused by infection
Mechanical pressure may cause a forward displacement of the defi- (as in osteomyelitis), bony fractures, or ligamentous sprains to pain
cient vertebra (spondylolisthesis). Heredity plays a significant role, referred from viscera or the posterior peritoneum. General processes
and spondylolysis is associated with an increased incidence of other resulting in low back pain include bone diseases, such as osteoporosis
congenital spinal defects. Symptoms include lower back and lower or osteomalacia, and hyperparathyroidism.
limb pain. Risk factors include occupations that require repetitious lifting in
Spondylolisthesis. Spondylolisthesis occurs when a vertebra slides the forward bent-and-twisted position; exposure to vibrations caused
forward and onto the vertebra below it, and may include a fracture of by vehicles or industrial machinery; obesity; and cigarette smok-
the pars interarticularis, commonly occurring at L5-S1. Spondylolis- ing. Osteoporosis increases the risk of spinal compression fractures
thesis is graded from 1 to 4 based on the percentage of slip that occurs. and may be why elderly women report more symptoms than men.
Grades 1 and 2 usually are managed symptomatically and nonsurgi- Genetic predispositions for low back pain include isthmic spondy-
cally. Individuals with grade 3 or 4 usually require operative decom- lolisthesis (vertebra slides forward or slips in relation to a vertebra
pression, stabilization, or both. below), spinal osteochondrosis, and spinal stenosis associated with
Spinal stenosis. Spinal stenosis is a narrowing of the spinal canal achondroplasia.
that causes pressure on the spinal nerves or cord and can be congenital The most commonly encountered causes of low back pain include
or acquired (more common) and associated with trauma or arthritis. lumbar disk herniation, degenerative disk disease, spondylolysis,
The lumbar and cervical areas of the spine are most often involved. spondylolisthesis, and spinal stenosis. Anatomically, low back pain
Acquired conditions include a bulging disk, facet hypertrophy, or a must originate from innervated structures, but deep pain is widely
thick ossified posterior longitudinal ligament. Symptoms can produce referred and varies. The nucleus pulposus has no intrinsic innervation,
pain, numbness, and tingling in the legs. Surgical decompression is but when extruded or herniated through a prolapsed disk, it irritates
recommended for those with chronic symptoms and those who do not the dural membranes and causes pain referred to the segmental area
respond to medical management. (­Figure 15-8). The interspinous bursae can be a source of pain between
L3, L4, L5, and S1 but also may affect L1, L2, and L3 spinous processes.
Low Back Pain The anterior and posterior longitudinal ligaments of the spine and the
Low back pain affects the area between the lower rib cage and gluteal interspinous and supraspinous ligaments are abundantly supplied with
muscles and often radiates into the thighs. About 1% of individuals pain receptors, as is the ligamentum flavum. All of these ligaments are
with acute low back pain have pain along the distribution of a lum- vulnerable to traumatic tears (sprains) and fracture. Muscle injury may
bar nerve root (radicular pain), most commonly involving the sciatic contribute to low back pain, with sprains and strains the most com-
nerve (sciatica). Sciatica often is accompanied by neurosensory and mon diagnoses.
388 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems

EVALUATION AND TREATMENT  Diagnosis of low back injury is

based on physical examination, electromyelography, CT with or with-
out myelography, MRI, nerve conduction studies, diskography, and
epidurography. Most individuals with acute low back pain benefit
from a nonspecific short-term treatment regimen of bed rest, anal-
gesic medications, exercises, physical therapy, and education. Surgi-
cal treatments, specifically diskectomy and spinal fusions, are used
for individuals not responding to medical management. Individuals
with chronic low back pain also are prescribed anti-inflammatory and
muscle relaxant medications; exercise programs; massage, topical heat,
spinal manipulation, and cognitive-behavioral therapies; and interdis-
ciplinary care.10

Herniated Intervertebral Disk

Herniation of an intervertebral disk is a displacement of disk material
(nucleus pulposus or annulus fibrosus [the fibrous capsule enclos-
ing the gelatinous center of the disk]) beyond the intervertebral disk
space (see Figure 15-8). Rupture of an intervertebral disk usually is
caused by trauma, degenerative disk disease, or both. Risk factors are
weight-bearing sports, light weight lifting, and certain work activities,
such as repeated lifting. Men are affected more often than women,
with the highest incidence in the 30- to 50-year age group. Most com-
monly affected are the lumbosacral disks—that is, L5-S1 and L4-L5.
Herniation is typically at a higher vertebrae in older persons. Disk
herniation occasionally occurs in the cervical area, usually at C5-C6
and C6-C7. Herniations at the thoracic level are extremely rare. The
injury may occur immediately, within a few hours, or months to years
after injury.

PATHOPHYSIOLOGY  In a herniated disk, the ligament and posterior

capsule of the disk are usually torn, allowing the gelatinous material
(the nucleus pulposus) to extrude and compress the nerve root. Occa-
sionally the injury tears the entire disk loose, and it protrudes onto the
nerve root or compresses the spinal cord. Multiple nerve root com- FIGURE 15-9  Clinical Features of a Herniated Nucleus Pulposus.
pression may be found at the L5-S1 level, where the cauda equina may
be compressed. Large amounts of extruded nucleus pulposus or com-
plete disk herniation (i.e., of both the capsule and the nucleus pulpo- EVALUATION AND TREATMENT  Diagnosis of a herniated inter-
sus) may compress the spinal cord. vertebral disk is made through the history and physical examination,
spinal x-ray films, electromyelography, CT scan, MRI, myelography,
CLINICAL MANIFESTATIONS  The location and size of the hernia- diskography, and nerve conduction studies. Multiple avenues of ther-
tion into the spinal canal, together with the amount of space in the apy are available, although there is little evidence to support use of
canal, determine the clinical manifestations associated with the injury analgesics, muscle relaxants, systemic corticosteroids, or antidepres-
(Figure 15-9). A herniated disk in the lumbosacral area is associated sants. Nonsteroidal anti-inflammatory drugs, bed rest, or traction does
with pain that radiates along the sciatic nerve course over the buttock not improve sciatica related to disk herniation.11 Most herniated disks
and into the calf or ankle. The pain occurs with straining, includ- heal spontaneously over time and do not require surgery. A surgical
ing coughing and sneezing, and usually on straight leg raising. Other approach is indicated if there is evidence of severe compression (weak-
clinical manifestations include limited range of motion of the lumbar ness or decreased deep tendon, bladder, or bowel reflexes) or if a con-
spine; tenderness on palpation in the sciatic notch and along the sciatic servative approach is unsuccessful.12
nerve; impaired pain, temperature, and touch sensations in the L5-S1
or L4-L5 dermatomes of the leg and foot; decreased or absent ankle Cerebrovascular Disorders
jerk reflex; and mild weakness of the foot. Cerebrovascular disease is the most frequently occurring neurologic
With the herniation of a lower cervical disk, paresthesias and pain disorder, accounting for more than 50% of the persons admitted to
are present in the upper arm, forearm, and hand along the affected general hospitals with neurologic problems. Any abnormality of the
nerve root distribution. Neck motion and straining, including cough- brain caused by a pathologic process in the blood vessels is referred
ing and sneezing, may increase neck and nerve root pain. Neck range to as a cerebrovascular disease. Included in this category are lesions of
of motion is diminished. Slight weakness and atrophy of biceps or the vessel wall, occlusion of the vessel lumen by thrombus or embolus,
triceps muscles may occur; the biceps or triceps reflex may decrease. rupture of the vessel, and alteration in blood quality such as increased
Occasionally, signs of corticospinal and sensory tract impairments blood viscosity.
appear, including motor weakness of the lower extremities, sensory The brain abnormalities induced by cerebrovascular disease are
disturbances in the lower extremities, and presence of a Babinski either (1) ischemia with or without infarction (death of brain tis-
reflex. sues) or (2) hemorrhage. The common clinical manifestation of
 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems 389

cerebrovascular disease is a cerebrovascular accident (CVA, stroke): definitive diagnosis and treatment, 80% of persons have a recurrence
a sudden, nonconvulsive focal neurologic deficit. of symptoms by 1 year and are at higher risk for subsequent stroke.
Embolic stroke. An embolic stroke involves fragments that break
Cerebrovascular Accidents (Stroke Syndromes) from a thrombus formed outside the brain or in the heart, aorta, or
Cerebrovascular accidents are the leading cause of disability and the common carotid artery. The embolus usually involves small brain ves-
third cause of death in the United States. About 75% of CVAs occur sels and obstructs at a bifurcation or other point of narrowing, thus
among those older than 65 years. Stroke tends to run in families and causing ischemia. An embolus may plug the lumen entirely and remain
is more common in men at younger ages. The incidence is about 2 in place or shatter into fragments and become part of the vessel’s blood
times greater in blacks than whites.13 Blacks between the ages of 55 flow. Risk factors for an embolic stroke include atrial fibrillation, left
and 64 who live in the Southern states are about 50% more likely to ventricular aneurysm or thrombus, left atrial thrombus, recent myo-
die of stroke than blacks of the same age who live in the North.14 In cardial infarction, endocarditis, rheumatic valve disease, mechanical
addition, persons with both hypertension and type 2 diabetes mellitus valvular prostheses, atrioseptal defects, patent foramen ovale, and pri-
have a fourfold increase in stroke incidence and an eightfold increase mary cardiac tumors. In persons who experience an embolic stroke, a
in stroke mortality.15 In its mildest form, a cerebrovascular accident is second stroke usually follows because the source of emboli continues
so minimal that it is almost unnoticed. In its most severe state, hemi- to exist. Embolization is usually in the distribution of the middle cere-
plegia, coma, and death result. bral artery (the largest cerebral artery).
Cerebrovascular accidents (stroke syndromes) are classified Hemorrhagic stroke. Hemorrhagic stroke (intracranial hemor-
pathophysiologically as global hypoperfusion (as in shock), ischemic rhage) is the third most common cause of cerebrovascular accident.
(thrombotic, embolic), or hemorrhagic. Risk factors for stroke include Hypertension, ruptured aneurysms or vascular malformation, bleed-
the following: ing into a tumor, or hemorrhage associated with anticoagulants or
• Arterial hypertension (both elevated systolic and diastolic blood clotting disorders, head trauma, or illicit drug use are common causes.
pressures) increases the risk for stroke. A hypertensive hemorrhage is associated with significantly
• Smoking increases the risk of stroke by 50%. increased systolic and diastolic blood pressure measurements over sev-
• Compared to a nondiabetic person, a person with diabetes is 21⁄2 to eral years and usually occurs in the brain tissue. A mass of blood is
31⁄2 times more likely to have an ischemic stroke. formed and grows, displacing and compressing adjacent brain tissue.
• Insulin resistance increases the risk for ischemic stroke. Rupture or seepage into the ventricular system occurs in many cases.
• Polycythemia and thrombocythemia place the person at risk for Hemorrhages are described as massive, small, slit, or petechial. Massive
ischemic stroke. hemorrhages are several centimeters in diameter; small hemorrhages
• The presence of lipoprotein-A is a risk factor for ischemic stroke. are 1 to 2 cm in diameter; a slit hemorrhage lies in the subcortical area;
• Impaired cardiac function increases the risk for ischemic stroke. and a petechial hemorrhage is the size of a pinhead bleed. The most
• Hyperhomocysteinemia increases the risk for ischemic stroke. common sites for hypertensive hemorrhages are in the putamen of the
• Nonrheumatic atrial fibrillation is associated with a fivefold basal ganglia (a portion of the lentiform nucleus) (40%), the thalamus
increase in the incidence of ischemic stroke. (15%), the cortex and subcortex (22%), the pons (7%), the caudate
• Chlamydia pneumoniae can increase the risk of stroke by infiltrat- nucleus (7%), and the cerebellar hemispheres (8%).
ing and inflaming the vascular endothelium. Lacunar stroke. Lacunar strokes (lacunar infarcts or small vessel
Thrombotic stroke. Thrombotic strokes (cerebral thromboses) disease) are caused by occlusion of a single deep perforating artery that
arise from arterial occlusions caused by thrombi formation in arteries supplies small penetrating subcortical vessels, causing ischemic lesions
supplying the brain or intracranial vessels. Cerebral thrombosis devel- (0.5 to 15 mm or lacunes) predominantly in the basal ganglia, internal
ops most often from atherosclerosis and inflammatory disease pro- capsules, and pons. Because of the location and small area of infarc-
cesses (arteritis) that damage arterial walls. Increased coagulation can tion, these strokes may have pure motor or sensory deficits.17
lead to thrombus formation. Conditions causing inadequate cerebral
perfusion (e.g., dehydration, hypotension, prolonged vasoconstric- PATHOPHYSIOLOGY
tion from malignant hypertension) increase the risk of thrombosis. It Cerebral infarction. Cerebral infarction results when an area of
may take as long as 20 to 30 years for atheromatous plaques (stenotic the brain loses its blood supply because of vascular occlusion. Causes
lesions) to develop at the branches and curvature found in the cere- include (1) abrupt vascular occlusion (e.g., embolus), (2) gradual ves-
bral circulation. The smooth stenotic area can degenerate, forming an sel occlusion (e.g., atheroma), and (3) partial occlusion of stenotic
ulcerated area of the vessel wall. Platelets and fibrin adhere to the dam- vessels. Cerebral thrombi and cerebral emboli most commonly pro-
aged wall, and a clot forms, gradually occluding the artery. The clot duce occlusion, but atherosclerosis and hypotension are the dominant
may enlarge both distally and proximally. Thrombotic strokes occur underlying processes.
when parts of the clot detach, travel upstream, and obstruct blood Cerebral infarctions are ischemic or hemorrhagic. In ischemic
flow, causing acute ischemia. infarcts, the affected area becomes slightly discolored and softens 6 to
The distinction between transient ischemic attacks (TIAs) and 12 hours after the occlusion. Necrosis, swelling around the insult, and
thrombotic stroke is losing importance. With increasing use of brain mushy disintegration appear by 48 to 72 hours after infarction. The
imaging modalities, many persons with symptoms lasting less than 24 necrosis resolves by about the second week, leaving a cavity.
hours are diagnosed as having a brain infarction. The new definition In hemorrhagic infarcts, bleeding occurs into the infarcted area
for transient ischemic attack (TIA) is a brief episode of neurologic when blood flow is restored. The embolic fragments may be moved
dysfunction caused by a focal disturbance of brain or retinal ischemia or lysed, or compressive forces may lessen, allowing blood flow to be
with clinical symptoms typically lasting no more than 1 hour; no evi- reestablished.
dence of infarction; and complete clinical recovery.16 Cerebral hemorrhage. The primary cause of cerebral hemorrhage
TIAs likely represent platelet clumps or vessel narrowing with is hypertension. Other causes include ruptured aneurysms or arterio-
spasm causing an intermittent blockage of circulation. Without venous malformations, tumors, coagulation disorders, and trauma.
390 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems

Hypertension involves primarily smaller arteries and arterioles, result- Intracranial Aneurysm
ing in thickening of the vessel walls and increased cellularity of the ves- Intracranial aneurysms may result from arteriosclerosis, congenital
sels and hyalinization. Necrosis may be present. Microaneurysms in abnormality, trauma, inflammation, and cocaine abuse. The size may
these smaller vessels or arteriolar necrosis may precipitate the bleeding. vary from 2 mm to 2 or 3 cm. Most aneurysms are located at bifurca-
A mass of blood is formed as bleeding continues into the brain tis- tions in or near the circle of Willis, in the vertebrobasilar arteries, or
sue. Adjacent brain tissue is deformed, compressed, and displaced, within the carotid system (see Figures 12-18 and 12-19). Aneurysms
producing ischemia, edema, and increased intracranial pressure. Rup- may be single, but in 20% to 25% of the cases, more than one is pres-
ture or seepage of blood into the ventricular system often occurs. ent. In these instances, the aneurysms may be unilateral or bilateral.
The cerebral hemorrhage resolves through reabsorption. Macro- Peak incidence of rupture occurs in persons 50 to 59 years of age, with
phages and astrocytes clear blood from the area. A cavity forms, sur- the incidence in women slightly higher than that in men.
rounded by a dense gliosis (glial scar) after removal of the blood.
Because neurons surrounding the ischemic or infarcted areas PATHOPHYSIOLOGY  No single pathologic mechanism exists. Aneu-
undergo changes that disrupt plasma membranes, cellular edema rysms may be classified on the basis of shape and form. Saccular aneu-
results, causing further compression of capillaries. Maximal cerebral rysms (berry aneurysms) occur frequently (in approximately 2% of
edema develops in approximately 72 hours and takes about 2 weeks to the population) and likely result from congenital abnormalities in the
subside. Most persons survive an initial hemispheric ischemic stroke tunica media of the arterial wall and degenerative changes.20 The sac
unless there is massive cerebral edema, which is nearly always fatal. gradually grows over time. A saccular aneurysm may be (1) round with a
narrow stalk connecting it to the parent artery, (2) broad-based without
CLINICAL MANIFESTATIONS  Clinical manifestations of throm- a stalk, or (3) cylindrical (Figure 15-10). Saccular aneurysms are rare in
botic stroke vary, depending on the artery obstructed. Different sites of childhood; their highest incidence of rupturing or bleeding (subarach-
obstruction create different occlusion syndromes (e.g., carotid artery noid hemorrhage) is among persons 20 to 50 years of age (Figure 15-11).
syndromes, middle cerebral artery syndromes, or vertebrobasilar sys-
tem syndromes).
With hemorrhagic stroke, clinical manifestations vary, depending
on the location and size of the bleed. Once a deep unresponsive state
occurs, the person rarely survives. The immediate prognosis is grave.
If the person survives, however, recovery of function often is possible. Berry aneurysm
Individuals experiencing intracranial hemorrhage from a ruptured
or leaking aneurysm have one of three sets of symptoms: (1) onset of
an excruciating generalized headache with an almost immediate lapse
into an unresponsive state, (2) headache but with consciousness main-
tained, and (3) sudden lapse into unconsciousness. If the hemorrhage
is confined to the subarachnoid space, there may be no local signs. If Berry aneurysm at bifurcation
bleeding spreads into the brain tissue, hemiparesis/paralysis, dyspha-
sia, or homonymous hemianopia may be present. Warning signs of
an impending aneurysm rupture include headache, transient unilateral
weakness, transient numbness and tingling, and transient speech dis- Broad-based
turbance. However, such warning signs often are absent. saccular berry aneurysm Fusiform aneurysm
FIGURE 15-10  Types of Aneurysms.
EVALUATION AND TREATMENT  MRI and magnetic resonance
angiography (MRA) are used to diagnose stroke. In thrombotic
stroke, thrombolytic therapy for acute ischemic stroke is within 3
hours of onset of symptoms. The American Heart Association/Ameri-
can Stroke Association (AHA/ASA) guidelines for the administration
of recombinant tissue plasminogen activator (rtPA) following acute
stroke were revised to expand the window of treatment from 3 hours
to 4.5 hours; however, this has not been approved by the Food and
Drug Administration.18 Treatment is directed at prevention of isch-
emic injury and supportive management to control cerebral edema
and increased intracranial pressure. Arresting the disease process
by control of risk factors is critical and antiplatelet therapy may be
instituted.19
In embolic strokes treatment is directed at preventing further
embolization by instituting anticoagulation therapy and correcting
the primary problem. Rehabilitation is indicated in both thrombotic
and embolic strokes. Treatment of an intracranial bleed, regardless of
cause, focuses on stopping or reducing the bleeding, controlling the
FIGURE 15-11  Berry Aneurysm, Angiogram. In this lateral view
increased intracranial pressure, preventing a rebleed, and preventing
with contrast filling a portion of the cerebral arterial circulation can be
vasospasm. Occasionally an attempt is made to evacuate or aspirate seen a berry aneurysm (arrow) involving the middle cerebral artery
the blood. Some surgeons drain the blood in a cerebral bleed but the of the circle of Willis at the base of the brain. (From Klatt EC: Rob-
benefit is not documented in studies. bins and Cotran atlas of pathology, Philadelphia, 2006, Saunders.)
 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems 391

Fusiform aneurysms (giant aneurysms) occur as a result of diffuse EVALUATION AND TREATMENT  A systolic bruit over the carotid
arteriosclerotic changes and are found most commonly in the basilar artery in the neck, the mastoid process, or the eyeball in a young per-
arteries or terminal portions of the internal carotid arteries (see Figure son is almost diagnostic of an AVM. Confirming diagnosis is made by
15-10). They act as space-occupying lesions. CT and MRI followed by MRA. Treatment options are direct surgical
Aneurysms rupture through thin areas, causing hemorrhage into intervention, embolization, or radiotherapy.
the subarachnoid space that spreads rapidly, producing localized
changes in the cerebral cortex and focal irritation of nerves and arteries Subarachnoid Hemorrhage
(see the discussion of the Laplace law in Chapter 22). Bleeding ceases With a subarachnoid hemorrhage, blood escapes from a defective or
when a fibrin-platelet plug forms at the point of rupture and as a result injured vessel into the subarachnoid space. Individuals at risk for a
of compression. Blood undergoes reabsorption through arachnoid villi subarachnoid hemorrhage are those with intracranial aneurysm, intra-
within 3 weeks. cranial arteriovenous malformation, or hypertension and those who
have sustained head injuries. Subarachnoid hemorrhages often recur,
CLINICAL MANIFESTATIONS  Aneurysms often are asymptomatic. especially from a ruptured intracranial aneurysm.
Of all persons undergoing routine autopsy, 5% are found to have
one or more intracranial aneurysms. Clinical manifestations may PATHOPHYSIOLOGY  When a vessel is leaking, blood oozes into
arise from cranial nerve compression, but the signs vary, depending the subarachnoid space. When a vessel tears, blood under pressure is
on the location and size of the aneurysm. Cranial nerves III, IV, V, pumped into the subarachnoid space. The blood increases intracra-
and VI are affected most often (see Table 12-6). Unfortunately, the nial volume, and it is also extremely irritating to the neural tissues and
most common first indication of the presence of an aneurysm is an produces an inflammatory reaction. In addition, the blood coats nerve
acute subarachnoid hemorrhage, intracerebral hemorrhage, or com- roots, clogs arachnoid granulations (impairing CSF reabsorption), and
bined subarachnoid-intracerebral hemorrhage (see Subarachnoid obstructs foramina within the ventricular system (impairing CSF cir-
Hemorrhage). culation). Intracranial pressure immediately increases to almost dia-
stolic levels but returns to near baseline in about 10 minutes. Cerebral
EVALUATION AND TREATMENT  Diagnosis before a bleeding epi- blood flow and cerebral perfusion pressure decrease. Autoregulation
sode is made through arteriography. After a subarachnoid or intra- of blood flow is impaired, and there is a compensatory increase in
cerebral hemorrhage, a tentative diagnosis of an aneurysm is based systolic blood pressure.24 The expanding hematoma acts like a space-
on clinical manifestations, history, CT scan, and MRI. Treatments for occupying lesion, compressing and displacing brain tissue. Granula-
intracranial aneurysm include surgical management and endovascular tion tissue is formed, and meningeal scarring with impairment of CSF
coil embolization for selected individuals.21,22 The location and size of reabsorption and secondary hydrocephalus often results. Mortality in
the aneurysm and the person’s clinical status determine whether inva- subarachnoid hemorrhage is 50% at 1 month.
sive therapy is feasible. Delayed cerebral ischemia, a syndrome of progressive neurologic
deterioration, is associated with cerebral artery vasospasm. From 40%
Vascular Malformation to 60% of persons with a subarachnoid hemorrhage experience vaso-
An arteriovenous malformation (AVM) is a tangled mass of dilated spasms in adjacent and, occasionally, in nonadjacent vessels. Vaso-
blood vessels creating abnormal channels between the arterial and spasm may occur because of leukocyte-endothelial cell interactions
venous systems (arteriovenous fistula). AVMs may occur in any part or the effects of vasoactive substances (e.g., calcium, prostaglandins,
of the brain and vary in size from a few millimeters to large malforma- serotonin, catecholamines) on the arteries of the subarachnoid space.
tions extending from the cortex to the ventricle. AVMs occur equally Edema, medial necrosis, and proliferation of the tunica intima have
in males and females and occasionally occur in families. Although been found. Vasospasm causes decreased cerebral blood flow, isch-
AVMs are usually present at birth, symptoms exhibit a delayed age of emia, and possibly infarct and can lead to delayed ischemic injury and
onset and commonly occur before 30 years of age. death 3 to 14 days after the initial hemorrhage.25

PATHOPHYSIOLOGY  AVMs have abnormal blood vessel structure, CLINICAL MANIFESTATIONS  Early manifestations associated with
are abnormally thin, and have complex growth and remodeling pat- leaking vessels are episodic and include headache, changes in mental
terns.23 One or several arteries may feed the AVM and become tortu- status or level of consciousness, nausea or vomiting, and focal neuro-
ous and dilated over time. With moderate to large AVMs, sufficient logic defects. A ruptured vessel causes a sudden, throbbing, “explosive”
blood is shunted into the malformation to deprive surrounding tissue headache, accompanied by nausea and vomiting, visual disturbances,
of adequate blood perfusion. motor deficits, and loss of consciousness related to a dramatic rise in
intracranial pressure. Meningeal irritation and inflammation often
CLINICAL MANIFESTATIONS  Twenty percent of persons with an occur, causing neck stiffness (nuchal rigidity), photophobia, blurred
AVM have a characteristic chronic, nondescript headache, although vision, irritability, restlessness, and low-grade fever. A positive Kernig
some experience migraine. Fifty percent of persons experience sei- sign (straightening the knee with the hip and knee in a flexed position
zures caused by compression. The other 50% experience an intra- produces pain in the back and neck regions) and a positive Brudzin-
cerebral, subarachnoid, or subdural hemorrhage. Bleeding from an ski sign (passive flexion of the neck produces neck pain and increased
AVM into the subarachnoid space causes symptoms identical to rigidity) may appear. No localizing signs are present if the bleed is con-
those associated with a ruptured aneurysm. If bleeding is into the fined completely to the subarachnoid space.
brain tissue, focal signs that develop resemble a stroke-in-evolu- The Hunt and Hess subarachnoid hemorrhage (SAH) grading
tion. Ten percent of persons experience hemiparesis or other focal system is based on description of the clinical manifestations (Table
signs. At times, noncommunicating hydrocephalus (see Chapter 15-7).26 Rebleeding is a significant risk with a high mortality (up to
14) develops with a large AVM that extends into the ventricular 70%). The period of greatest risk is the first month, with the peak
lining. incidence of rebleeding during the first 2 weeks after the initial bleed.
392 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems

Rebleeding is manifested by a sudden increase in blood pressure and Headache

intracranial pressure, along with a deteriorating neurologic status. Headache is a common neurologic disorder and is usually a benign
Seizures occur in 25% of persons with an SAH, and hydrocephalus symptom. However, it can be associated with serious disease such as
after a bleed occurs in 20% of cases. Hypothalamic dysfunction, mani- brain tumor, meningitis, or cerebral vascular disease (e.g., giant cell
fested by salt wasting, hyponatremia, and ECG changes, is common. arteritis, cerebral aneurysm, or cerebral bleeds). The headache syn-
dromes discussed here are the chronic, recurring type not associated
EVALUATION AND TREATMENT  The diagnosis of an SAH is based with structural abnormalities or systemic disease and include migraine,
on the clinical presentation as well as the results of a noncontrast CT cluster, and tension headaches. Characteristics of the major types of
scan and a lumbar puncture. Arteriography is the definitive diagnostic headache syndromes are summarized in Table 15-8.
measure for identifying an aneurysm or arteriovenous malformation.
Treatment is directed at controlling intracranial pressure, improving Migraine
cerebral perfusion pressure, preventing ischemia and hypoxia of neu- Migraine is a familial, episodic neurological disorder whose marker is
ral tissues, and avoiding rebleeding episodes.27 The primary problem headache28 and is defined as repeated, episodic headache lasting 4 to
must be diagnosed and corrected as well. 72 hours. It is diagnosed when any two of the following features occur:
unilateral head pain, throbbing pain, pain worsens with activity, mod-
erate or severe pain intensity; and at least one of the following: nausea
4 QUICK CHECK 15-2 and/or vomiting, or photophobia and phonophobia.29 Migraine can
occur in children and is more common in women and those 25 to 55
1. Why is atherosclerosis a risk factor for thrombotic stroke?
2. Why do TIA’s signs and symptoms resolve completely? years of age. In susceptible women, migraine occurs most frequently
3. Why do lacunar strokes involve small infarcts? before and during menstruation and is decreased during pregnancy
4. How is an AVM different from an aneurysm? and menopause. The cyclic withdrawal of estrogen and progesterone
may trigger attacks of migraine.30
Migraine is caused by a combination of multiple genetic and envi-
ronmental factors. Persons with migraine have an increased risk for
TABLE 15-7 SUBARACHNOID epilepsy, depression, anxiety disorders, cardiovascular disease, and
HEMORRHAGE stroke. Triggers believed to precipitate migraine attacks include altered
CLASSIFICATION SCALE sleep patterns (becoming tired or oversleeping), missed meals, over-
exertion, weather change, stress or relaxation from stress, hormonal
CATEGORY DESCRIPTION changes (menstrual periods), excess afferent stimulation (bright lights,
Grade I Neurologic status intact; mild headache, slight nuchal strong smells), and chemicals (alcohol or nitrates).
rigidity The pathophysiologic basis for migraine is not clearly established
Grade II Neurologic deficit evidenced by cranial nerve involvement; and includes neurologic, vascular, hormonal, and neurotransmit-
moderate to severe headache with more pronounced ter components.28 Migraine is broadly classified as (1) migraine with
meningeal signs (e.g., photophobia, nuchal rigidity) aura with visual, sensory, or motor symptoms and, more commonly,
Grade III Drowsiness and confusion with or without focal neuro- (2) migraine without aura. The clinical phase of a migraine attack and
logic deficits; pronounced meningeal signs the associated pathophysiologic manifestations follow:
Grade IV Stuporous with pronounced neurologic deficits (e.g., 1. Premonitory phase: Up to one third of persons have premonitory
hemiparesis, dysphasia); nuchal rigidity symptoms (tiredness, irritability, loss of concentration, food crav-
Grade V Deep coma state with decerebrate posturing and other ing) hours to days before onset of aura or headache; the pathogen-
brain stem functioning esis is unknown.
2. Migraine aura: Up to one third of persons have aura symptoms at
From Cook HS: Aneurysmal subarachnoid hemorrhage: neuroscience
frontiers and nursing challenges. In Winkelman C, editor: AACN clinical least some of the time that may last 1 hour or sometimes much
issues in critical nursing, Philadelphia, 1991, Lippincott. longer; the pathophysiologic basis appears to involve a cortical

TABLE 15-8 CHARACTERISTICS OF COMMON HEADACHES

MIGRAINE CLUSTER HEADACHE/ TENSION TYPE
WITHOUT AURA WITH AURA PROXIMAL HEMICRANIA OF HEADACHE
Age of onset Childhood, adolescence, Childhood, adolescence, or young Young adulthood, middle age Young adulthood,
or young adulthood adulthood middle age
Gender Female Female Male Not gender specific
Family history of headaches Yes Yes No Yes
Onset and evolution Slow to rapid Slow to rapid Rapid Slow to rapid
Time course Episodic Episodic Clusters in time Episodic, may become
constant
Quality Usually throbbing Usually throbbing Steady Steady
Location Variable, often unilateral Variable, often unilateral Orbit, temple, cheek Variable
Associated features Prodrome, vomiting Prodrome, vomiting Lacrimation, rhinorrhea, Horner None
syndrome
 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems 393

spreading depression (CSD) (a spreading wave of depolarization unknown. Headache sufferers have more localized pain and tender-
accompanied by transient increased cerebral perfusion followed by ness of craniocervical muscles. Many individuals have both tension-
reduction in electrical activity, and a decrease in blood flow that type and migraine headaches.
slowly spreads across the cerebral cortex from the occipital region). Mild headaches are treated with ice, and more severe forms are
3. Headache phase: Includes associated symptoms and may last from treated with aspirin or nonsteroidal anti-inflammatory drugs. Chronic
4 to 72 hours (usually about a day); pain mechanisms are initiated tension-type headaches are best managed with a tricyclic antidepres-
in the brain with disturbances in serotonin and other neurotrans- sant and behavioral therapy. Long-term use of analgesics or other
mitters, resulting in compensatory overactivity in the trigemino- drugs, such as muscle relaxants, antihistamines, tranquilizers, caffeine,
vascular system of the brain because afferents from dural-vascular and ergot alkaloids, should be avoided.35
structures are innervated by branches of the trigeminal nerve. Trig-
gers can include strong odors, lack of sleep, sun glare, high altitude, Infection and Inflammation of the Central
and foods containing vasoactive amines. Nervous System
Differentiation of types of migraine headache is summarized in The CNS may be infected by bacteria, viruses, fungi, parasites, and
Table 15-8. The diagnosis of migraine is made from medical history mycobacteria. The invading organisms enter the nervous system
and physical examination. Differential diagnosis is confirmed with CT either by spreading through arterial blood vessels (Figure 15-12) or
and MRI scans and EEG. The management of migraine includes avoid- by directly invading the nervous tissue from another site of infection.
ance of triggers and education that migraine is a chronic physiologic Neurologic infections produce disease by several mechanisms: direct
disorder and not psychosomatic. Darkening the room, applying ice, neuronal or glial infection, mass lesion formation, inflammation with
and sleeping can provide some relief with the onset of acute migraine. subsequent edema, interruption of cerebrospinal fluid pathways, neu-
Pharmacologic management varies and is related to the severity of ronal or vascular damage, and secretion of neurotoxins. An immune
attack. Drug prophylaxis for migraine is considered when attacks can- process may initiate an inflammatory reaction.
not be treated effectively.31,32

Cluster Headache
Cluster headaches are one of a group of disorders referred to as tri- Oligodendrocyte:
geminal autonomic cephalagias.33 They occur in one side of the head JCV, CMV
primarily in men between 20 and 50 years of age. These uncommon Neuron:
headaches occur in clusters for a period of days followed by a long HSV-1, 2, rabies
period of spontaneous remission. Cluster headache has an episodic West Nile, Nipah
and a chronic form with extreme pain intensity and short duration. equine encephalitides
If the cluster of attacks occurs more frequently without sustained mumps, VZV
spontaneous remission, they are classified as chronic cluster headaches measles (SSPE), CMV
(20% of cases) (see Table 15-8). Triggers are similar to those that cause
migraine headache.
Trigeminal activation occurs but the mechanism is unclear. There Microglia, perivascular Astrocyte: Equine
is unilateral trigeminal distribution of severe pain with ipsilateral auto- macrophages: encephalitis viruses,
nomic manifestations including tearing on affected side, ptosis of the HIV, CMV HIV, JVC, CMV, HTLV-1
ipsilateral eye, and congestion of the nasal mucosa. The pathogenic
mechanism for pain is related to the release of vasoactive peptides and
the formation of neurogenic inflammation. Autonomic dysfunction
is characterized by sympathetic underactivity and parasympathetic
activation. The rhythmicity of attacks is associated with changes in
the inferior posterior hypothalamus. There may be altered serotoner-
gic nerve transmission, but at different loci than in migraine head- Blood-brain
ache.33 Prophylactic drugs are used to treat cluster headache, as well barrier
as avoidance of triggers. Acute attacks are managed with oxygen inha-
lation, sumatriptan or inhaled ergotamine administration, and nerve Endothelia:
stimulation.34 Nipah virus, CMV
Tension-type headache. Tension-type headache is the most com- FIGURE 15-12  Viral Infection in the Central Nervous System
mon type of headache. The average age of onset is during the sec- (CNS). Viruses infect specific cell types within the CNS depending
ond decade of life. It is a mild to moderate bilateral headache with a on the particular properties of the virus together with individual cell
sensation of a tight band or pressure around the head with gradual membrane proteins expressed on permissive cell types. Normally
onset of pain. The headache occurs in episodes and may last for the brain is protected from circulating pathogens and toxins by the
several hours or several days. It is not aggravated by physical activ- blood-brain barrier. CMV, Cytomegalovirus; HIV, human immuno-
ity. Chronic tension-type headache (CTTH) evolves from episodic deficiency virus; HSV, herpes simplex virus; HTLV-1, human T cell
lymphotropic virus (causes T cell leukemia); JCV, John Cunning-
tension-type headache and represents headache that occurs at least
ham virus (a polyomavirus causing progressive multifocal leuko-
15 days per month for at least 3 months. A central pain mechanism encephalopathy); SSPE, subacute sclerosing panencephalitis; VZV,
is associated with chronic tension headache and a peripheral mech- varicella-zoster virus. (Adapted from Power C, Noorbakhsh G: Cen-
anism with episodic tension headache. The mechanism involves tral nervous system viral infections: clinical aspects and pathogenic
hypersensitivity of pain fibers from the trigeminal nerve and con- mechanisms. In Gilman S, editor, Neurobiology of disease, p 488,
traction of jaw and neck muscles, but the exact mechanisms are Burlington, Mass, 2007, Elsevier.)
394 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems

Meningitis pressure increases, papilledema develops and delirium may progress

Meningitis is inflammation of the brain or spinal cord. The causes of to unconsciousness and death.
meningitis (infection of the meninges) include bacteria, viruses, fungi, The clinical manifestations of aseptic meningitis are similar to those
parasites, or toxins. The infection may be acute, subacute, or chronic of bacterial meningitis but milder. Fungal meningitis develops slowly
with the pathophysiology, clinical manifestations, and treatment dif- and insidiously. The first manifestations are often those of dementia
fering for each type of microorganism. (see Chapter 14) or communicating hydrocephalus (see Chapter 14).
Bacterial meningitis is primarily an infection of the pia mater The individual is characteristically afebrile.
and arachnoid, the subarachnoid space, the ventricular system, and
the CSF. Meningococcus (Neisseria meningitidis) and pneumococcus EVALUATION AND TREATMENT  Diagnosis of bacterial meningi-
(Streptococcus pneumoniae) are the most common causes of bacte- tis is based on physical examination and the results of nasopharyn-
rial meningitis. About 1.3 in 100,000 persons are affected annually.36 geal smear and antigen tests. CSF cultures are required for differential
Meningococcus has been identified worldwide. Meningococcal men- diagnosis. Bacterial meningitis and fungal meningitis are treated with
ingitis occurs predominantly in men and boys and in the fall, winter, appropriate antibiotic therapy and other supportive measures. Aseptic
and spring of the year. Epidemics of meningococcal meningitis occur meningitis is managed pharmacologically with antiviral drugs and ste-
in approximately 10-year cycles, predominantly affecting children and roids. There are vaccinations to prevent meningococcal, pneumococ-
adolescents. With pneumococcal meningitis, young persons and those cal, and Haemophilus influenzae meningitis.40
over 40 years of age are mostly affected. Predisposing conditions are
otitis or sinusitis (25%), immunocompromise (16%), and pneumonia Brain or Spinal Cord Abscess
(12%).37,38 Abscesses are localized collections of pus within the parenchyma of the
Aseptic meningitis (viral meningitis, nonpurulent meningitis) is brain or spinal cord. They develop in about 1 of every 100,000 hospital
believed to be limited to the meninges. It produces various symptoms admissions and are more common in middle-aged men. They occur
and is caused by several infectious agents, primarily viruses. Bacterial (1) after open trauma and during neurosurgery; (2) from contiguous
infections not adequately treated also cause aseptic meningitis. spread of infection from the middle ear, mastoid cells, nasal cavity, and
Fungal meningitis is a chronic, much less common condition than nasal sinuses; (3) through metastatic or hematogenous distribution
bacterial or viral meningitis. The infection occurs most often in per- from distant foci, such as the heart, lungs, pelvic organs, skin, tonsils,
sons with impaired immune responses or alterations in normal body abscessed teeth, osteomyelitis (with the exception of cranial bones),
flora. It develops insidiously, usually over days or weeks. and dirty needles (especially in compromised hosts); and (4) from
cryptogenic factors, arising without other associated areas of infection.
PATHOPHYSIOLOGY  A systemic or bloodstream infection or a Streptococci, staphylococci, and Bacteroides, often combined with
direct extension from an infected area, usually respiratory, is the access anaerobes, are the most common bacteria that cause abscesses; how-
route to the subarachnoid space. With bacterial infection, large num- ever, yeast and fungi may also be involved. Toxoplasma gondii is pro-
bers of neutrophils are recruited to the subarachnoid space. Release ducing an ever-increasing number of CNS abscesses in persons with
of cytotoxic inflammatory agents and bacterial toxins alter the blood- acquired immunodeficiency syndrome (AIDS). Most CNS abscesses
brain barrier and damage brain tissue. Prognosis depends on the type are located in the cerebrum and immunosuppressed persons are par-
of pathogen.39 The meningeal vessels become hyperemic and increas- ticularly at risk.
ingly permeable. The inflammatory exudate thickens the CSF and Brain abscesses are classified as extradural or intracerebral. Extra-
interferes with normal CSF flow around the brain and spinal cord, dural brain abscesses are associated with osteomyelitis in a cranial
possibly obstructing arachnoid villi and producing hydrocephalus. bone. Intracerebral brain abscesses arise from a vascular source. Spi-
Meningeal cells become edematous, and the combined exudate and nal cord abscesses are classified as epidural or intramedullary. Epi-
edematous cells increase intracranial pressure. Engorged blood vessels dural spinal abscesses usually originate as osteomyelitis in a vertebra;
and thrombi can disrupt blood flow, causing further injury. the infection then spreads into the epidural space. (Osteomyelitis is
Fungi in the nervous system usually produce a granulomatous reac- discussed in Chapter 37.)
tion, forming granulomata or gelatinous masses in the meninges at the
base of the brain. Fungi also may extend along the perivascular sites PATHOPHYSIOLOGY  Microorganisms gain entrance to the CNS
in the subarachnoid space and into the brain tissue, producing arte- by direct extension or distribution along the wall of a vein. Infective
ritis with thrombosis, infarction, and communicating hydrocephalus. emboli carry organisms from distant sites. Brain abscesses evolve
Meningeal fibrosis develops later in the inflammatory process. Cra- through four stages:
nial nerve dysfunction, caused by compression, often results from the 1. In early cerebritis (days 1 to 3) localized inflammation and the pres-
granulomata and fibrosis. ence of inflammatory cells surrounding a core of necrosis are seen;
marked cerebral edema is evident (Figure 15-13).
CLINICAL MANIFESTATIONS  The clinical manifestations of bac- 2. During late cerebritis (days 4 to 9) a necrotic center surrounded
terial meningitis can be grouped into infectious signs, meningeal by macrophages and fibroblasts is present; new blood vessels form
signs, and neurologic signs. The clinical manifestations of systemic rapidly around the abscess, a thin capsule develops, and edema still
infection include fever, tachycardia, chills, and a petechial rash. The persists.
clinical manifestations of meningeal irritation are a severe throbbing 3. During early capsule formation (days 10 to 13) the necrotic center
headache, severe photophobia, nuchal rigidity, and positive Kernig decreases in size, more fibroblasts and macrophages are present,
and Brudzinski signs. The neurologic signs include a decrease in con- and mature collagen evolves, forming a capsule.
sciousness, cranial nerve palsies, focal neurologic deficits (such as 4. In the late capsule formation stage (days 14 and longer), a well-
hemiparesis/hemiplegia and ataxia), and seizures. Often there is pro- formed necrotic center surrounded by a dense collagen capsule
jectile vomiting. With meningococcal meningitis, a petechial or pur- develops.
puric rash covers the skin and mucous membranes. As intracranial Existing abscesses also tend to spread and form daughter abscesses.
 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems 395

CLINICAL MANIFESTATIONS  Clinical manifestations of brain EVALUATION AND TREATMENT  The diagnosis is suggested by clin-
abscesses are associated with (1) an intracranial infection or (2) an ical features and confirmed by imaging studies. Aspiration through a
expanding intracranial mass. Early manifestations include low-grade burr hole and excision through craniotomy accompanied by antibiotic
fever, headache (most common symptom), neck pain and stiffness therapy are treatment options. In addition, intracranial pressure may
with mild nuchal rigidity, confusion, drowsiness, sensory deficits, and have to be managed.
communication deficits. Later clinical manifestations include inatten- Because decompression is necessary, spinal cord abscesses are
tiveness (distractibility), memory deficits, decreased visual acuity and treated with surgical excision or aspiration. Antibiotic therapy and
narrowed visual fields, papilledema, ocular palsy, ataxia, and dementia. support therapy also are instituted.
The development of symptoms may be very insidious, often making an
abscess difficult to diagnose. Encephalitis
Extradural brain abscesses are associated with localized pain, puru- Encephalitis is an acute febrile illness, usually of viral origin, with
lent drainage from the nasal passages or auditory canal, fever, localized nervous system involvement. The most common forms are caused by
tenderness, and neck stiffness. Occasionally the individual experiences arthropod-borne (mosquito-borne) viruses and herpes simplex type 1.
a focal seizure. Viruses infect specific cell types in the CNS as shown in Figure 15-12,
Clinical manifestations of spinal cord abscesses have four stages: p. 393. Referred to as infectious viral encephalitides, encephalitis may
(1) spinal aching; (2) severe root pain, accompanied by spasms of the occur as a complication of systemic viral diseases such as poliomyeli-
back muscles and limited vertebral movement; (3) weakness caused by tis, rabies, or mononucleosis, or it may arise after recovery from viral
progressive cord compression; and (4) paralysis. infections such as rubella or rubeola. Encephalitis also may follow
vaccination with a live attenuated virus vaccine if the vaccine has an
encephalitis component, for example, measles, mumps, and rubella.
Typhus, trichinosis, malaria, and schistosomiasis also are associated
with encephalitis. Toxoplasmosis may acutely reactivate in immuno-
suppressed persons when the once-dormant parasite in cyst form dis-
seminates in brain tissues.
With the exception of the California viral encephalitis, which is
endemic, the arthropod-borne (mosquito-borne) encephalitides occur
in epidemics, varying in geographic and seasonal incidence (Table 15-9
and Health Alert: West Nile Virus). Eastern equine encephalitis is the
most serious but least common of the encephalitides.

PATHOPHYSIOLOGY  Meningeal involvement is present in all

encephalitides. The various encephalitides may cause widespread
nerve cell degeneration. Edema, necrosis with or without hemorrhage,
and increased intracranial pressure develop. Infectious encephalitis
may result from a postinfectious autoimmune response to the virus or
from direct invasion of the CNS.
FIGURE 15-13  Brain Abscess. Early brain abscess appearing as a
poorly demarcated area (arrow) of cerebritis at the gray-white junc- CLINICAL MANIFESTATIONS  Encephalitis ranges from a mild
tion. (From Damjanov I, Linder J, editors: Anderson’s pathology, infectious disease to a life-threatening disorder. Dramatic clinical
ed 10, St Louis, 1996, Mosby.) manifestations include fever, delirium, or confusion progressing to

TABLE 15-9 CLASSIFICATION AND CHARACTERISTICS OF ARBOVIRUSES CAUSING

ENCEPHALITIS
PERIOD
INCUBATION VIRUSES (DAYS) LOCATION SEASON AFFECTED POPULATION
Eastern equine encephalitis 5-15 Atlantic, Gulf Coast, and Great Lakes regions Midsummer to early Infants, children, and adults
fall >50 yr
Western equine encephalitis 5-10 All parts of United States, especially western two Summer to early fall Infants and young children
thirds of country
Venezuelan equine encephalitis 2-5 Texas, Florida, Mexico, Central and South America All seasons Infants and young children
St Louis encephalitis 4-21 United States and Canada, especially Mississippi Summer and fall Adults >40 yr; elderly more often
River, Pacific Coast, Texas, and Florida affected than younger ages
California encephalitis 5-15 Midwestern United States, Eastern seaboard, and Late summer and early Children <15 yr
Canada fall
West Nile encephalitis 3-14 Lower 48 states of United States Summer and fall Elderly most seriously
Dengue 5-10 Florida, Texas, Mexico, Asia, Central and South All seasons Adults and children
encephalitis America, and the Caribbean

Modified from Barker E: Neuroscience nursing, ed 2, St Louis, 2002, Mosby.

396 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems

unconsciousness, seizure activity, cranial nerve palsies, paresis and

HEALTH ALERT
paralysis, involuntary movement, and abnormal reflexes. Signs of
West Nile Virus marked intracranial pressure may be present.
West Nile virus (WNV) is the most common cause of epidemic meningoen-
cephalitis in North America and the leading cause of arboviral encephalitis in EVALUATION AND TREATMENT  Diagnosis is made by history and
the United States. It is spread by infected mosquitoes. The illness is seasonal clinical presentation aided by CSF examination and culture, sero-
in the summer and continues into the fall. logic studies, white blood cell count, CT scan, or MRI. Most cases
Symptoms: There may be no symptoms or there may be illness of vary- of viral meningitis are self-limiting, and until recently no definitive
ing severity with central nervous system involvement including fever, treatment was available. However, herpes encephalitis in immuno-
headache, stiff neck, vision loss, and altered mental status ranging from compromised persons is now being treated with antiviral agents, such
confusion to coma with or without additional signs of brain dysfunction as acyclovir and steroids. Measures to control intracranial pressure
(e.g., paresis or paralysis, cranial nerve palsies, sensory deficits, abnor- are paramount.
mal reflexes, generalized convulsions, and abnormal movements). When
Neurologic Complications of AIDS
the central nervous system is affected, clinical syndromes ranging from
febrile headache to aseptic meningitis to encephalitis may occur, and From 40% to 60% of all persons with AIDS have neurologic compli-
these are usually indistinguishable from similar syndromes caused by cations. The most common neurologic disorder is HIV-associated
other viruses. Symptoms usually develop between 3 and 14 days after dementia (HIV encephalopathy). Others are peripheral neuropathies,
a bite by an infected mosquito and may last for a few days to several vacuolar (spongy softening) myelopathy, opportunistic infections of
weeks. The diagnosis is made by serologic examination. the CNS, and neoplasms.
Transmission: WNV is generally distributed by the bite of an infected mos- Human immunodeficiency virus–associated dementia (HIV
quito. Mosquitoes are WNV carriers that become infected when they encephalopathy). HIV-associated dementia (HIV-associated cogni-
feed on infected birds. The bite of infected mosquitoes can then spread tive dysfunction, HIV encephalopathy, subacute encephalitis, HIV-
WNV to humans and other animals. In a very small number of cases, associated dementia complex, HIV cognitive motor complex, AIDS
WNV also has been transferred through blood transfusions, organ trans- encephalopathy, AIDS dementia complex, AIDS-related dementia)
plants, breast-feeding, and even maternal-fetal contact, but the risk is may affect adults or children and is characterized by progressive cogni-
low. WNV is not distributed through casual contact such as touching or tive dysfunction with motor and behavioral alterations. The syndrome
kissing a person with the virus. typically develops later in the disease but may be an early or singular
Risk: Less than 20% of people who are bitten by mosquitoes develop any manifestation in some persons.
symptoms of the disease, and relatively few mosquitoes actually carry In HIV–associated dementia, HIV-infected macrophages and
WNV. People older than age 50 and immunocompromised persons are monocytes from blood accumulate in the brain by up-regulation
more likely to develop serious symptoms. of proinflammatory mediators that enable activated macrophages
Prevention: Prevent mosquito bites. Avoid outdoor activities dusk to dawn and monocytes to penetrate the blood-brain barrier, promoting
or wear protective clothing—long sleeves, long pants, and socks. Treat chronic neuroinflammation and neurodegeneration. The virus can
clothes with insect repellents containing DEET. Higher concentrations of be isolated in the CSF at approximately the time of seroconversion.
active ingredients provide longer protection. Maintain fully functioning Chronic drug abuse (cocaine, opiates, methamphetamine) potentiates
screens on windows and doors. Eradicate mosquito breeding sites by neurotoxicity.41
eliminating or treating standing water. Do not handle dead birds with HIV-associated dementia is insidious in onset and unpredict-
bare hands. No West Nile vaccine has been developed for humans. able in its course. Most persons experience a steady progression with
Since 2003 all blood banks use blood-screening tests for West Nile abrupt accelerations of signs over several months to more than 1 year.
virus. In addition, blood banks will not take donations from people who Impaired concentration and memory deficits are common, and apa-
had a fever and headache in the week before they volunteered to donate thy, lack of motivation, social withdrawal, irritability, and emotional
blood. lability appear. Later, difficulties with language, spatial or temporal
Treatment: There is no specific treatment for WNV infection. Severe symp- disorientation, and visual construction are present. Some persons
toms require hospital care. A subset of persons remain profoundly weak manifest an organic psychosis with agitation, inappropriate behavior,
and limited in daily functioning 1 year following acute illness. Work is in and hallucinosis. Motor signs include difficulty speaking, progressive
progress to develop a vaccine and antiviral therapy. loss of balance, gait ataxia, spastic paraparesis or paralysis, and general-
ized hyperreflexia sometimes accompanied by decreased writing abil-
Data from Avalos-Bock SA: West Nile virus and the US blood supply: ity, tremor, myoclonus, and seizure.
new tests substantially reduce the risk of transmission via donated Diagnosis is difficult, especially in early stages, and CSF analysis, CT
blood products, Am J Nurs 105(12):34–37, 2005; Centers for Dis- scan, and MRI data help establish the diagnosis. Treatment consists of
ease Control and Prevention: Surveillance for human West Nile virus
controlling the disease with antiretroviral agents, protease inhibitors,
disease-United States 1999–2008, MMWR 59(SS2), 2010; Centers for
and reverse transcriptase inhibitors.42
Disease Control and Prevention, Division of Vector Borne Infectious
Diseases: West Nile virus. Available at: http://www.cdc.gov/mmwr/ HIV myelopathy. Myelopathy involving diffuse degeneration of the
preview/mmwrhtml/ss5902a1.htm; Davis LE et al: West Nile virus spinal cord may occur in persons with AIDS (HIV myelopathy). Vacu-
neuroinvasive disease, Ann Neurol 60(3):286–300, 2006; Beasley DW: olar myelopathy is believed to be a direct consequence of HIV. The
Vaccines and immunotherapeutics for the prevention and treatment of lateral and posterior columns of the lumbar spinal cord are affected.
infections with West Nile virus, Immunotherapy 3(2):269–285, 2011. Progressive spastic paraparesis with ataxia is the predominant clinical
manifestation. Leg weakness, upper motor neuron signs, incontinence,
and posterior column sensory loss may be present. Diagnosis is made
on the basis of history, physical findings, and supporting data from
diagnostic procedures. Treatment is supportive.
 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems 397

HIV peripheral neuropathy. HIV has been isolated from peripheral Dendrites
nerves; consequently, the virus may directly infect nerves and cause
neuropathy (HIV distal symmetric polyneuropathy), most com-
monly sensory. Persons experience neuropathic pain including pain-
ful, burning dysesthesias and paresthesias, typically in the extremities.
Weakness and decreased or absent distal reflexes may be present. Diag-
nosis is established through history and physical findings, laboratory
data, and nerve conduction and electromyogram (EMG) studies.
Aseptic viral meningitis. Some persons develop acute aseptic men- Nucleus
Cell body
ingitis at approximately the time of seroconversion. This may repre-
sent the initial infection of the nervous system by the virus. Symptoms
Myelin sheath
include headache, fever, and meningismus (headache, photophobia,
nuchal rigidity). Cranial nerve involvement, especially V and VII, may
appear, but the disease is self-limiting and requires only symptomatic Normal Nerve
treatment.
Opportunistic infections. Opportunistic infections may be bacte-
rial, fungal, or viral in origin and may produce disease. Typically, bac-
terial infections are caused by unusual microorganisms. Cryptococcal Synapses
Nucleus
infection is the most common fungal disorder and the third leading
cause of neurologic disease in persons with AIDS. The symptoms
are vague, such as fever, headache, malaise, and meningismus. Her-
pes encephalitis and herpes varicella-zoster radiculitis may develop. Myelin Damaged Nerve
Papovavirus may produce a demyelinating disorder. Cytomegalovirus
encephalitis and toxoplasmosis (a protozoal infection) are common in Axon
persons with AIDS. Tuberculosis has a high incidence, particularly in Damaged myelin
African countries.
CNS neoplasms. CNS neoplasms associated with AIDS include
CNS lymphoma, systemic non-Hodgkin lymphoma, and metastatic
Kaposi sarcoma. Primary CNS lymphoma is a large-cell tumor that
Exposed axon
presents as rapidly developing and expanding multicentric intracranial
Macrophages
mass lesions. The meninges and, possibly, the cranial nerves and spinal
(microglia)
cord are invaded in systemic non-Hodgkin lymphoma. Metastasis of a
Kaposi sarcoma to the CNS is uncommon.
Other CNS complications. Persons with AIDS may develop multi-
focal ischemic infarctions, hemorrhagic infarctions, hemorrhage into
tumors, subdural hematomas, and epidural hemorrhage. Reported neu-
rologic symptoms produced by AIDS therapeutics include extrapyrami-
dal movements, myoclonus, dysphasia, delirium, and acute myelopathy.
Exposed axon
Demyelinating Degenerative Disorders
Demyelinating disorders result from damage to the myelin nerve
sheath and affect neural transmission. Either the central or the periph- Activated Damaged myelin
eral nervous system can be affected. CNS demyelinating disorders are T cell
subclassified as primary or secondary. Multiple sclerosis is a major
FIGURE 15-14  Pathogenesis of Multiple Sclerosis.
demyelinating syndrome. A disorder is classified as degenerative when
the cause of the degeneration is unclear, which is the case with amyo-
trophic lateral sclerosis. inflammation and demyelination lead to irreversible axonal degen-
eration and scarring (sclerosis). Activated microglia and macrophages
Multiple Sclerosis release nitric acid and oxygen free radicals, and activated immune cells
Multiple sclerosis (MS) is a relatively common acquired autoimmune also produce glutamate, a neurotoxin (Figure 15-14).43a
inflammatory disorder involving destruction of axonal myelin in the MS not only has focal inflammatory changes but also manifests dif-
brain and spinal cord. The onset of MS is usually between 20 and 40 fuse injury throughout the CNS called MS lesions (see Figure 15-14).
years of age and is more common in women. Men may have a more MS lesions can occur anywhere in gray or white matter with localized
severe progressive course. The prevalence rate is affected by gene-envi- areas of demyelination (plaques), changes in the constituents of myelin,
ronment interactions in susceptible individuals.43 damage to oligodendrocytes, substantial loss of neurons over time, and
atrophy of the brain. Even normal appearing white matter is microscop-
PATHOPHYSIOLOGY  MS involves an autoimmune process that ically very abnormal. The multifocal, multistaged features of MS lesions
develops when a previous viral insult to the nervous system has in established disease produce symptoms that are multiple and variable.
occurred in a genetically susceptible individual. B lymphocytes, plasma
cells, and activated T cells, along with proinflammatory cytokines, CLINICAL MANIFESTATIONS  Various events occur immediately
cause inflammation, oligodendrocyte injury, and demyelination. Early before the onset or exacerbation of symptoms and are regarded as
398 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems

precipitating factors, including infection, trauma, and pregnancy. The Amyotrophic Lateral Sclerosis
most common initial symptoms are paresthesias of the face, trunk, or Amyotrophic lateral sclerosis (ALS, sporadic motor neuron disease,
limbs; weakness; visual disturbances; or urinary incontinence, indicat- sporadic motor system disease, motor neuron disease [MND]) is a
ing diffuse CNS involvement. worldwide neurodegenerative disorder that diffusely involves lower
The subtypes of MS are based on the clinical course: remitting- and upper motor neurons, resulting in progressive muscle weakness.
relapsing (RR), primary-progressive (PP), secondary-progressive Amyotrophic (without muscle nutrition or progressive muscle wasting)
(SP), and progressive-relapsing (PR). Initially, 90% of persons pre­ refers to the predominant lower motor neuron component of the syn-
sent with a remitting-relapsing course and without treatment transi- drome. Lateral sclerosis, scarring of the corticospinal tract in the lateral
tion to the progressive types with insidious neurologic decline. Early column of the spinal cord, refers to the upper motor neuron compo-
cognitive changes are common and may include poor judgment, nent of the syndrome.
apathy, emotional lability, and depression. Short-lived attacks of neu- Classic ALS (Lou Gehrig disease) may begin at any time from the
rologic deficits (paresthesias, dysarthria, and ataxia) are the tempo- fourth decade of life; its peak occurrence is in the early fifties. The
rary appearance or worsening of symptoms. The mechanism of these male/female ratio is about 1.5:1, equalizing after menopause. Ten per-
attacks is complete, reversible conduction block in partially demy- cent of persons with ALS have a familial form and specific genes have
elinated axons. Conditions that cause short-lived attacks include (1) been identified.47
minor increases in body temperature or serum calcium (Ca++) con-
centration and (2) functional demands exceeding conduction capac- PATHOPHYSIOLOGY  The cause of motor neuron death in ALS is
ity. An increase in body temperature or serum Ca++ level increases unknown. A subset of persons with familial ALS have a genetic muta-
current leakage through demyelinated neurons. Other triggering tion in copper-zinc superoxide dismutase (SODI) on the glial cells sur-
events include hypercalcemia and physical and emotional stress. Par- rounding the motor neuron that contributes to neurotoxicity through
oxysmal attacks may persist for weeks or months and may be followed oxidative stress, mitochondrial dysfunction, and impaired axonal
by progressive symptoms of MS. transport.48,49 The reuptake of glutamate by glial cells also is dimin-
Individuals with advanced MS have cerebellar symptoms including ished, and glutamate-induced neurotoxicity contributes to neuron
ataxia, slurred speech, and intention tremor. Painful sensory events, degeneration.
spastic paralysis, and bowel and bladder incontinence are common The principal pathologic feature of ALS is lower and upper motor
and disabling with progressive disease.44 neuron degeneration, although without inflammation. There are fewer
large motor neurons in the spinal cord, brain stem, and cerebral cor-
EVALUATION AND TREATMENT  There is no single test available tex (premotor and motor areas), with ongoing degeneration in the
to diagnose or rule out MS and the diagnosis is based on the history remaining motor neurons. Death of the motor neuron results in axo-
and physical examination in combination with MRI and CSF findings. nal degeneration and secondary demyelination with glial proliferation
Persistently elevated levels of CSF immunoglobulin G (IgG) are found and sclerosis (scarring). Widespread neural degeneration of nonmotor
in about two thirds of individuals with MS, and oligoclonal (IgG) neurons in the spinal cord and motor cortices, as well as in the premo-
bands on electrophoresis are found in more than 90% of MS patients. tor, sensory, and temporal cortices, has been found.
Evoked potential studies aid diagnosis by detecting decreased conduc- Lower motor neuron degeneration denervates motor units. Adja-
tion velocity in visual, auditory, and somatosensory pathways. MRI is cent, still viable lower motor neurons attempt to compensate by distal
the most sensitive available method of detecting the disease. intramuscular sprouting, reinnervation, and enlargement of motor
The treatment goal in MS is prevention of exacerbations and units. The initial symptoms of the disease may be related to lower or
permanent neurologic damage and control of symptoms. Disease-­ upper motor neuron dysfunction or to both.
modifying drugs include corticosteroids, immunosuppressants, and
immune system modulators. Drugs are also available for symptom CLINICAL MANIFESTATIONS  About 60% of individuals have a spi-
control.45 Supportive care includes participation in a regular exercise nal form of the disease with focal muscle weakness beginning in the
program, cessation of smoking, and avoidance of overwork, extreme arms and legs and progressing to muscle atrophy, spasticity, and loss
fatigue, and heat exposure. Vitamin D may prevent disease progres- of manual dexterity and gait. No associated mental, sensory, or auto-
sion.46 Stem cell therapy is under investigation (see Health Alert: Stem nomic symptoms are present. ALS with progressive bulbar palsy pre­
Cells: Neuroprotection and Restoration). sents with difficulty speaking and swallowing, and peripheral muscle
weakness and atrophy usually occur within 1 to 2 years. Progressive
muscle atrophy and paralysis lead to respiratory failure and death
HEALTH ALERT within 2 to 5 years although a small percentage of individuals may live
Stem Cells: Neuroprotection and Restoration 10 years or longer.50

Transplantation of adult neural stem cells can protect and restore brain func- EVALUATION AND TREATMENT  Diagnosis of the syndrome is
tions in animal models of ischemic and inflammatory brain injury. Some sub- based predominantly on the history and physical examination with
sets of stem cells replace damaged tissue and also have modulated immune no evidence of other neuromuscular disorders. Electromyography and
responses, providing neuroprotection and potential benefit in diseases such as muscle biopsy results verify lower motor neuron degeneration and
multiple sclerosis. Progress toward the use of stem cells for neuroprotective denervation. Imaging studies and cerebrospinal fluid biomarkers can
and regenerative interventions holds much promise for the future. assist in making the diagnosis. Little treatment is available to alter the
Data from Martino G et al: Stem Cells in Multiple Sclerosis (STEMS)
overall course of the ALS syndrome. The drug riluzole (Rilutek) has
Consensus Group. Stem cell transplantation in multiple sclerosis: cur- extended time not requiring ventilatory assistance. Supportive man-
rent status and future prospects, Nat Rev Neurol 6(5):247–255, 2010; agement and rehabilitative management are directed toward prevent-
Ucelli A, Mancardi G: Stem cell transplantation in multiple sclerosis, ing complications of immobility. Psychologic support of the affected
Curr Opin Neurol 23(3):218–225, 2010. individual and the family is extremely important.51
 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems 399

TABLE 15-10 PERIPHERAL NERVOUS SYSTEM DISORDERS

DISORDER PATHOLOGY CLINICAL MANIFESTATIONS
Radiculopathies Injury to spinal roots as they exit or enter vertebral canal; Affects strength, tone, and bulk of muscles innervated by involved roots;
caused by compression, inflammation, direct trauma pattern similar to that seen in amyotrophies, with tone and deep
tendon reflexes decreased, rarely absent; fasciculations; mild fatigue;
sensory alterations, pain
Plexus injuries Involve nerve plexus distal to spinal roots but proximal to forma- Motor weakness, muscle atrophy, sensory loss in affected areas;
tion of peripheral nerves; caused by trauma, compression, infil- paralysis common
tration, or iatrogenic (positioning or intramuscular injection)
Neuropathies Called sensorimotor if sensory, motor, and reflex effects; Affects muscle strength, tone, and bulk; whole muscles or groups may
pure sensory caused by leprosy, industrial solvents, chlor- be paretic or paralyzed; muscles of feet and legs first, then hands and
amphenicol, and hereditary mechanisms; motor caused by arms; tone and deep tendon reflexes generally decreased with atrophy
Guillain-Barré syndrome, infectious mononucleosis, viral and fasciculation; mild fatigue; some specific symptoms of paresthesia
hepatitis, acute porphyria, or lead, mercury, and triortho- and dysesthesia; altered reflexes; autonomic disturbances; deformities;
cresylphosphate (TCP) poisoning metabolic changes
Guillain-Barré syndrome Acute onset of motor, sensory, or autonomic symptoms Clinical manifestations are related to antibody subtypes; manifestations
(several antibody caused by autoimmune inflammatory response, resulting can include paresis of legs to complete quadriplegia, paralysis of eye
subtypes have been in axonal demyelination; most commonly manifests as muscles, respiratory insufficiency, autonomic nervous system instabil-
identified) ascending motor paralysis; often preceded by respiratory or ity; sensory symptoms (pain, numbness, paresthesias); may progress to
gastrointestinal viral infection respiratory arrest or cardiovascular collapse

From Vucic S, Kiernan MC, Cornblath DR: Guillain-Barré syndrome: an update, J Clin Neurosci 16(6):733–741, 2009.

4 QUICK CHECK 15-3

Myasthenia Gravis
Myasthenia gravis is an acquired chronic autoimmune disease mediated
1. Why is multiple sclerosis an autoimmune disease? by antibodies against the acetylcholine receptor (AChR) at the neuro-
2. Why is amyotrophic lateral sclerosis a motor neuron disease? muscular junction, and is characterized by muscle weakness and fatiga-
bility. The incidence is about 9 to 21 per million population52 and it is
more common in women. Thymic tumors, pathologic changes in the
PERIPHERAL NERVOUS SYSTEM AND thymus, and other autoimmune diseases are associated with the disorder.
NEUROMUSCULAR JUNCTION DISORDERS (Autoimmune mechanisms are discussed in Chapter 7.) Ocular myas-
thenia, more common in males, involves weakness of the eye muscles
Peripheral Nervous System Disorders and eyelids, and may include swallowing difficulties and slurred speech.
Disease processes may injure the axons traveling to and from the brain
stem and spinal cord neuronal cell bodies. The injury may affect a dis- PATHOPHYSIOLOGY  Myasthenia gravis results from a defect in
tinct anatomic area on the axon, or the spinal nerves may be injured nerve impulse transmission at the neuromuscular junction. The post-
at the roots, at the plexus before peripheral nerve formation, or at the synaptic AChRs on the muscle cell’s plasma membrane are no longer
nerves themselves. The cranial nerves do not have roots or plexuses recognized as “self” and elicit the generation of autoantibodies. IgG
and are affected only within themselves. Autonomic nerve fibers may antibody is produced against the AChR and fixes onto the receptor
be injured as they travel in certain cranial nerves and emerge through sites, blocking the binding of acetylcholine. Eventually the antibody
the ventral root and plexuses to pass through the peripheral nerves action destroys receptor sites. This causes diminished transmission of
of the body. Peripheral nervous system disorders are summarized in the nerve impulse across the neuromuscular junction and lack of mus-
Table 15-10. cle depolarization. Symptomatic individuals without anti-AChR anti-
bodies may have antibodies against muscle-specific-kinase (MuSK)
Neuromuscular Junction Disorders with similar symptoms. Why this autosensitization occurs is unknown.
Transmission of the nerve impulse at the neuromuscular junction
requires the release of adequate amounts of neurotransmitter from CLINICAL MANIFESTATIONS  Myasthenia gravis has an insidious
the presynaptic terminals of the axon and effective binding of the onset with the foremost complaint of muscle fatigue and progressive
released transmitter to the receptors on the membranes of muscle cells weakness. Clinical manifestations may first appear during pregnancy,
(see Figure 12-14). Four neuromuscular junction disorders have been during the postpartum period, or in conjunction with the administra-
identified: acetylcholine receptor (AChR) myasthenia gravis, muscle- tion of certain anesthetic agents. The person often complains of fatigue
specific-kinase protein (MuSK) antibody-associated myasthenia gra- after exercise and the muscles of the eyes, face, mouth, throat, and neck
vis, Lambert-Eaton myasthenic syndrome (presynaptic antibodies to usually are affected first. The muscles of the neck, shoulder girdle, and
voltage-dependent calcium channels), and acquired neuromyoto- hip flexors are less frequently affected. The respiratory muscles of the
nia. Nutritional deficits, certain drugs (e.g., reserpine, methyldopa diaphragm and chest wall can become weak with impaired ventilation.
[Aldomet]), certain toxins (e.g., botulism), some venoms, and cer- Myasthenic crisis occurs when severe muscle weakness causes extreme
tain disorders that interfere with the synthesis or packaging of the quadriparesis or quadriplegia, respiratory insufficiency with short-
neurotransmitter or its release into the synaptic cleft may result in ness of breath, and extreme difficulty in swallowing. The individual in
weakness. myasthenic crisis is in danger of respiratory arrest.
400 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems

Cholinergic crisis may arise from anticholinesterase drug toxicity Cranial Tumors
with increased intestinal motility, episodes of diarrhea and complaints Tumors within the cranium can be either primary or metastatic as
of intestinal cramping, bradycardia, pupillary constriction, increased follows:
salivation, and diaphoresis. These are caused by the smooth muscle • Primary—Intracerebral tumors originate from brain substance,
hyperactivity secondary to excessive accumulation of acetylcholine at the including neuroglia, neurons, cells of blood vessels, and connective
neuromuscular junctions and excessive parasympathetic-like activity. As tissue. Extracerebral tumors originate outside substances of brain
in myasthenic crisis, the individual is in danger of respiratory arrest. and include meningiomas, acoustic nerve tumors, and tumors of
pituitary and pineal glands.
EVALUATION AND TREATMENT  The diagnosis of myasthenia gra- • Metastatic—These tumors are found inside or outside brain
vis is made on the basis of a response to edrophonium chloride (Ten- substance.
silon), results of EMG studies, and detection of anti-AChR or MuSK • Sites of intracranial tumors are illustrated in Figure 15-15.
antibodies. With the intravenous administration of the drug, imme- Primary brain tumors (both malignant and nonmalignant) have an
diate demonstrable improvement in muscle strength usually persists estimated incidence rate of 20,020 with 13,140 deaths in the United
for several minutes. Mediastinal tomography and MRI help determine States for 2010.55 The incidence of CNS tumors increases to age 70
whether a thymoma is present. The progression of myasthenia gravis years and then decreases. CNS tumors are the second most common
varies, appearing first as a mild case that spontaneously remits, with a group of tumors occurring in children. Approximately 70% to 75% of
series of relapses and symptom-free intervals ranging from weeks to all intracranial tumors in children are located infratentorially, and in
months. Over time the disease can progress, leading to death. Ocular adults 70% are located supratentorially. Peripheral nerve tumors are
myasthenia has a very good prognosis. rare in children and common in adults.
Anticholinesterase drugs, steroids, and immunosuppressant drugs Local effects of cranial tumors are caused by the destructive action
(e.g., azathioprine and cyclosporine) are used to treat myasthenia of the tumor itself on a particular site in the brain and by compression
gravis and myasthenic crisis. For individuals with cholinergic crisis, causing decreased cerebral blood flow. Effects include seizures, visual
anticholinergic drugs are withheld until blood levels are nontoxic; in disturbances, unstable gait, and cranial nerve dysfunction. Generalized
addition, ventilatory support is provided and respiratory complica- effects result from increased intracranial pressure caused by obstruc-
tions are prevented. Thymectomy is the treatment of choice in indi- tion of the ventricular system, hemorrhages in and around the tumor,
viduals with a thymoma and those with anti-AChR antibodies because or cerebral edema (Figure 15-16).
this terminates the produciton self-reactive T cells and B cells that pro- Intracranial brain tumors do not metastasize as readily as tumors
duce the antibodies.53,54 in other organs because there are no lymphatic channels within the
brain substance. If metastasis does occur, it is usually through seeding
4 QUICK CHECK 15-4 of cerebral blood or CSF during cranial surgery or through artificial
shunts.
1. Where in the peripheral nervous system can disease occur?
2. Why do antibodies contribute to the symptoms of myasthenia gravis?
Primary Brain (Intracerebral) Tumors
Primary brain (intracerebral) tumors, also called gliomas, include
TUMORS OF THE CENTRAL NERVOUS SYSTEM astrocytomas, oligodendrogliomas, and ependymomas. They comprise
CNS tumors include both brain and spinal cord tumors. No proven 50% to 60% of all adult brain tumors and make up about 2% of all can-
causative agents for CNS tumors have been established. Carcinogenesis cers in the United States (Table 15-11). The World Health Organiza-
is discussed in Chapter 9. tion (WHO) divides gliomas into four grades based on histopathologic

Parasagittal Oligodendroglioma Frontal astrocytoma

meningioma

Glioblastoma
multiforme
Metastatic
tumor
from lung

Cystic Sphenoidal
astrocytoma ridge
meningioma Cerebellar
of cerebellum
medulloblastoma
Craniopharyngioma
Pituitary
adenoma Ependymoma of
the fourth
ventricle

FIGURE 15-15  Common Sites of Intracranial Tumors.

 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems 401

Diminished cognitive Behavioral

Neoplasm functioning alteration

Increased Headache
intracranial
pressure Vomiting

Seizures
Invasion Compression
Papilledema

Unsteady gait
Focal deficits Cerebral
depending on edema
location Loss of sphincter
control
FIGURE 15-16  Origin of Clinical Manifestations Associated With an Intracranial Neoplasm.

TABLE 15-11 BRAIN AND SPINAL CORD TUMORS

NEOPLASM LOCATION CHARACTERISTICS CELL OF ORIGIN
Gliomas
Astrocytoma Anywhere in brain or spinal cord Slow growing, invasive Astrocytes
Glioblastoma multiforme Predominantly in cerebral hemispheres Highly invasive and malignant Thought to arise from mature astro-
cytes
Oligodendrocytoma Most commonly in frontal lobes deep in white Relatively avascular; tends to be Oligodendrites
matter; may arise in brain stem, cerebellum, encapsulated; more malignant
and spinal cord form called oligodendroblastoma
Ependymoma Intramedullary: wall of ventricles; may arise in More common in children, variable Ependymal cells
caudal tail of spinal cord growth rates; more malignant,
invasive form is called ependy-
moblastoma; may extend into
ventricle or invade brain tissue

Neuronal Cell
Medulloblastoma Posterior cerebellar vermis, roof of fourth Well-demarcated but infiltrating, Embryonic cells
ventricle rapid growing; fills fourth ventricle

Mesodermal Tissue
Meningioma Intradural, extramedullary: sylvian fissure region, Slow growing, circumscribed, Arachnoid cells; may be from fibro-
superior parasagittal surface of frontal and encapsulated, sharply demarcated blasts
parietal lobes, olfactory groove, wing of from normal tissues, compressive
sphenoid bone, superior surface of cerebellum, in nature
cerebellopontine angle, spinal cord

Choroid Plexus
Papillomas Choroid plexus of ventricular system, lateral Usually benign; slow expansion Epithelial cells
ventricle in children, fourth ventricle in adults inducing hemorrhage and hydro-
cephalus; malignant tumor is rare

Cranial Nerves and Spinal Nerve Roots

Neurilemmoma Cranial nerves (most commonly vestibular division Slow growing Schwann cells
of cranial nerve VIII)
Neurofibroma Extramedullary—spinal cord Slow growing Neurilemma, Schwann cells

Continued
402 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems

TABLE 15-11 BRAIN AND SPINAL CORD TUMORS—cont’d

NEOPLASM LOCATION CHARACTERISTICS CELL OF ORIGIN
Pituitary Tumors
Pituitary gland; may extend to or invade floor of Age linked, several types, slow Pituitary cells, pituitary chromophobes,
third ventricle growing, macroadenomas and basophils, eosinophils
microadenomas

Germ Cell Tumors

Neurohypophysis, hypothalamus, pineal region Rare, 0.5% of all primary brain tumors Several types—germinoma, embryonal
Primarily in adolescents carcinoma, yolk sac tumor, choriocar-
Male > female cinoma, teratoma, mixed germ cell
Variable prognosis tumor—with different cell origins
Pineal region Pineal region; pineal parenchyma Several types (germinoma, pineocy- Several types with different cell
toma, teratoma) origins

Blood Vessel Tumors

Angioma Predominantly in posterior cerebral hemispheres Slow growing Arising from congenitally malformed
arteriovenous connections
Hemangioblastomas Predominantly in cerebellum Slow growing Embryonic vascular tissue

TABLE 15-12 CLASSIFICATION SYSTEMS FOR ASTROCYTOMAS

GRADE* TYPE DESCRIPTION CHARACTERISTICS
I Pilocytic astrocytoma Common in children and young adults and people with Least malignant, well differentiated, grow slowly, near
neurofibromatosis type 1; common cerebellum normal microscopic appearance, non-infiltrating
II Diffuse, low grade Common in young adults, more common in cerebrum Abnormal microscopic appearance, grows slowly, infiltrates
­astrocytoma but can occur in any part of brain to adjacent tissue, may recur at higher grade
(fibrillary, gemistocytic
­protoplasmic)
III Anaplastic (malignant) Common in young adults Malignant, many cells undergoing mitosis, infiltrates adja-
­astrocytoma cent tissue, frequently recur at higher grade
IV Glioblastoma Common in older adults particularly men Poorly differentiated, increased number of cells undergo-
(glioblastoma multiforme) ing cell division, bizarre microscopic appearance, widely
infiltrates, neovascularization, central necrosis

*World Health Organization grading of central nervous system tumors.

Data from: Louis DN et al: The 2007 WHO classification of tumours of the central nervous system, Acta Neuropathol 114(2):97-109, 2007.
­American Brain Tumor Association: A Primer of Brain Tumors, Updated January, 2009. Available at http://www.abta.org/Tumor_&_Treatment_Info/
A_Primer_of_Brain_Tumors/170.

features, cellular density, atypia, mitotic activity, microvascular prolif- They may occur anywhere in the brain or spinal cord; they gener-
eration, and necrosis (Table 15-12). Etiology for primary brain tumors ally are located in the cerebrum, hypothalamus, or pons. Low-grade
is unknown. astrocytomas tend to be located laterally or supratentorially in adults
Surgical or radiosurgical excision, surgical decompression, che- and in a midline or near-midline position in children.
motherapy, radiotherapy, and hyperthermia are treatment options Headache and subtle neurobehavioral changes may be early signs
for these tumors. Supportive treatment is directed at reducing edema. with other neurologic symptoms evolving slowly and increased
(Cancer treatment is discussed in Chapters 10 and 11.) intracranial pressure occurring late in the tumor’s course. Onset
Astrocytoma. Astrocytomas are the most common glioma (about of a focal seizure disorder between the second and sixth decade of
50% of all tumors of the brain and spinal cord)56 and are graded by two life suggests an astrocytoma. Low-grade astrocytomas are treated
classification systems (see Table 15-12). These tumor cells are believed with surgery or by external radiation. Fifty percent of persons sur-
to have lost normal growth restraint and thus proliferate uncontrol- vive 5 years when surgery is followed by radiation therapy (RT).55
lably. Astrocytomas are graded I through IV with grades I and II being Grade I and II astrocytomas commonly progress to a higher grade
slow-growing tumors that may form cavities. tumor.
 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems 403

Grades III and IV astrocytomas are found predominantly in the Malignant degeneration occurs in approximately one third of per-
frontal lobes and cerebral hemispheres, although they may occur in sons with oligodendrogliomas, and the tumors are then referred to as
the brain stem, cerebellum, and spinal cord. Men are twice as likely oligodendroblastomas.
to have astrocytomas as women; in the 15- to 34-year-old age group More than 50% of individuals experience a focal or generalized
they are the third most common brain cancer, whereas in the 35- to seizure as the first clinical manifestation. Only half of those with an
54-year-old age group they are the fourth most common. oligodendroglioma have increased intracranial pressure at the time
Grade IV astrocytoma, glioblastoma multiforme, is the most of diagnosis and surgery, and only one third develop focal manifesta-
lethal and common type of primary brain tumor. They are highly tions. Treatment includes surgery, radiotherapy, and chemotherapy
vascular and extensively infiltrative. Fifty percent of glioblastomas and these tumors may be more sensitive to treatment than other
are bilateral or at least occupy more than one lobe at the time of gliomas.58
death. The typical clinical presentation for a glioblastoma multi- Ependymoma. Ependymomas are nonencapsulated gliomas that
forme is that of diffuse, nonspecific clinical signs, such as headache, arise from ependymal cells; they are rare in adults, usually occurring
irritability, and “personality changes” that progress to more clear- in the spinal cord.59 However, in children ependymomas are typically
cut manifestations of increased intracranial pressure, headache on located in the brain. They constitute about 6% of all primary brain
position change, papilledema, vomiting, or seizure activity. Symp- tumors in adults and 10% in children and adolescents. Approximately
toms may progress to include definite focal signs, such as hemipa- 70% of these tumors occur in the fourth ventricle, with others found
resis, dysphasia, dyspraxia, cranial nerve palsies, and visual field in the third and lateral ventricles and caudal portion of the spinal cord.
deficits. Approximately 40% of infratentorial ependymomas occur in children
Higher grade astrocytomas are treated surgically and with younger than 10 years. Cerebral (supratentorial) ependymomas occur
­radiotherapy and chemotherapy. Recurrence is common and sur- at all ages.
vival time is about 1 to 5 years.57 (See Health Alert: Stereotactic Fourth ventricle ependymomas present with difficulty in balance,
Radioneurosurgery.) unsteady gait, uncoordinated muscle movement, and difficulty with
fine motor movement. The clinical manifestations of a lateral and third
ventricle ependymoma that involves the cerebral hemispheres are sei-
zures, visual changes, and hemiparesis. Blockage of the CSF pathway
HEALTH ALERT produces hydrocephalus and presents with headache, nausea, and
Stereotactic Radioneurosurgery vomiting.
The interval between first manifestations and surgery may be as
Stereotactic radiosurgery is a treatment modality in which a minimally inva- short as 4 weeks or as long as 7 or 8 years. Ependymomas are treated
sive series of radiation beams converge on a specific target from various with radiotherapy, radiosurgery, and chemotherapy. About 20% to
angles; no incision is needed. A high dose of radiation can be directed to a 50% of persons survive 5 years. Some persons benefit from a shunting
specific target with minimal radiation to adjacent normal tissue. Applications procedure when the ependymoma has caused a noncommunicating
in the brain include benign and malignant brain tumors, vascular lesions such hydrocephalus.
as arteriovenous malformations, pain syndromes such as trigeminal neuralgia,
movement disorders, and epilepsy. The techniques can be used with excep- Primary Extracerebral Tumors
tional geometric and dosimetric accuracy for primary treatment or as an adju- Meningioma. Meningiomas constitute about 30% of all intracra-
vant to surgical resection or whole-brain radiation therapy. Radiographs and nial tumors. These tumors usually originate from the arachnoidal
CT and/or MRI scans are required for precise localization of the target in three (meningeal) cap cells in the dura mater and rarely from arachnoid cells
dimensions. The skull is secured in position by either a headframe or a plastic of the choroid plexus of the ventricles. Meningiomas are located most
mask. Frameless and maskless positioning systems will soon be available. commonly in the olfactory grooves, on the wings of the sphenoid bone
(at the base of the skull), in the tuberculum sellae (a structure next to
From Suh JH: Stereotactic radiosurgery for the management of brain
metastases, N Engl J Med 362(12):1119–1127, 2010; Rahman M et al:
the sella turcica), on the superior surface of the cerebellum, and in the
Stereotactic radiosurgery and the linear accelerator: accelerating elec- cerebellopontine angle and spinal cord. The cause of meningiomas is
trons in neurosurgery, Neurosurg Focus 27(3):E13, 2009; Hoeffelt CS: unknown.
Gamma Knife vs CyberKnife, Oncology Issues September, October A meningioma is sharply circumscribed and adapts to the shape
18–29, 2006. Available at http://www.swmedicalcenter.com/ it occupies. It may extend to the dural surface and erode the cranial
documents/Cyberknife/OncologyIssuesVol21No5.pdf; Kilby W et al: bones or produce an osteoblastic reaction. A few meningiomas exhibit
The CyberKnife Robotic Radiosurgery System in 2010, Technol Cancer malignant, invasive qualities.
Res Treat 9(5):433–452, 2010; Cervińo LI et al: Frame-less and mask- Meningiomas are slow growing and clinical manifestations occur
less cranial stereotactic radiosurgery: a feasibility study, Phys Med Biol when they reach a certain size and begin to indent the brain paren-
55(7):1863–1873, 2010.
chyma. Focal seizures are often the first manifestation and increased
intracranial pressure is less common than with gliomas.
There is a 20% recurrence rate even with complete surgical exci-
Oligodendroglioma. Oligodendrogliomas constitute about 2% of sion. If only partial resection is possible, the tumor recurs. Radiation
all brain tumors and 10% to 15% of all gliomas. They are typically therapies also are used to slow growth.
slow-growing tumors, and most oligodendrogliomas are macroscopi- Nerve sheath tumors. Neurofibromas (benign nerve sheath
cally indistinguishable from other gliomas and may be a mixed type tumors) are a group of autosomal dominant disorders of the ner-
of oligodendroglioma and astrocytoma. The majority are found in vous system. They include neurofibromatosis type 1 (NF1, previously
the frontal and temporal lobes, often in the deep white matter, but known as von Recklinghausen disease) and neurofibromatosis type
they are found also in other parts of the brain and spinal cord. Many 2 (NF2), also known as peripheral and central neurofibromatosis,
are found in young adults with a history of temporal lobe epilepsy. respectively.
404 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems

Neurofibromatosis type 1 is the most prevalent with an incidence (astrocytomas and ependymomas). Gliomas are difficult to resect
of about 1 in 3500 people and causes multiple cutaneous neurofibro- completely and radiotherapy is required. Spinal ependymomas may
mas, cutaneous macular lesions (café-au-lait spots and freckles), and be completely resected and are more common in adults. Extramed-
less commonly bone and soft tissue tumors.60 Inactivation of the NF1 ullary tumors are either peripheral nerve sheath tumors (neurofi-
gene results in loss of function of neurofibromin in Schwann cells and bromas or schwannomas) or meningiomas. Neurofibromas are
promotes tumorigenesis (neurofibromas). Learning disabilities are generally found in the thoracic and lumbar region, whereas menin-
present in about 50% of affected individuals.61 giomas are more evenly distributed through the spine. Complete
Neurofibromatosis type 2 is rare and occurs in about 1 in 60,000 resection of these tumors can be curative. Other extramedullary
people. The NF2 gene product is neurofibromin 2 (merlin), a tumor- tumors are sarcomas, vascular tumors, chordomas, and epidermoid
suppressor protein, and mutations promote development of central tumors.
nervous system tumors, particularly schwannomas, although other Metastatic spinal cord tumors are usually carcinomas, lymphomas,
tumor types can occur (meningiomas, ependymomas, astrocytomas, or myelomas. Their location is often extradural, having proliferated to
and neurofibromas). Schwannomas of the vestibular nerves present the spine through direct extension from tumors of the vertebral struc-
with hearing loss and deafness. Other symptoms may include loss of tures or from extraspinal sources extending through the interventricu-
balance and dizziness. Schwannomas also may develop in other cra- lar foramen or bloodstream.
nial, spinal, and peripheral nerves and cutaneous signs are less promi-
nent. Intracranial meningiomas can involve the optic nerve with loss PATHOPHYSIOLOGY  Extramedullary spinal cord tumors produce
of visual acuity and cataracts, or be intraspinal with formation of dysfunction by compressing adjacent tissue, not by direct invasion.
ependymomas.62 Intramedullary spinal cord tumors produce dysfunction by both inva-
Genetic testing is available for the management of NF families and sion and compression. Metastases from spinal cord tumors occur from
prenatal diagnosis is possible. Diagnosis is based on clinical manifes- direct extension or seeding through the CSF or bloodstream.
tations and neuroimaging studies, and diagnostic criteria have been
established for NF1.63 Surgery is the major treatment. Individuals with CLINICAL MANIFESTATIONS  The acute onset of clinical manifes-
NF2 have extensive morbidity and reduced life expectancy, particularly tations suggests a vascular occlusion of vessels supplying the spinal
with early age of onset. Genetically tailored drugs are likely to provide cord whereas gradual and progressive symptoms suggest compres-
huge improvements for both of these devastating conditions. sion. The compressive syndrome (sensorimotor syndrome) involves
Pituitary tumors are discussed in Chapter 18 and cerebral tumors both the anterior and the posterior spinal tracts, and motor function
in children are discussed in Chapter 16. and sensory function are affected as the tumor grows. Pain is usually
Metastatic carcinoma. Metastatic brain tumors from systemic present.
cancers are 10 times more common than primary brain tumors and The irritative syndrome (radicular syndrome) combines the clini-
20% to 40% of persons with cancer have metastasis to the brain.64 cal manifestations of a cord compression with radicular pain (occurs
Common primary sites include lung, breast, skin (e.g., melanomas), in the sensory root distribution and indicates root irritation). The
kidney, and colorectal.65 Other types of cancer can also metastasize to segmental manifestations include segmental sensory changes (pares-
the brain. thesias and impaired pain and touch perception); motor disturbances,
Metastatic brain tumors produce signs resembling those of glio- including cramps, atrophy, fasciculations, and decreased or absent
blastomas, although several unusual syndromes do exist. Carcino- deep tendon reflexes; and continuous spinal pain.
matous encephalopathy causes headache, nervousness, depression,
trembling, confusion, and forgetfulness. In carcinomatosis of the cer- EVALUATION AND TREATMENT  The diagnosis of a spinal cord
ebellum, headache, dizziness, and ataxia are found. Carcinomatosis of tumor is made through bone scan, PET, CT-guided needle biopsy,
the craniospinal meninges (carcinomatous meningitis) manifests with or open biopsy. Involvement of specific cord segments is established.
headache, confusion, and symptoms of cranial or spinal nerve root Any metastases also are identified. Treatment varies depending on
dysfunction. the nature of the tumor and the person’s clinical status, but surgery is
Metastatic brain tumors carry a poor prognosis. If one to three essential for all spinal cord tumors.67
tumors are present, surgical excision is indicated. Radiotherapy is used
frequently. With the development of new drugs that cross the blood-
brain barrier, chemotherapy is increasingly recommended.66 Survival
is about 1 year. 4 QUICK CHECK 15-5
1. How is an encapsulated CNS tumor different from a nonencapsulated CNS
Spinal Cord Tumors
tumor?
Spinal cord tumors are rare and represent about 2% of CNS tumors. 2. What are three types of spinal cord tumors?
They may be intramedullary tumors (originating within the neural 3. What are some common signs and symptoms of compressive and irritative
tissues) or extramedullary tumors (originating from tissues out- spinal cord tumor syndromes?
side the spinal cord). Intramedullary tumors are primarily gliomas
 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems 405

DID YOU UNDERSTAND?

Central Nervous System Disorders 19. Transient ischemic attacks (TIAs) are temporary decreases in brain blood
1. Motor vehicle crashes are the major cause of traumatic CNS injury. Trau- flow.
matic injuries to the head are classified as closed-head trauma (blunt) or 20. Intracranial aneurysms result from defects in the vascular wall and are
open-head trauma (penetrating). Closed-head trauma is the more common classified on the basis of form and shape. They are often asymptomatic, but
type of trauma. the signs vary depending on the location and size of the aneurysm.
2. Different types of focal brain injury include contusion (bruising of the brain), 21. An arteriovenous malformation (AVM) is a tangled mass of dilated blood
laceration (tearing of brain tissue), extradural hematoma (accumulation of vessels. Although sometimes present at birth, AVM exhibits a delayed age
blood between the bony skull and the dura mater), subdural hematoma of onset.
(blood between the dura mater and arachnoid membrane), intracerebral 22. A subarachnoid hemorrhage occurs when blood escapes from defective
hematoma (bleeding into the brain), and open-head trauma. or injured vasculature into the subarachnoid space. When a vessel tears,
3. Open-head trauma involves a skull fracture with exposure of the cranial blood under pressure is pumped into the subarachnoid space. The blood
vault to the environment. The types of open-head trauma (compound frac- produces an inflammatory reaction in these tissues.
ture, perforated fracture are linear, comminuted, compound, and basilar 23. Migraine headache is an episodic headache that can be associated with
skull fractures) of the cranial vault or at the base of the skull. triggers, and may have an aura associated with a cortical spreading depres-
4. Diffuse brain injury (diffuse axonal injury [DAI]) results from the effects of sion that alters cortical blood flow. Pain is related to overactivity in the
head rotation. The brain experiences shearing stresses that result in axonal trigeminovascular system.
damage ranging from concussion to a severe DAI state. 24. Cluster headaches are a group of disorders known as trigeminal auto-
5. Secondary brain trauma develops from systemic and intracranial responses nomic cephalalgias and occur primarily in men. They occur in clusters over
to primary brain trauma that result in further brain injury and neuronal a period of days with extreme pain intensity and short duration, and are
death. associated with trigeminal activation.
6. Spinal cord injury involves damage to vertebral or neural tissues by com- 25. Tension-type headache is the most common headache. Episodic-type
pressing tissue, pulling or exerting tension on tissue, or shearing tissues so ­headaches involve a peripheral pain mechanism and the chronic type
that they slide into one another. involves a central pain mechanism and may be related to hypersensitivity
7. Spinal cord injury may cause spinal shock with cessation of all motor, sen- to pain in craniocervical muscles.
sory, reflex, and autonomic functions below the transected area. Loss of 26. Infection and inflammation of the CNS can be caused by bacteria, viruses,
motor and sensory function depends on the level of injury. fungi, protozoa, and rickettsiae. Bacterial infections are pyogenic or pus
8. Paralysis of the lower half of the body with both legs involved is called producing.
paraplegia. Paralysis involving all four extremities is called quadriplegia. 27. Meningitis (infection of the meninges) is classified as bacterial, aseptic
9. Return of spinal neuron excitability occurs slowly. Reflex activity can return (nonpurulent), or fungal. Bacterial meningitis primarily is an infection of the
in 1 to 2 weeks in most persons with acute spinal cord injury. A pattern of pia mater, the arachnoid, and the fluid of the subarachnoid space. Aseptic
flexion reflexes emerges, involving first the toes, then the feet and the legs. meningitis is believed to be limited to the meninges. Fungal meningitis is a
Eventually, reflex voiding and bowel elimination appear and mass reflex chronic, less common type of meningitis.
(flexor spasms accompanied by profuse sweating, piloerection, and auto- 28. The meningeal vessels become hyperemic, and neutrophils migrate into
matic bladder emptying) may develop. the subarachnoid space with bacterial meningitis. An inflammatory reac-
10. Degenerative disk disease is an alteration in intervertebral disk tissue and tion occurs, and exudate is formed and increases rapidly.
can be related to normal aging. 29. Brain abscesses often originate from infections outside the CNS. Organ-
11. Spondylolysis is a structural defect of the spine with displacement of the isms gain access to the CNS from adjacent sites or spread along the wall
vertebra. of a vein. A localized inflammatory process develops with formation of exu-
12. Spondylolisthesis involves forward slippage of the vertebra and can date, thrombosis of vessels, and degeneration of leukocytes. After a few
include a crack or fracture of the pars interarticularis, usually at the L5-S1 days, the infection becomes delimited with a center of pus and a wall of
vertebrae. granular tissue.
13. Low back pain is pain between the lower rib cage and gluteal muscles and 30. Clinical manifestations of brain abscesses include headache, nuchal
often radiates into the thigh. rigidity, confusion, drowsiness, and sensory and communication defi-
14. Most causes of low back pain are unknown; however, some secondary cits. Treatment includes antibiotic therapy and surgical excision or
causes are disk prolapse, tumors, bursitis, synovitis, degenerative joint dis- aspiration.
ease, osteoporosis, fracture, inflammation, and sprain. 31. Encephalitis is an acute, febrile illness of viral origin with nervous system
15. Herniation of an intervertebral disk is a protrusion of part of the nucleus involvement. The most common encephalitides are caused by arthropod-
pulposus. Herniation most commonly affects the lumbosacral disks (L5-S1 borne (mosquito-borne) viruses and herpes simplex type 1. Meningeal
and L4-5). The extruded pulposus compresses the nerve root, causing pain involvement appears in all encephalitides.
that radiates along the sciatic nerve course. 32. Clinical manifestations of encephalitis include fever, delirium, confusion,
16. Cerebrovascular disease is the most frequently occurring neurologic disor- seizures, abnormal and involuntary movement, and increased intracranial
der. Any abnormality of the blood vessels of the brain is referred to as a pressure.
cerebrovascular disease. 33. Herpes encephalitis is treated with antiviral agents. No definitive treatment
17. Cerebrovascular disease is associated with two types of brain abnormali- exists for the other encephalitides.
ties: (a) ischemia with or without infarction and (b) hemorrhage. 34. The common neurologic complications of AIDS are HIV-associated demen-
18. Cerebrovascular accidents (stroke syndromes) are classified according to tia, HIV myelopathy, opportunistic infections, cytomegalovirus, parasitic
pathophysiologic mechanisms and include global hypoperfusion, ischemic infection, and neoplasms. Pathologically, there may be diffuse CNS involve-
(thrombotic or embolic), and hemorrhagic (intracranial hemorrhage). ment, focal pathologic changes, and obstructive hydrocephalus.
406 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems

DID YOU UNDERSTAND?—cont’d

Demyelinating Degenerative Disorders 5. Myasthenia gravis is a disorder of voluntary muscles characterized by muscle
1. Multiple sclerosis (MS) is a relatively common demyelinating disorder involv- weakness and fatigability. It is considered an autoimmune disease and is
ing CNS myelin. Although the pathogenesis is unknown, the demyelination is associated with an increased incidence of other autoimmune diseases.
thought to result from an immunogenetic-viral cause. A previous viral insult 6. Myasthenia gravis results from a defect in nerve impulse transmission at
to the nervous system in a genetically susceptible individual yields a subse- the neuromuscular junction. IgG antibody is secreted against the “self”
quent abnormal immune response in the CNS. AChR receptors and blocks the binding of acetylcholine. The antibody action
2. Amyotrophic lateral sclerosis (ALS) is a degenerative disorder diffusely destroys the receptor sites, causing decreased transmission of the nerve
involving lower and upper motor neurons. The pathogenesis of ALS is not impulse across the neuromuscular junction.
fully known; however, there is lower and upper motor neuron degeneration.
Tumors of the Central Nervous System
Peripheral Nervous System and Neuromuscular Junction 1. Two main types of tumors occur within the cranium: primary and metastatic.
Disorders Primary tumors are classified as intracerebral tumors (astrocytomas, oligo-
1. With disorders of the roots of spinal cord nerves, the roots may be com- dendrogliomas, and ependymomas) or extracerebral tumors (meningioma or
pressed, inflamed, or torn. Clinical manifestations include local pain or par- nerve sheath tumors). Metastatic tumors can be found inside or outside the
esthesias in the sensory root distribution. Treatment may involve surgery, brain substance.
antibiotics, steroids, radiation therapy, and chemotherapy 2. CNS tumors cause local and generalized manifestations. The effects are var-
2. P  lexus injuries involve the plexus distal to the spinal roots. Paralysis can ied, and local manifestations include seizures, visual disturbances, loss of
occur with complete plexus involvement. equilibrium, and cranial nerve dysfunction.
3. When peripheral nerves are affected, axon and myelin degeneration may be 3. Spinal cord tumors are classified as intramedullary tumors (within the neural
present. These syndromes are classified as sensorimotor, sensory, or motor tissues) or extramedullary tumors (outside the spinal cord). Metastatic spinal
and are characterized by varying degrees of sensory disturbance, paresis, cord tumors are usually carcinomas, lymphomas, or myelomas.
and paralysis. Secondary atrophy may be present. 4. Extramedullary spinal cord tumors produce dysfunction by compression of
4. G
 uillain-Barré syndrome is a demyelinating disorder caused by a humoral adjacent tissue, not by direct invasion. Intramedullary spinal cord tumors
and cell-mediated immunologic reaction directed at the peripheral nerves. produce dysfunction by both invasion and compression.
The clinical manifestations may vary from paresis of the legs to complete 5. The onset of clinical manifestations of spinal cord tumors is gradual and
quadriplegia, respiratory insufficiency, and autonomic nervous system progressive, suggesting compression. Specific manifestations depend on the
instability. Plasmapheresis is used during the acute phase and followed by location of the tumor; for example, there may be paresis and spasticity of one
aggressive rehabilitation. leg with thoracic tumors, followed by involvement of the opposite leg.

 KEY TERMS
• A myotrophic lateral sclerosis (ALS, •  mbolic stroke  389
E • I ntramedullary tumor  404
sporadic motor neuron disease, sporadic • Encephalitis  395 • Irritative syndrome (radicular
motor system disease, motor neuron • Ependymoma  403 syndrome)  404
disease [MND])  398 • Extradural brain abscess  394 • Kernig sign  391
• Arteriovenous malformation (AVM)  391 • Extradural hematoma  379 • Lacunar stroke (lacunar infarct)  389
• Aseptic meningitis (viral meningitis, non- • Extramedullary tumor  404 • Meningioma  403
purulent meningitis)  394 • Focal brain injury  379 • Meningitis  394
• Autonomic hyperreflexia (dysreflexia)  385 • Fungal meningitis  394 • Migraine headache  392
• Bacterial meningitis  394 • Fusiform aneurysm (giant • Mild concussion  381
• Brain abscess  394 aneurysm)  391 • Mild diffuse axonal injury  381
• Brudzinski sign  391 • Glioblastoma multiforme  403 • Moderate diffuse axonal injury  381
• Cerebrovascular accident (CVA, • Glioma  400 • Multiple sclerosis (MS)  397
stroke)  389 • Guillain-Barré syndrome  406 • Myasthenia gravis  399
• Cholinergic crisis  400 • Headache  392 • Myasthenic crisis  399
• Classic ALS (Lou Gehrig disease)  398 • Hemorrhagic stroke (intracranial • Neurofibroma (benign nerve sheath
• Classic cerebral concussion  381 hemorrhage)  389 tumor)  403
• Closed (blunt) trauma  377 • HIV distal symmetric polyneuropathy  397 • Neurofibromatosis type 1  404
• Cluster headache  393 • HIV myelopathy  396 • Neurofibromatosis type 2  404
• Compound skull fracture  380 • HIV-associated dementia (HIV-associated • Ocular myasthenia  399
• Compressive syndrome (sensorimotor cognitive dysfunction, HIV encephalopa- • Oligodendroblastoma  403
syndrome)  404 thy, subacute encephalitis, HIV-associated • Oligodendroglioma  403
• Contrecoup injury  379 dementia complex, HIV cognitive • Open (penetrating) brain tumor  380
• Contusion  379 motor complex, AIDS encephalopathy, • Open trauma  377
• Coup injury  379 AIDS dementia complex, AIDS-related • Plexus injuries  406
• Degenerative disk disease (DDD)  387 dementia)  396 • Postconcussive syndrome  381
• Diffuse brain injury (diffuse axonal injury • Intracerebral brain abscess  394 • Primary brain (intracerebral) tumor
[DAI])  381 • Intracerebral hematoma  380 (glioma)  400
 CHAPTER 15  Disorders of the Central and Peripheral Nervous Systems 407

 KEY TERMS—cont’d
• S accular aneurysm (berry • S pinal stenosis  387 • T hrombotic stroke (cerebral
aneurysm)  390 • Spondylolisthesis  387 thrombosis)  389
• Secondary brain trauma  381 • Spondylolysis  387 • Toxoplasmosis  395
• Severe diffuse axonal injury  381 • Subarachnoid hemorrhage  391 • Transient ischemic attack (TIA)  389
• Spinal cord abscess  391 • Subdural hematoma  380 • Vacuolar myelopathy  396
• Spinal shock  383 • Tension-type headache  393 • West Nile virus (WNV)  396

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 CHAPTER

16
Alterations of Neurologic Function
in Children
Vinodh Narayanan

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Normal Growth and Development of the Nervous System, 409 Seizure Disorders, 417
Structural Malformations, 410 Acute Encephalopathies, 418
Defects of Neural Tube Closure, 410 Cerebrovascular Disease in Children, 419
Malformations of the Axial Skeleton, 413 Tumors, 419
Encephalopathies, 415 Brain Tumors, 419
Static Encephalopathies, 415 Embryonal Tumors, 421
Inherited Metabolic Disorders of the Central Nervous System, 415

Neurologic disorders in children can occur from infancy through developmental stage at which it acts. Nutritional deficiency (in par-
adolescence and include congenital malformations, genetic defects in ticular, folic acid deficiency) during formation of the neural tube (3 to
metabolism, brain injuries, infection, tumors, and other disorders that 4 weeks’ gestation) can result in failure of neural tube closure, whereas
affect neurologic function. Compared to adults, the symptoms, diag- a fetal viral infection during the proliferative stage (3 to 5 months’ ges-
nosis, and management of neurologic disorders in children are often tation) can cause the development of a small brain. Micronutrients,
different. including iron, are also important for the development of the nervous
system1,2 (see Health Alert: Iron and Cognitive Function).
NORMAL GROWTH AND DEVELOPMENT OF THE The growth and development of the brain occur rapidly during the
third and fourth months of gestation and again from the fifth month
NERVOUS SYSTEM of gestation through the first year of life, reflecting the proliferation
The nervous system develops from the embryonic ectoderm through a of neurons and glial cells. The head is the fastest growing body part
complex, sequential process that can be arbitrarily divided into stages. during infancy. One half of postnatal brain growth is achieved by the
These include (1) formation of the neural tube (3 to 4 weeks’ gesta- first year and is 90% complete by age 6 years. The cortex thickens with
tion), (2) development of the forebrain from the neural tube (2 to 3 maturation, and the sulci deepen as a result of rapid expansion of the
months’ gestation), (3) neuronal proliferation and migration (3 to 5 surface area of the brain. Cerebral blood flow and oxygen consump-
months’ gestation), (4) formation of network connections and syn- tion during these years are about twice those of the adult brain.
apses (5 months’ gestation to many years postnatally), and (5) myelin- The bones of the infant’s skull are separated at the suture lines,
ation (birth to many years postnatally). Environmental factors (e.g., forming two fontanelles or “soft spots”: one diamond-shaped ante-
nutrition, hormones, oxygen levels, toxins, alcohol, drugs, maternal rior fontanelle and one triangular-shaped posterior fontanelle. The
infections, maternal disease) can have a significant effect on neural sutures allow for expansion of the rapidly growing brain. The poste-
development. The effect of an environmental factor depends on the rior fontanelle may be open until 2 to 3 months of age; the anterior

409
410 CHAPTER 16  Alterations of Neurologic Function in Children

Metopic suture
HEALTH ALERT Anterior
fontanelle
Iron and Cognitive Function Frontal bone
Iron deficiency is the single most significant nutrient deficiency, affecting 15%
of the world population and causing anemia in 40% to 50% of children. Iron is Coronal
essential for neurologic activity, including synthesis of dopamine, serotonin, suture
and catecholamine and, possibly, formation of myelin. Children with iron
deficiency have decreased attentiveness, narrow attention spans, short-term Sagittal
memory changes, and perceptual restrictions. In some studies, cognitive defi- suture
cits caused by iron deficiency can be reversed with iron supplements. Contin-
ued research is in progress to determine effects of acute versus chronic iron
Parietal
deficiency and the relationship between severity of deficiency and cognitive bone
and other neurophysiologic functions.

Data from Carter RC et al: Iron deficiency anemia and cognitive func-
tion in infancy, Pediatrics 126(2):e427–e434, 2010; Madan N et al:
Developmental and neurophysiologic deficits in iron deficiency in
children, Indian J Pediatr 78(1):58–64, 2011.

Lambdoidal
suture
fontanelle normally does not fully close until 18 months of age (Figure
16-1). Head growth almost always reflects brain growth. Monitoring Posterior fontanelle Occipital bone
the fontanelles and careful measurement and plotting of the head cir-
FIGURE 16-1  Cranial Sutures and Fontanelles in Infancy. Fibrous
cumference on standardized growth charts are essential elements of the union of suture lines and interlocking of serrated edges (occurs by 6
pediatric examination.3 A common cause of accelerating head growth months; solid union requires approximately 12 years). (Head growth
and macrocephaly is hydrocephalus, a condition in which the cerebral charts are available from the Centers for Disease Control and Pre-
spinal fluid (CSF) compartment (ventricles) is enlarged. Increased vention at www.cdc.gov/nchs/data/series/sr_11/sr11_246.pdf.)
intracranial pressure, with distention or bulging of the fontanelles, and
separation of the sutures are key signs of hydrocephalus. Microcephaly
(head circumference below the 2nd percentile for age) can be the result
of prenatal infection, toxin exposure, or malnutrition, or have a pri- TABLE 16-1 REFLEXES OF INFANCY
mary genetic etiology. AGE OF AGE AT WHICH REFLEX
Because of the immaturity of much of the human forebrain at birth, APPEARANCE SHOULD NO LONGER BE
neurologic examination of the infant detects mostly reflex responses REFLEX OF REFLEX OBTAINABLE
that require an intact spinal cord and brain stem. Some of these reflex
Moro Birth 3 months
patterns are inhibited as cerebral cortical function matures, and these
Stepping Birth 6 weeks
patterns disappear at predictable times during infancy (Table 16-1).
Sucking Birth 4 months awake
Absence of expected reflex responses at the appropriate age indicates
7 months asleep
general depression of central or peripheral motor functions. Asymmet-
Rooting Birth 4 months awake
ric responses may indicate lesions in the motor cortex or peripheral
7 months asleep
nerves, or may occur with fractures of bones after traumatic delivery or
Palmar grasp Birth 6 months
postnatal injury. As the infant matures, the neonatal reflexes disappear
Plantar grasp Birth 10 months
in a predictable order as voluntary motor functions supersede them.
Tonic neck 2 months 5 months
Abnormal persistence of these reflexes is seen in infants with develop-
Neck righting 4-6 months 24 months
mental delays or with central motor lesions.
Landau 3 months 24 months
Parachute reaction 9 months Persists indefinitely
STRUCTURAL MALFORMATIONS
Also see demonstration of primitive or postural reflexes at http://library. 
Central nervous system (CNS) malformations are responsible for 75% med.utah.edu/pedineurologicexam/html/home_exam.html.
of fetal deaths and 40% of deaths during the first year of life. CNS mal-
formations account for 33% of all apparent congenital malformations,
and 90% of CNS malformations are defects of neural tube closure. of disorders collectively referred to as the myelodysplasias (dys = bad;
plassein = to form). Anterior midline defects may cause brain and face
Defects of Neural Tube Closure abnormalities, with the most extreme form being cyclopia, in which
The incidence of neural tube defects ranges from 1.0 to 10 per 1000 the child has a single midline orbit and eye with a protruding nose-like
live births in the United States each year.4 Fetal death often occurs proboscis above the orbit. Disorders of embryonic development are
in the more severe forms, thereby reducing the actual prevalence of summarized in Figure 16-2. The cause of neural tube defects is believed
neural defects at birth.5 These defects are divided into two catego- to be multifactorial (a combination of genes and environment). No
ries: (1) posterior defects (dorsal induction) and (2) anterior midline single gene has been found to cause neural tube defects.6 Folic acid
defects (ventral induction). Posterior defects are more common and deficiency during early stages of pregnancy increases the risk for neural
include anencephaly (an = without; enkephalos = brain) and a group tube defects,7 but preconceptional supplementation ensures adequate
 CHAPTER 16  Alterations of Neurologic Function in Children 411

Dorsal (posterior) Ventral (anterior)

Gestation time induction induction
(days) (3—4 weeks) (3—6 weeks)

0—18 days 18 26 28 32 42
Development of Development of Closure Closure of Beginning of Development of
three germ layers neural plate of anterior posterior vascular five cerebral
and formation of and groove neuropore neuropore circulation vesicles, choroid
early neural plate plexus, dorsal
root ganglion
Disorders
No effect or death Anterior midline Anencephaly Posterior midline Microcephaly
defects (faciotel- defects (primary)
encephalopathies) Myelomeningocele (30—175 days)
Cyclopia Encephalocele
Holoprosencephaly, Cranium bifidum
cleft lip and/or palate Spina bifida occulta

Proliferation Migration Organization

(2—4 months) (3—6 months) (5th fetal month to
24th postnatal month)
56 90 150 175 7—9 months
Differentiation of Corpus Primary fissures of End of neuronal Formation of
cerebral cortex, callosum cerebral cortex; end proliferation in secondary and
meninges, ventricular development of spinal cord at cerebral cortex tertiary sulci
foramina, and CSF L3 level
circulation

Disorders

“True” microcephaly Abnormalities of the cerebral Destructive pathologic

hemispheres and convolutions changes:
Microcephaly
Visual abnormalities (secondary)
Mental retardation
Myelination Seizure disorders
(6 months’ gestation to adulthood)

6 months Adulthood
Development of myelin wrapping

Disorders
Congenital hypomyelination
Leukodystrophies

FIGURE 16-2  Disorders Associated With Specific Stages of Embryonic Development.

folate status. Other risk factors include heredity, maternal blood glu- face-on at birth. Both of these malformations result in spontaneous
cose concentrations, use of anticonvulsant drugs (particularly valproic abortion or early neonatal death.
acid), and maternal hyperthermia.4,5 Encephalocele refers to a herniation or protrusion of brain and
The most severe malformation that results from complete failure of meninges through a defect in the skull, resulting in a saclike structure.
posterior neural tube closure is craniorachischisis totalis. A platelike The incidence is approximately 1.4 per 10,000 live births in the United
structure is present on the back without overlying skeleton or skin. In States each year.9,10 In Europe and the United States, most encepha-
anencephaly, the soft, bony component of the skull and part of the loceles occur in the occipital region, whereas in Russia and Southeast
brain are missing. This is a relatively common disorder, with an inci- Asia, encephaloceles are most often in the frontonasal region.10
dence of approximately 1 per 8000 total live births in the United States Meningocele, which is a saclike cyst of meninges filled with spi-
each year.8 The infant’s head has a froglike appearance when viewed nal fluid, is a mild form of posterior neural tube closure defect
412 CHAPTER 16  Alterations of Neurologic Function in Children

TABLE 16-2 FUNCTIONAL ALTERATIONS

Skin IN MYELODYSPLASIA
Vertebra
RELATED TO LEVEL OF
LESION
Meninges LEVEL OF LESION FUNCTIONAL IMPLICATIONS
Thoracic Flaccid paralysis of lower extremities; variable
Spinal cord
weakness in abdominal trunk musculature;
high thoracic level may mean respiratory com-
promise; absence of bowel and bladder control
A
High lumbar Voluntary hip flexion and adduction; flaccid
paralysis of knees, ankles, and feet; may walk
with extensive braces and crutches; absence
Meninges of bowel and bladder control
Mid lumbar Strong hip flexion and adduction; fair knee
extension; flaccid paralysis of ankles and feet;
absence of bowel and bladder control
Skin
Low lumbar Strong hip flexion, extension, and adduction and
knee extension; weak ankle and toe mobility;
may have limited bowel and bladder function
Cystic sac Sacral Normal function of lower extremities; normal
filled with CSF bowel and bladder function
B
Modified from Farley JA, Dunleavy MJ: Myelodysplasia. In Allen PJ,
Vessey JA, editors: Primary care of the child with a chronic condition,
ed 4, St Louis, 2004, Mosby.
Spinal cord

Skin
prominences of the unfused neural arches can be palpated at the lateral
border of the defect. The defect usually is covered by a transparent
Meninges membrane that may have neural tissue attached to its inner surface.
This membrane may be intact at birth or may leak cerebrospinal fluid
(CSF), thereby increasing the risks of infection and neuronal damage.
CSF
Surgical repair is critical and is usually performed during the first 24
C to 48 hours of life.
FIGURE 16-3  Normal Spine, Meningocele, and Myelomeningo- The spinal cord and nerve roots are malformed at the level of the
cele. Diagram showing section through normal spine (A), meningo- myelomeningocele, resulting in loss of motor, sensory, reflex, and
cele (B), and myelomeningocele (C). autonomic functions below the level of the lesion. A brief neurologic
examination concentrating on motor function in the legs, reflexes, and
sphincter tone is usually sufficient to determine the level above which
(Figure 16-3). This cystic dilation of meninges protrudes through the spinal cord and nerve root function is preserved (Table 16-2). This is
vertebral defect but does not involve the spinal cord or nerve roots useful to predict if the child will ambulate, require bladder catheteriza-
and may produce no neurologic deficit. Meningoceles occur with equal tion, or be at high risk for developing scoliosis.
frequency in the cervical, thoracic, and lumbar spine areas. Spina bifida Hydrocephalus occurs in 85% of infants with myelomeningo-
occulta is a term used to describe a purely vertebral defect and is the cele.12 Seizures also occur in 30% of those with myelodysplasia. Visual
mildest form of posterior neural tube closure defect (see p. 413). and perceptual problems, including ocular palsies, astigmatism, and
Myelomeningocele (meningomyelocele; spina bifida cystica) is a visuoperceptual deficits, are common. Motor and sensory functions
hernial protrusion of a saclike cyst (containing meninges, spinal fluid, below the level of the lesions are altered. Often these problems worsen
and a portion of the spinal cord with its nerves) through a defect in the as the child grows and the cord ascends within the vertebral canal, pull-
posterior arch of a vertebra. Eighty percent of myelomeningoceles are ing primary scar tissue and tethering the cord.13 Several musculoskel-
located in the lumbar and lumbosacral regions, the last regions of the etal deformities are related to this diagnosis, as are spinal deformities.
neural tube to close. Myelomeningocele is one of the most common Myelomeningoceles are almost always associated with the type II
developmental anomalies of the nervous system, with an incidence rate Chiari malformation (also known as the Arnold-Chiari malforma-
ranging from 0.2 to 0.4 per 1000 live births.11 tion).14 This is a complex malformation of the brain stem and cerebel-
lum in which the cerebellar tonsils are displaced downward into the
CLINICAL MANIFESTATIONS  Most cases of myelomeningocele cervical spinal canal; the upper medulla and lower pons are elongated
are diagnosed prenatally by a combination of maternal serologic test- and thin; and the medulla is also displaced downward and sometimes
ing (alpha-fetoprotein) and prenatal ultrasound. In these cases, the has a “kink” (Figure 16-4). The Chiari II malformation also is associ-
fetus is usually delivered by elective cesarean section to minimize ated with hydrocephalus and syringomyelia, an abnormality causing
trauma during labor. Myelomeningoceles are evident at birth as a pro- cysts at multiple levels within the spinal cord. Other forms of Chiari
nounced skin defect on the infant’s back (see Figure 16-3). The bony malformation include type I, which is a milder form of type II and
 CHAPTER 16  Alterations of Neurologic Function in Children 413

Periconceptual maternal folate deficiency and genetic alterations are

commonly associated with the defect.7 Approximately 80% of these
vertebral defects are located in the lumbosacral region, most com-
monly in the fifth lumbar vertebra and the first sacral vertebra. Certain
cutaneous or subcutaneous abnormalities suggest underlying spina
bifida, including the following:
1. Abnormal growth of hair along the spine, which often is either very
coarse or very silky
2. A midline dimple with or without a sinus tract
Pons
3. A cutaneous angioma, usually of the “port wine” variety
Cerebellum
4. A subcutaneous mass, usually representing a lipoma or dermoid
cyst
Cerebral
Medulla tonsils
When the defect occurs without any visible exposure of meninges
or neural tissue, the term spina bifida occulta is used. In spina bifida
Fourth occulta, the posterior vertebral laminae have failed to fuse. Extremely
A ventricle
common, the defect occurs to some degree in 10% to 25% of infants.
About 3% of normal adults have spina bifida occulta of the atlas
(C1). Spina bifida occulta usually causes no serious neurologic dys-
functions. Symptoms become evident during periods of rapid growth
and are a result of tethering of the spinal cord (attachment of the
spinal cord to adjacent tissue that results in abnormal stretching of
the cord). Neurologic signs of spina bifida occulta include gait abnor-
mality (toe walking), foot deformity (equinovarus), and sphincter
disturbance of the bladder. Surgical treatment is usually directed at
associated intraspinal abnormalities (tethered cord, sacral lipoma, or
dermoid cyst).

Cranial Deformities
Pons
Skull malformations range from minor, insignificant defects to major
Tentorium defects that are incompatible with life. In acrania, the cranial vault is
almost completely absent, and an extensive defect of the vertebral col-
umn often is present. Acrania associated with anencephaly (absence of
brain) occurs in approximately 1 per 1000 live births and is incompat-
Fourth ventricle
ible with life.
Downward displacement Craniosynostosis (craniostenosis) is the premature closure
of cerebellar tonsils
of one or more of the cranial sutures (sagittal, coronal, lambdoid,
through foramen
magnum metopic) during the first 18 to 20 months of the infant’s life. The
Area of incidence of craniosynostosis is 1 per 2100 live births.15 Males are
Medulla
compression affected twice as often as females. Fusion of a cranial suture pre-
vents growth of the skull perpendicular to the suture line, resulting
in an asymmetric shape of the skull. The general term plagioceph-
aly, meaning “misshapen skull,” is used to describe deformities
that result from craniosynostosis or from asymmetric head posture
B (positional). When a single coronal suture fuses prematurely, the
head is flattened on that side in front. When the sagittal suture fuses
FIGURE 16-4  Normal Brain and Arnold-Chiari II Malformation. prematurely, the head is elongated in the anteroposterior direction
A, Diagram of normal brain. B, Diagram of Arnold-Chiari II malforma- (scaphocephaly).16 Single suture craniosynostosis is usually only
tion with downward displacement of cerebellar tonsils and medulla a cosmetic issue. Rarely, when multiple sutures fuse prematurely,
through foramen magnum causing compression and obstruction brain growth may be restricted, and surgical repair may prevent neu-
to flow of CSF. (B modified from Barrow Neurological Institute of rologic dysfunction (Figure 16-5).
St Joseph’s Hospital and Medical Center. Reprinted with permission.)
Microcephaly is a defect in brain growth as a whole (see Figure
16-5). Cranial size is significantly below average for the infant’s age,
may be asymptomatic; type III, in which the brain stem or cerebellum gender, race, and gestation. True (primary) microcephaly is usually
extend into a high cervical myelomeningocele; and type IV, which is caused by an autosomal recessive genetic or chromosomal defect.
characterized by lack of cerebellar development. Secondary (acquired) microcephaly is associated with various causes.
Infection, toxin or radiation exposure, trauma, metabolic disorders,
Malformations of the Axial Skeleton and anoxia experienced during the third trimester of pregnancy, the
Spina Bifida perinatal period, or early infancy may be responsible. Table 16-3 sum-
When defects of neural tube closure, such as meningocele and myelo- marizes the causes of microcephaly. Microcephaly may develop later in
meningocele, occur, an accompanying vertebral defect allows the pro- life in certain genetic disorders (e.g., Rett syndrome) or in degenerative
trusion of the neural tube contents. Such a defect is called spina bifida. brain disorders.
414 CHAPTER 16  Alterations of Neurologic Function in Children

Sagittal Coronal
suture suture

BRACHYCEPHALY
NORMAL SKULL

MICROCEPHALY AND CRANIOSTENOSIS

OXYCEPHALY OR ACROCEPHALY

SCAPHOCEPHALY OR DOLICHOCEPHALY PLAGIOCEPHALY

FIGURE 16-5  Normal and Abnormal Head Configurations. Normal skull: Bones separated by mem-
branous seams until sutures gradually close. Microcephaly and craniostenosis: Microcephaly is head
circumference more than 2 standard deviations below the mean for age, gender, race, and gestation
and reflects a small brain; craniosynostosis is premature closure of sutures. Scaphocephaly or dolicho-
cephaly (frequency 56%): Premature closure of sagittal suture, resulting in restricted lateral growth.
Brachycephaly: Premature closure of coronal suture, resulting in excessive lateral growth. Oxycephaly
or acrocephaly (frequency 5.8% to 12%): Premature closure of all coronal and sagittal sutures, result-
ing in accelerated upward growth and small head circumference. Plagiocephaly (frequency 13%): Uni-
lateral premature closure of coronal suture, resulting in asymmetric growth. (From Hockenberry MJ:
Wong’s nursing care of infants and children, ed 7, St Louis, 2003, Mosby.)

Congenital hydrocephalus is characterized by enlargement of the

TABLE 16-3 CAUSES OF MICROCEPHALY cerebral ventricles. It may be caused by blockage within the ventricular
PERINATAL system where the CSF flows, an imbalance in the production of CSF, or a
DEFECTS IN BRAIN INTRAUTERINE AND POSTNATAL reduced reabsorption of CSF.17 The pressure within the ventricular sys-
DEVELOPMENT INFECTIONS DISORDERS tem pushes and compresses the brain tissue against the skull cavity. When
Hereditary (recessive) Congenital rubella Intrauterine or
hydrocephalus develops before fusion of the cranial sutures, the skull can
­microcephaly ­neonatal anoxia
expand to accommodate this additional space-occupying volume and
Down syndrome and other Cytomegalovirus Severe malnutrition
preserve neuronal function. The overall incidence of hydrocephalus is
trisomy syndromes infection in early infancy
approximately 3 per 1000 live births. The incidence of hydrocephalus that
Fetal ionizing radiation Congenital Neonatal herpesvirus
is not associated with myelomeningocele is approximately 0.5 to 1 per
exposure ­toxoplasmosis infection
1000 live births.18 (Types of hydrocephalus are discussed in Chapter 14.)
Maternal phenylketonuria
The Dandy-Walker malformation (DWM) is a congenital defect of
Cornelia de Lange syndrome
the cerebellum characterized by a large posterior fossa cyst that com-
Rubinstein-Taybi syndrome
municates with the fourth ventricle and an atrophic, upwardly rotated
Smith-Lemli-Opitz syndrome
cerebellar vermis.19 DWM is commonly associated with hydrocepha-
Fetal alcohol syndrome
lus caused by compression of the aqueduct of Sylvius. Other causes of
Angelman syndrome obstructions within the ventricular system that can result in hydro-
Seckel syndrome cephalus include brain tumors, cysts, trauma, arteriovenous malfor-
mations, blood clots, and infections.
 CHAPTER 16  Alterations of Neurologic Function in Children 415

Congenital hydrocephalus may cause fetal death in utero, or the symptoms of each of these cerebral palsy types, which leads to a mixed
increased head circumference may require cesarean delivery of the disorder accounting for approximately 13% of cases.23
infant. Symptoms depend directly on the cause and rate of hydroceph- Children with cerebral palsy often have associated neurologic dis-
alus development. When there is separation of the cranial sutures, a orders, such as seizures (about 50%), and intellectual impairment
resonant note sounds when the skull is tapped, a manifestation termed ranging from mild to severe (about 67%). Other complications include
Macewen sign or “cracked pot” sign. The eyes may assume a star- visual impairment, communication disorders, respiratory problems,
ing expression, with sclera visible above the cornea, called sunsetting. bowel and bladder problems, and orthopedic disabilities.24
Cognitive impairment in children with hydrocephalus is often related Although often caused by a fixed lesion (remote injury), the clinical
to associated brain malformations, or episodes of shunt failure or picture of cerebral palsy may change with growth and development.
infection. Approximately two thirds of children with uncomplicated Therefore an effective treatment regimen includes ongoing assess-
congenital hydrocephalus who have been treated successfully with ment, evaluation, and revision of the child’s overall management plan.
shunting may have normal to borderline normal intelligence.20 The use of oral baclofen, intrathecal baclofen infusion, and botulinum
toxin injections, has positively impacted many children with cerebral
4 QUICK CHECK 16-1
palsy. Family-focused interdisciplinary team management provides
the best treatment outcomes.25,26
1. List two defects of neural tube closure.
2. Why do motor and sensory functions worsen with growth in a child with a Inherited Metabolic Disorders of the Central
neural tube defect?
Nervous System
A large number of inherited metabolic disorders have been identified,
typically leading to diffuse brain dysfunction. Early diagnosis and treat-
ENCEPHALOPATHIES
ment is vital if these infants are to survive without severe neurologic
Encephalopathy, meaning brain dysfunction, is a general category that problems. Table 16-4 lists some of these inherited metabolic disorders.
includes a number of syndromes and diseases (see Chapter 15). These
disorders may be acute or chronic, as well as static or progressive.
TABLE 16-4 INHERITED METABOLIC
Static Encephalopathies DISORDERS OF THE CENTRAL
Static or nonprogressive encephalopathy describes a neurologic con- NERVOUS SYSTEM
dition caused by a fixed lesion without active and ongoing disease.
AGE OF ONSET DISORDER
Causes include brain malformations (disorders of neuronal migra-
tion) or brain injury that may occur during the fetal period, around Neonatal period Pyridoxine dependency, galactosemia, urea cycle
birth, or later during childhood. The degree of neurologic impairment defects, maple syrup urine disease and its ­variant,
is directly related to the extent of the injury or malformation. Anoxia, phenylketonuria (PKU), Menkes kinky hair syndrome
trauma, and infections are the most common factors that cause injury Early infancy Tay-Sachs disease and its variants, infantile
to the nervous system in the perinatal period. Infections, metabolic Gaucher disease, infantile Niemann-Pick
disturbances (acquired or genetic), trauma, toxins, and vascular dis- disease, Krabbe disease (leukodystrophy), Farber
ease may injure the nervous system in the postnatal period. lipogranulomatosis, Pelizaeus-Merzbacher
Cerebral palsy is a term used to describe a group of nonprogressive disease and other sudanophilic leukodystrophies,
syndromes that affect the brain and cause motor dysfunction begin- spongy degeneration of CNS (Canavan disease),
ning in early infancy. The causes include prenatal or perinatal cerebral Alexander disease, Alpers disease, Leigh disease
hypoxia, hemorrhage, or infection. It can be classified on the basis of (subacute necrotizing encephalomyelopathy), con-
neurologic signs and motor symptoms, with the major types involving genital lactic acidosis, Zellweger encephalopathy,
spasticity, ataxia, or dystonia, or a combination of these symptoms. Lowe disease (oculocerebrorenal disease)
Diplegia, hemiplegia, or tetraplegia may be present.21 Cerebral palsy Late infancy and Disorders of amino acid metabolism, ­metachromatic
is one of the most common crippling disorders of childhood, affecting early childhood leukodystrophy, adrenoleukodystrophy, late
approximately 764,000 children and adults in the United States alone. infantile GM1 gangliosidosis, late infantile
The incidence of cerebral palsy is about 2 to 2.5 cases per 1000 live Gaucher and Niemann-Pick diseases, neuroaxonal
births.22 dystrophy, mucopolysaccharidosis, mucolipidosis,
Spastic cerebral palsy is associated with increased muscle tone, fucosidosis, mannosidosis, aspartylglycosamin-
persistent primitive reflexes, hyperactive deep tendon reflexes, clonus, uria, neuronal ceroid lipofuscinoses (Jansky-­
rigidity of the extremities, scoliosis, and contractures. This accounts Bielschowsky disease, Batten disease, Vogt-­
for approximately 70% to 80% of cerebral palsy cases. Dystonic cere- Spielmeyer disease, neuronal ceroid lipofuscinosis),
bral palsy is associated with extreme difficulty in fine motor coordina- Cockayne syndrome, ataxia telangiectasia (AT)
tion and purposeful movements. Movements are stiff, uncontrolled, Later childhood and Progressive cerebellar ataxias of childhood and ado-
and abrupt, resulting from injury to the basal ganglia or extrapyrami- adolescence lescence, hepatolenticular degeneration (Wilson
dal tracts. This form of cerebral palsy accounts for approximately 10% disease), Hallervorden-Spatz disease, Lesch-Nyhan
to 20% of cases. Ataxic cerebral palsy manifests with gait disturbances syndrome, Aicardi-Goutieres syndrome, progres-
and instability. The infant with this form of cerebral palsy may have sive myoclonus epilepsies, homocystinuria, Fabry
hypotonia at birth, but stiffness of the trunk muscles develops by late disease
infancy. Persistence of this increased tone in truncal muscles affects the Data from Lyon G, Kolodny E, Pastores GM, editors: Neurology of
child’s gait and ability to maintain equilibrium. This form of cerebral hereditary metabolic diseases of children, ed 3, New York, 2006,
palsy accounts for approximately 5% to 10% of cases. A child may have McGraw Hill.
416 CHAPTER 16  Alterations of Neurologic Function in Children

Dietary
phenylalanine

Abnormal Increased
Alternate
metabolites serum levels of
pathway
formed phenylalanine
Normal
metabolic
pathway
Phenylpyruvic blocked Central nervous
acid in urine system damage

Decreased
tyrosine Mental retardation
Hyperactivity
Seizures

Decreased Decreased Decreased

tryptophan dopa melanin

Decreased plasma Fair skin

Decreased levels Blue eyes
levels of
of serotonin Blond hair
catecholamines
FIGURE 16-6  Metabolic Error and Consequences in Phenylketonuria. (From Hockenberry MJ:
Wong’s nursing care of infants and children, ed 8, St Louis, 2007, Mosby.)

Defects in amino acid and lipid metabolism are among the most com- levels remain high. Nonselective newborn screening is used to detect
mon. Some of these disorders (e.g., urea cycle defects, organic acidurias) PKU in the United States and in more than 30 other countries. Treat-
present in the newborn period with hyperammonemia and coma. ment, consisting of reduction of dietary phenylalanine (PKU diet), is
effective and allows for normal development of most of these children.
Defects in Amino Acid Metabolism Some individuals have a positive response when sapropterin, a synthetic
Biochemical defects in amino acid metabolism include (1) those in form of tetrahydrobiopterin, is included in their treatment.28
which the transport of an amino acid is impaired, (2) those involving
an enzyme or cofactor deficiency, and (3) those encompassing certain Defects in Lipid Metabolism
chemical components, such as branched-chain or sulfur-containing Disorders of lipid metabolism are termed lysosomal storage diseases
amino acids. Most of these disorders are caused by genetic defects because each disorder in this group can be traced to a missing lyso-
resulting in lack of a normal protein and absence of enzymatic activity. somal enzyme. Lysosomal storage disorders include more than 50
Phenylketonuria. Phenylketonuria (PKU) is an inborn error of known genetic disorders caused by an inborn error of metabolism.
metabolism characterized by the inability of the body to convert the The incidence of lysosomal storage disorders is approximately 1 in
essential amino acid phenylalanine to tyrosine (Figure 16-6). PKU is 7500 live births.29 These disorders cause an excessive accumulation of
caused by phenylalanine hydroxylase deficiency and has an incidence a particular cell product, occurring in the brain, liver, spleen, bone,
of 1:15,000 in the United States.27,27a Most natural food proteins con- and lung, and thus involving several organ systems. Some of these dis-
tain about 15% phenylalanine, an essential amino acid. Phenylalanine orders may be treated with enzyme replacement therapy.29a
hydroxylase controls the conversion of this essential amino acid to tyro- Perhaps the best known of the lysosomal storage disorders is Tay-
sine in the liver. The body uses tyrosine in the biosynthesis of proteins, Sachs disease (GM2 gangliosidosis), an autosomal recessive disor-
melanin, thyroxine, and the catecholamines in the brain and adrenal der related to a deficiency of the enzyme hexosaminidase A (HEXA).
medulla. Phenylalanine hydroxylase deficiency causes an accumulation Approximately 80% of individuals diagnosed are of Jewish ancestry,
of phenylalanine in the serum. Other types of PKU involve impaired although sporadic cases appear in the non-Jewish population. In Tay-
synthesis of cofactors (e.g., tetrahydrobiopterin [BH4]), which contrib- Sachs disease, GM2 ganglioside accumulates in neurons throughout
utes to elevated levels of phenylalanine. Elevated phenylalanine levels the body, although the pathologic progressive changes prevail in the
result in developmental abnormalities of the cerebral cortical layers, CNS. Onset of this disease usually occurs when the infant is 4 to 6
defective myelination, and cystic degeneration of the gray and white months old. Symptoms of Tay-Sachs include an exaggerated startle
matter. Unfortunately, brain damage occurs before the metabolites can response to loud noise, seizures, developmental regression, dementia,
be detected in the urine, and damage continues as long as phenylalanine and blindness. Death from this disease is almost universal and occurs
 CHAPTER 16  Alterations of Neurologic Function in Children 417

TABLE 16-5 MAJOR TYPES OF SEIZURE DISORDERS FOUND IN CHILDREN

DISORDER PATHOLOGY
Generalized Seizure First clinical manifestations indicate that seizure activity starts in or involves both cerebral hemispheres; consciousness
may be impaired

Convulsive Activity
Tonic-clonic Musculature stiffens, then intense jerking as trunk and extremities undergo rhythmic contraction and relaxation
Atonic Sudden, momentary loss of muscle tone; drop attacks
Myoclonic Sudden, brief contractures of a muscle or group of muscles

Nonconvulsive Activity
Absence Brief loss of consciousness with minimal or no loss of muscle tone; may experience 20 or more episodes a day lasting
approximately 5-10 sec each; may have minor movement, such as lip smacking, twitching of eyelids
Epilepsy Syndromes Seizure disorders that display a group of signs and symptoms that occur collectively and characterize or indicate a particu-
lar condition
Infantile spasms (West syndrome) Form of epilepsy with episodes of sudden flexion or extension involving neck, trunk, and extremities; clinical manifesta-
tions range from subtle head nods to violent body contractions (jackknife seizures); onset between 3 and 12 months of
age; may be idiopathic, genetic, result of metabolic disease, or in response to CNS insult; spasms occur in clusters of
5-150 times per day; EEG shows large-amplitude, chaotic, and disorganized pattern called “hypsarrhythmia”
Lennox-Gastaut syndrome Epileptic syndrome with onset in early childhood, 1-5 yr of age; includes various generalized seizures—tonic-clonic, atonic
(drop attacks), akinetic, absence, and myoclonic; EEG has characteristic “slow spike and wave” pattern; results in mental
retardation and delayed psychomotor developments
Juvenile myoclonic epilepsy Onset in adolescence; multifocal myoclonus; seizures often occur early in morning, aggravated by lack of sleep or after
excessive alcohol intake; occasional generalized convulsions; require long-term medication treatment

Partial Seizure Types Seizure activity that begins and usually is limited to one part of left or right hemisphere
Simple Seizure activity that occurs without loss of consciousness
Complex Seizure activity that occurs with impairment of consciousness
Benign rolandic epilepsy Epileptic syndrome typically occurring in the pre-adolescent age (6-12 yr); strong association with sleep (seizures typically
occur few hours after sleep onset or just before waking in morning); complex partial seizures with orofacial signs (drool-
ing, distortion of facial muscles); characteristic EEG with centrotemporal (Rolandic fissure) spikes

Unclassified Epileptic Seizures

Neonatal seizures Wide variety of abnormal clinical activity, including rhythmic eye movements, chewing, and swimming movements; com-
mon in neonatal seizures
Simple febrile seizures Common in children younger than 5-6 yr of age; brief (less than a few minutes) generalized convulsions associated with
high fever; important to exclude meningitis as cause of seizures; usually do not develop epilepsy
Pseudoseizures Non-epileptic phenomena that look like epileptic seizures; diagnosis often requires video-EEG monitoring to capture spells,
and determine that EEG is normal during clinical events; frequently occurs in setting of child abuse

Status Epilepticus
Nonconvulsive Continuing or recurring seizure activity in which recovery from seizure activity is incomplete; unrelenting seizure activity can
Convulsive last 30 min or more; other forms can evolve into status epilepticus; medical emergency that requires immediate intervention

by 5 years of age. Screening for carriers of the gene defect concomitant primarily neurologic (CNS) or are systemic and affect CNS function
with counseling to prevent disease transmission is possible.30 secondarily (such as diabetes). Seizures can be caused by structural
abnormalities of the brain, hypoxia, intracranial hemorrhage, CNS
infection, traumatic injury, electrolyte imbalance, or inborn metabolic
4 QUICK CHECK 16-2 disturbances. Febrile seizures occur in up to 5% of children between
ages 6 months and 5 years and are usually benign. Seizures are some-
1. List three types of cerebral palsy.
2. Why does failure to metabolize phenylalanine produce such widespread times clearly familial. Often the cause of epilepsy is unknown and pre-
and devastating consequences? sumed to have a genetic basis.
The incidence of epilepsy varies greatly with age and is estimated to
occur in 0.5% to 1% of children, with onset developing during infancy
Seizure Disorders or childhood.31 It decreases with age; 75% to 80% of epilepsy cases ini-
Epilepsy tially occur before 20 years of age, with 30% of the cases initially occur-
Seizures are the abnormal discharge of electrical activity within the ring within the first 4 years of life. Approximately 200,000 individuals
brain. Epilepsy is a neurologic condition characterized by a predispo- in the United States are newly affected each year; 45,000 are under age
sition to recurrent seizures. Seizures may result from diseases that are 15 years.32 Table 16-5 summarizes the major types of seizures.
418 CHAPTER 16  Alterations of Neurologic Function in Children

TABLE 16-6 COMMONLY INGESTED

Acute Encephalopathies
Reye Syndrome
POISONS
Reye syndrome is characterized by encephalopathy, hyperammone- PHARMACOLOGIC MISCELLANEOUS
mia, and fatty changes in the liver. The incidence of Reye syndrome AGENTS HEAVY METALS AGENTS
has declined sharply since the 1980s, coinciding with increased public Acetaminophen Arsenic Alcohols
awareness of the association between ingestion of aspirin or aspirin- Amphetamines Lead Ethyl
containing products during illness and subsequent development of Anticonvulsants Acute Isopropyl
Reye syndrome.33 Antidepressants Chronic Methyl
An overview of Reye syndrome is important for the following rea- Antihistamines Mercury Botulism toxin
sons: (1) it may be considered a prototype for acute hepatic encepha- Atropine Thallium Chlorinated hydrocarbons
lopathies, (2) the potential for recurrence is a factor, and (3) the use of Barbiturates Ethylene glycol
acetaminophen rather than aspirin during childhood febrile illnesses Methadone Mushrooms
should be discussed with the parents. Phencyclidine Organophosphates
Typically, Reye syndrome develops in a previously healthy child Salicylates Pesticides
who is recovering from varicella, influenza B, upper respiratory tract Tranquilizers Snakebite
infection, or gastroenteritis. The manifestations of the various clinical Tick bites
states are as follows: Venoms
Stage I: vomiting, lethargy, drowsiness
Stage II: disorientation, delirium, aggressiveness and combativeness, Data from Swaiman KF, Ashwal S, Ferriero DM: Pediatric neurology:
central neurologic hyperventilation, shallow breathing, hyperactive principles and practice, ed 4, St Louis, 2006, Mosby.
reflexes, stupor
Stage III: obtundation, coma, hyperventilation, decorticate rigidity
Stage IV: deepening coma, decerebrate rigidity, loss of ocular reflexes,
large fixed pupils, divergent eye movements bacterial meningitis affects males more often than females and is most
Stage V: seizures, loss of deep tendon reflexes, flaccidity, respiratory prevalent during infancy.38 Conditions associated with increased inci-
arrest dence of respiratory tract infection heighten the occurrence of bacterial
Reye syndrome is a result of a toxin interfering with normal mito- meningitis. The introduction of the protein conjugate vaccines against
chondrial function. Treatment and outcome depend on the stage of Haemophilus influenzae type B, Streptococcus pneumoniae, and Neis-
development at diagnosis and the individual child’s symptoms. seria meningitidis has decreased the incidence of bacterial meningitis.39
Haemophilus influenzae type B was once the most common pathogen
Intoxications of the Central Nervous System of bacterial meningitis in children younger than 5 years, but H. influ-
Drug-induced encephalopathies must always be considered a possibil- enzae meningitis has declined dramatically since the introduction of
ity in the child with unexplained neurologic changes. Such encepha- the Hib vaccine.40-41
lopathies may result from accidental ingestion, therapeutic overdose, Now the most common microorganism to cause bacterial menin-
intentional overdose, or ingestion of environmental toxins (the most gitis is Neisseria meningitidis (meningococcus)—60% of all pediatric
commonly ingested poisons are listed in Table 16-6). Approximately cases of meningitis.42 Approximately 4% to 5% of infants and 23% to
1.6 million children were exposed to poisons and approximately 650 27% of 19 year olds are carriers of N. meningitidis.43 The risk of devel-
children died in the United States in 2007 as a result of poisoning 34,34a oping meningitis from day-care center contact of children with menin-
High blood levels of lead occur in lead poisoning. If lead poisoning gococcal disease is 1 per 1000.44
is untreated, lead encephalopathy results and is responsible for serious The second most common microorganism that causes meningitis is
and irreversible neurologic damage. Those at greatest risk are children Streptococcus pneumoniae, which is likely to be found in children older
ages 2 to 3 years and children prone to the practice of pica—the habit- than 4 years. Staphylococcal or streptococcal meningitis shows a predi-
ual, purposeful, and compulsive ingestion of non–food substances, lection for children who have undergone neurosurgical procedures or
such as clay, soil, and paint chips. Lead intoxication also may occur fractured their skull; it also can develop as a complication of systemic
from chronic exposure to lead in cosmetics, inhalation of gasoline bacterial infection. Infections that originate in the middle ear, sinuses,
vapors, and ingestion of airborne lead.35 or mastoid cells also may lead to S. pneumoniae meningitis in chil-
An estimated 250,000 children ages 1 to 5 years in the United dren. In addition, 1 in every 24 children with sickle cell disease devel-
States (2.2% of children 1 month to 5 years of age) have excessive ops pneumococcal meningitis by the age of 4 years. Escherichia coli
amounts of lead in their blood.36 The incidence in black children is and group B β-hemolytic streptococci are the most common causes of
five times greater than that in white children. Most lead exposures are meningitis in the newborn.
preventable.37 Viral meningitis. The hallmark of viral meningitis, or aseptic men-
ingitis, is a mononuclear response in the CSF and the presence of nor-
Meningitis mal glucose levels as well. Viral meningitis may result from a direct
Meningitis refers to the inflammation of the meningeal coverings of infection of a virus, or it may be secondary to disease, such as measles,
the brain. In most cases, meningitis is a result of viral or bacterial infec- mumps, herpes, or leukemia.
tion. It also can develop secondary to a chemical irritant (e.g., drugs, Onset of symptoms may be sudden or gradual. Malaise, fever,
contrast agents) or result from diffuse infiltration with malignant cells headache and stiff neck, abdominal pain, and nausea and vomiting are
(cancer). common. Sore throat, chest pain, photophobia, and maculopapular
Bacterial meningitis. Bacterial meningitis is one of the most seri- rash can develop also. The child usually recovers spontaneously within
ous infections to which infants and children are susceptible. In general, 3 to 10 days. Treatment is usually symptomatic.
 CHAPTER 16  Alterations of Neurologic Function in Children 419

Medulloblastoma, ependymoma, astrocytoma, brain stem glioma,

CEREBROVASCULAR DISEASE IN CHILDREN
craniopharyngioma, and optic nerve glioma constitute approximately
Cerebrovascular disease in children differs from that in adults in three 75% to 80% of all pediatric brain tumors. Most brain tumors in chil-
ways: dren are located in the posterior fossa (Figure 16-7); treatment strate-
1. An absence of predisposing factors, such as high blood pressure and gies and prognosis are listed in Table 16-8.
arteriosclerosis Signs and symptoms of brain tumors in children vary from general-
2. Significant differences in the clinical response related to the devel- ized and vague to localized and related specifically to an anatomic area.
oping nervous system, and thus greater capacity for the pediatric Signs of increased intracranial pressure may occur, including head-
brain to recovery from vascular insult ache, vomiting, lethargy, and irritability. If a young child complains
3. The anatomic site of the pathologic condition of repeated and worsening headache, a thorough investigation should
Occlusive cerebrovascular disease is rare in children and may take place because headache is an uncommon complaint in young
result from embolism, sinovenous thrombosis, or congenital or iat- children. Headache caused by increased intracranial pressure usually
rogenic narrowing of vessels, which leads to a decreased flow of blood is worse in the morning and gradually improves during the day when
and oxygen to areas of the brain. Stroke is among the top 10 causes of the child is upright and venous drainage is enhanced. The frequency of
death in children. Risk factors include cardiac diseases, hematologic headache and other symptoms increases as the tumor grows. Irritabil-
and vascular disorders, and infection. Half of acute ischemic strokes ity or possible apathy and increased somnolence also may result. Like
occur with no known risk factors.45 Sickle cell disease is the most com- headache, vomiting occurs more commonly in the morning. Often it
mon hematologic risk factor for ischemic stroke and is more common is not preceded by nausea and may become projectile, differing from a
at 2 to 5 years of age, with hemorrhagic stroke more frequent at 20 gastrointestinal disturbance in that the child may be ready to eat imme-
to 30 years of age. A combination of chronic hemolytic anemia and diately after vomiting. Other signs and symptoms include increased
vaso-occlusion contributes to brain ischemia and infarction. Congeni- head circumference with bulging fontanelle in the child younger than
tal cerebral arteriovenous malformations are the most common cause 2 years, cranial nerve palsies, and papilledema (Box 16-1).
of intracranial bleeding and hemorrhagic stroke in children.46 Localized findings relate to the degree of disturbance in physiologic
Moyamoya disease is a rare, chronic, progressive vascular steno- functioning in the area where the tumor is located. Children with
sis of the circle of Willis with obstruction of arterial flow to the brain infratentorial tumors exhibit localized signs of impaired coordination
and the development of basal arterial collateral vessels that vascularize and balance, including ataxia, gait difficulties, truncal ataxia, and loss
hypoperfused brain distal to the occluded vessels.47 Moyamoya means of balance. Medulloblastoma occurs as an invasive malignant tumor
a “puff of smoke” in Japanese. The disease is idiopathic or associated that develops in the vermis of the cerebellum and may extend into
with other disorders (moyamoya syndrome). the fourth ventricle. Ependymoma develops in the fourth ventricle
Clinical presentation varies according to the vessels involved, the and arises from the ependymal cells that line the ventricular system.
cause of the disease, and the age of the individual. Symptoms include Because both tumors are located in the posterior fossa region along
hemiplegia, weakness, seizures, headaches, high fever, nuchal rigid- the midline, presenting signs and symptoms are similar and are usually
ity, hemianopia, sensory changes, facial palsy, and temporary aphasia. related to hydrocephalus and increased intracranial pressure. In con-
Obtaining a thorough history of evolving symptoms and risk factors is trast, cerebellar astrocytomas are located on the surface of the right or
important for diagnosis. Laboratory studies may be indicated. Neuro- left cerebellar hemisphere and cause unilateral symptoms (occurring
imaging studies assist in determining the cause of the disease.48 Surgery
is an option for treatment and anticoagulants and antithrombotics
may be used in selected cases. TABLE 16-7 BRAIN TUMORS IN CHILDREN
TYPE CHARACTERISTICS
TUMORS Astrocytoma Arises from astrocytes, often in cerebellum
or lateral hemisphere
Brain Tumors
Slow growing, solid or cystic
Brain tumors are the most common solid tumor and most prevalent pri- Often very large before diagnosed
mary neoplasm in children. Overall, brain tumors account for nearly 20% Varies in degree of malignancy
of all childhood cancers, with an annual incidence of 2.4 to 4 per 100,000 Optic nerve glioma Arises from optic chiasm or optic nerve
in the United States; approximately 4150 brain tumors are diagnosed each (association with neurofibromatosis type 1)
year.49,50 Five year survival for childhood brain tumors is about 72%.51 Slow-growing, low-grade astrocytoma
Astrocytomas are the most frequent type of brain tumor in children.52 Medulloblastoma Often located in cerebellum, extending into
The cause of brain tumors is largely unknown, although genetic, (infiltrating glioma) fourth ventricle and spinal fluid pathway
environmental, and immune factors have been implicated in some Rapidly growing malignant tumor
tumor development. Factors that have been investigated as the cause Can extend outside CNS
of brain tumors include familial tendencies as well as exposure to radi- Brain stem glioma Arises from pons
ation, oncologic viruses, and chemical carcinogens.53 Alterations in Numerous cell types
embryologic development may play a part in the occurrence of child- Compresses cranial nerves V through X
hood brain tumors. Ependymoma Arises from ependymal cells lining ventricles
Two thirds of all pediatric brain tumors are found in the posterior Circumscribed, solid, nodular tumors
fossa (infratentorial) region of the brain, and approximately one third Craniopharyngioma Arises near pituitary gland, optic chiasm, and
of childhood brain tumors are located in the supratentorial space. hypothalamus
Brain tumors can arise from any CNS cell, and tumors are classified by Cystic and solid tumors that affect vision,
cell type. The types and characteristics of childhood brain tumors are pituitary, and hypothalamic functions
summarized in Table 16-7.
420 CHAPTER 16  Alterations of Neurologic Function in Children

Craniopharyngiomas
• Located adjacent to the sella turcica (structure containing the pituitary gland), often
considered to lie supratentorial
• Considered to have benign properties but is life threatening because of its location
near vital structures
• 4.9% of brain tumors in children
5%
Cerebral tumors
• Astrocytomas invade
surrounding structures
Optic nerve but grow slowly
gliomas 8% Supratentorial
• Most often a
• Ependymomas arise
low-grade
from lining tissue of
astrocytoma
lateral ventricle
6%
6%

Brain stem gliomas Medulloblastomas

• Arise from pons or medulla • Arise from cerebellum
• 10% of childhood brain tumors • Can invade fourth
• Slow growing ventricle, subarachnoid
• May involve cranial nerves V - X space, and cerebrospinal
10% fluid pathways
Infratentorial ependymomas • 18% of brain tumors in Infratentorial
Cerebellar astrocytomas children
• Arise from lining tissue
• Most common brain • Fast growing
of fourth ventricle
tumor of childhood (20%) • Arise from embryonic
• Comprise 13% of childhood
• Slow growing cerebellum
brain tumors together with
• Grading system I to IV 18%
supratentorial ependymomas
with I and II less malig-
13%
nant than III and IV
20%
FIGURE 16-7  Location of Brain Tumors in Children.

TABLE 16-8 TREATMENT STRATEGIES FOR CHILDHOOD BRAIN TUMORS

TUMOR TYPE TREATMENT AND PROGNOSIS
Cerebellar astrocytoma Surgery; possibly curative
Radiation and chemotherapy not proved successful but may delay recurrence
90%-100% 5-yr survival rate if pilocytic type; if tumor recurs, it does so very slowly
Medulloblastoma Surgery, primarily as partial resection to relieve increased intracranial pressure and “debulk” tumor
Type of treatment is age and tumor type dependent
Radiation as primary treatment; may include spinal radiation
Chemotherapy showing some promise in conjunction with craniospinal radiation
65%-85% 5-yr survival rate depending on stage/type
Brain stem glioma Surgery, resection occasionally possible
Radiation, primarily palliative treatment
Chemotherapy not yet proven beneficial, but new protocols being studied
20%-40% 5-yr survival rate
Ependymoma Tumor possibly indolent for many years
Surgery rarely curative; risk of resecting an infratentorial tumor too great
Radiation for palliation (current controversy over whether local or craniospinal radiation is best)
Chemotherapy used for recurrent disease but with disappointing results
20%-80% 5-yr survival rate dependent on total resection
Craniopharyngioma Surgery possibly successful when complete resection is performed (partial resection usually requires further treatment)
Radiation after partial surgical resection
Chemotherapy not commonly used
80%-95% 5-yr survival rate
Optic nerve glioma In setting of visual impairment, or progression (increase in size), chemotherapy is usual initial treatment
Surgery for hydrocephalus or other complications; rarely for diagnosis
Radiation therapy for those tumors that progress or recur in spite of chemotherapy
Cerebral astrocytoma Surgery used if resection is possible
Radiation useful for all grades of astrocytoma
Chemotherapy beneficial in higher grade tumors but further study required
75% 5-yr survival rate with lower grade tumors

Data from Packer RJ, Macdonald T, Vezina G: Central nervous system tumors, Hematol-Oncol Clin North Am 24(1):87–108, 2010; Merchant TE, Pollack
IF, Loeffler JS: Brain tumors across the age spectrum: biology, therapy, and late effects, Semin Radiat Oncol 20(1):58–66, 2010; Gurney JG, Smith,
MA, Bunin GR: CNS and miscellaneous intracranial and intraspinal neoplasms, ICCC III, Cancer incidence and survival among children and adolescents:
United States SEER Program 1975–1995, National Cancer Institute, pp 51–63. Available at http://seer.cancer.gov/publications/childhood/cns.pdf.
 CHAPTER 16  Alterations of Neurologic Function in Children 421

BOX 16-1 CLINICAL MANIFESTATIONS OF BRAIN TUMORS

Headache Behavioral Changes
Recurrent and progressive Irritability
In frontal or occipital area Decreased appetite
Worse on arising, pain lessens during the day Failure to thrive
Intensified by lowering head and straining, such as when defecating, coughing, Fatigue (frequent naps)
sneezing Lethargy
Coma
Vomiting Bizarre behavior (staring, automatic movements)
With or without nausea or feeding
Progressively more projectile Cranial Nerve Neuropathy
More severe in morning Cranial nerve involvement varies according to tumor location
Relieved by moving and changing position Most common signs
Head tilt
Neuromuscular Changes Visual defects (nystagmus, diplopia, strabismus, episodic “graying out” of
Uncoordination or clumsiness vision, and visual field defects)
Loss of balance (use of wide-based stance, falling, tripping, banging into object)
Poor fine motor control Vital Sign Disturbances
Weakness Decreased pulse and respiratory rates
Hyporeflexia or hyperreflexia Increased blood pressure
Positive Babinski sign Decreased pulse pressure
Spasticity Hypothermia or hyperthermia
Paralysis
Other Signs
Seizures
Cranial enlargement*
Tense, bulging fontanelle at rest*
Nuchal rigidity
Papilledema (edema of optic nerve)

From Hockenberry MN: Wong’s essentials of pediatric nursing, ed 7, St Louis, 2005, Mosby.
*Present only in infants and young children.

on the same side as the tumor), such as head tilt, limb ataxia, and Occasionally, these tumors have been diagnosed at birth with metas-
nystagmus. tasis apparent in the placenta. It is seen more commonly in white chil-
Brain stem gliomas often cause a combination of cranial nerve dren (9.6 per million) than in black children (7 per million). Although
involvement (facial weakness, limitation of horizontal eye move- it accounts for only 8% to 10% of pediatric malignancies,54 neuroblas-
ment), cerebellar signs of ataxia, and corticospinal tract dysfunction. toma causes 15% of cancer deaths in children.
Increased intracranial pressure generally does not occur. Neuroblastoma is the most common and immature form of the
The area of the sella turcica, the structure containing the pituitary sympathetic nervous system tumors. Areas of necrosis and calcifica-
gland, is the site of several childhood brain tumors; most common tion often are present in the tumor. More than with any other cancer,
of this group is the craniopharyngioma. This tumor originates from neuroblastoma has been associated with spontaneous remission, com-
the pituitary gland or hypothalamus. Usually slow growing, it may monly in infants. Prognosis is worse for children older than 2 years of
be quite large by the time of diagnosis. Symptoms include headache, age with disseminated disease.55
seizures, diabetes insipidus, early onset of puberty, and growth delay. Although familial tendency has been noted in individual cases, a
Other tumors located in this region of the brain include optic glio- nonfamilial or sporadic pattern is found in most children with neu-
mas. Optic nerve gliomas are associated with neurofibromatosis type roblastoma. Familial cases of neuroblastoma are considered to have
1, a neurocutaneous condition characterized by café-au-lait mac- an autosomal dominant pattern of inheritance (mechanisms of inheri-
ules on the skin and benign tumors of the skin. Tumors that involve tance are discussed in Chapter 2).
the optic tract may cause complete unilateral blindness and hemi- The most common location of neuroblastoma is in the retroperi-
anopia of the other eye. Optic atrophy is another common finding. toneal region (65% of cases), most often the adrenal medulla. The
Supratentorial tumors of the cerebral hemispheres in children are tumor is evident as an abdominal mass and may cause anorexia, bowel
uncommon. and bladder alteration, and sometimes spinal cord compression. The
second most common location of neuroblastoma is the mediastinum
Embryonal Tumors (15% of cases), where the tumor may cause dyspnea or infection
Neuroblastoma related to airway obstruction. Less commonly, neuroblastoma may
Neuroblastoma is an embryonal tumor originating in neural crest arise from the cervical sympathetic ganglion (3% to 4% of cases). Cer-
cells that normally develop into sympathetic ganglia and the adrenal vical neuroblastoma often causes Horner syndrome, which consists of
medulla. Because neuroblastoma involves a defect of embryonic tis- miosis (pupil contraction), ptosis (drooping eyelid), enophthalmos
sue, it most commonly is diagnosed during the first 2 years of life, (backward displacement of the eyeball), and anhidrosis (sweat defi-
and 75% of neuroblastomas are found before the child is 5 years old. ciency). Neuroblastoma rarely presents with a neurologic syndrome
422 CHAPTER 16  Alterations of Neurologic Function in Children

called opsoclonus-myoclonus syndrome.56 Children develop con-

jugate chaotic eye movements, jerky movements of the limbs, and
ataxia.
A number of systemic signs and symptoms are characteristic of neu-
roblastoma, including weight loss, irritability, fatigue, and fever. Intrac-
table diarrhea occurs in 7% to 9% of children and is caused by tumor
secretion of a hormone called vasoactive intestinal polypeptide (VIP).
More than 90% of children with neuroblastoma have increased
amounts of catecholamines and associated metabolites in their urine.
High levels of urinary catecholamines and serum ferritin are associated
with a poor prognosis.

FIGURE 16-8  Retinoblastoma. The tumor occupies a large portion

Retinoblastoma
of the inside of the eye bulbus. (From Damjanov I: Pathology for Retinoblastoma is a rare congenital eye tumor of young children that
the health professions, ed 3, St Louis, 2006, Saunders. Courtesy originates in the retina of one or both eyes (Figure 16-8). Two forms
Dr. Walter Richardson and Dr. Jamsheed Khan, Kansas City, Kan.) of retinoblastoma are exhibited: inherited and acquired. The inherited

FAMILIAL FORM PATHOGENESIS OF SPORADIC FORM

RETINOBLASTOMA

Somatic cells
of parents
Mutant
Normal RB gene
gene

Germ cells

Zygote

Somatic cells
of child

Retinal cells

Mutation
Mutation

Mutation

Retinoblastoma

FIGURE 16-9  The Two-Mutation Model of Retinoblastoma Development. In inherited retinoblas-

toma, the first mutation is transmitted through the germline of an affected parent. The second mutation
occurs somatically in a retinal cell, leading to development of the tumor. In sporadic retinoblastoma,
development of a tumor requires two somatic mutations.
 CHAPTER 16  Alterations of Neurologic Function in Children 423

form of the disease generally is diagnosed during the first year of life. t­ ransformation to cancer. This is much less likely to happen. Figure 16-9
The acquired disease most commonly is diagnosed in children 2 to illustrates the two-mutation model for these two patterns of mutation.
3 years of age and involves unilateral disease. The primary sign of retinoblastoma is leukocoria, a white pupillary
Approximately 40% of retinoblastomas are inherited as an autoso- reflex also called cat’s eye reflex, which is caused by the mass behind the
mal dominant trait with incomplete penetrance (see Figure 2-2). The lens (see Figure 16-8). Other signs and symptoms include strabismus;
remaining 60% are acquired. In the early 1970s, Knudson proposed the a red, painful eye; and limited vision.
“two-hit” hypothesis to explain the occurrence of both hereditary and Because retinoblastoma is a treatable tumor, dual priorities are sav-
acquired forms of the disease.57 This hypothesis predicts that two sepa- ing the child’s life and restoring useful vision. The prognosis for most
rate transforming events or “hits” must occur in a normal retinoblast children with retinoblastoma is excellent, with a greater than 90%
cell to cause the cancer. Further, it proposes that in the inherited form, long-term survival.
the first hit or mutation occurs in the germ cell (inherited from either
parent), and the mutation is contained in every cell of the child’s body.
Only a second, random mutation in a retinoblast cell is needed to trans-
form that cell into cancer. Multiple tumors are observed in the inherited
form because these second mutations are likely to occur in several of the
approximately 1 to 2 million retinoblast cells. In contrast, the acquired
4 QUICK CHECK 16-3
1. Why are the principal symptoms of brain tumors in children related to brain
form of retinoblastoma requires two independent hits or mutations stem function?
to occur in the same somatic cell (after the egg is fertilized) for the

DID YOU UNDERSTAND?

Normal Growth and Development of the Nervous System 3. Inherited metabolic disorders that damage the nervous system include
1. Growth and development of the brain occur most rapidly during fetal devel- defects in amino acid metabolism (phenylketonuria) and lipid metabolism
opment and during the first year of life. (Tay-Sachs disease) and result in abnormal behavior, seizures, and defi-
2. The bones of the skull are joined by sutures, and the wide, membranous junc- cient psychomotor development.
tions of the sutures (known as fontanelles) allow for brain growth and close 4. Seizure disorders are abnormal discharges of electrical activity within the
by 18 months of age. brain. They are associated with numerous nervous system disorders and
3. At birth neurologic function is primarily at the subcortical level with transi- more often are a generalized rather than a partial type of seizure.
tion in reflexes as motor development progresses during the first year. 5. Generalized forms of seizures include tonic-clonic, myoclonic, atonic, aki-
netic, and infantile spasms.
Structural Malformations 6. Partial seizures suggest more localized brain dysfunction.
1. Defects of neural tube closure include anencephaly (absence of part of the skull 7. Febrile seizures usually are limited to children ages 6 months to 6 years,
and brain), encephalocele (herniation of the meninges and brain through a skull with a pattern of one seizure per febrile illness.
defect), meningocele (a saclike meningeal cyst that protrudes through a verte- 8. Reye syndrome is an encephalopathy with fatty changes in the liver and
bral defect), and myelomeningocele that occurs with spina bifida (failure of the hyperammonemia associated with influenza B, varicella viruses, and aspi-
vertebrae to close and the resulting protrusion of neural tube contents). rin ingestion. Progressive manifestations include lethargy, stupor, rigidity,
2. Spina bifida occulta is a vertebral defect without visible exposure of menin- seizures, and respiratory arrest.
ges or neural tissue. 9. Accidental poisonings from a variety of toxins can cause serious neurologic
3. Acrania is nearly complete absence of the cranial vault. damage.
4. Premature closure of the cranial sutures causes craniosynostosis and prevents 10. Bacterial meningitis is commonly caused by Neisseria meningitidis or
normal skull expansion, resulting in compression of growing brain tissue. Streptococcus pneumoniae and may result from respiratory or gastroin-
5. Microcephaly is lack of brain growth with retarded mental and motor testinal infections; symptoms include fever, headaches, photophobia, sei-
development. zures, rigidity, and stupor.
6. Congenital hydrocephalus results from overproduction, impaired absorption, 11. Viral meningitis may result from direct infection or be secondary to a sys-
or blockage of circulation of cerebrospinal fluid. Dandy-Walker deformity is temic viral infection (e.g., measles, mumps, herpes, or leukemia).
caused by cystic dilation of the fourth ventricle and aqueductal compression.
Cerebrovascular Disease in Children
Encephalopathies 1. Occlusive cerebrovascular disease is rare in children but can occur from
1. Static encephalopathies are nonprogressive disorders of the brain that can embolism, sinovenous thrombosis, or congenital narrowing of vessels.
occur during gestation, birth, or childhood and can be caused by endog- 2. Stroke can occur in association with cardiac disease, hematologic disorders
enous or exogenous factors. (e.g., sickle cell disease), vascular disorders, and infection.
2. Cerebral palsy can be caused by prenatal cerebral hypoxia or perinatal 3. Moyamoya is a rare, progressive vascular stenosis of the circle of Willis that
trauma, with symptoms of motor dysfunction (including increased muscle obstructs arterial blood flow to the brain.
tone, increased reflexes, and loss of fine motor coordination), mental retar-
dation, seizure disorders, or developmental disabilities.

Continued
424 CHAPTER 16  Alterations of Neurologic Function in Children

DID YOU UNDERSTAND?—cont’d

Tumors 5. Localized signs of infratentorial tumors in the cerebellum include impaired
1. Brain tumors are the most common tumors of the nervous system and the coordination and balance. Cranial nerve signs occur with tumors in or near
second most common type of childhood cancer. the brain stem.
2. Tumors in children most often are located below the tentorial plate. 6. Supratentorial tumors may be located near the cortex or deep in the brain.
3. Fast-growing tumors produce symptoms early in the disease, whereas Symptoms depend on the specific location of the tumor.
slow-growing tumors may become very large before symptoms appear. 7. Neuroblastoma is an embryonal tumor of the sympathetic nervous system
4. Symptoms of brain tumors may be generalized or localized. The most com- and can be located anywhere there is sympathetic nervous tissue. Symp-
mon general symptoms are the result of increased intracranial pressure toms are related to tumor location and size of metastasis.
and include headache, irritability, vomiting, somnolence, and bulging of 8. Retinoblastoma is a congenital eye tumor that has two forms: inherited and
fontanelles. acquired.

 KEY TERMS
•  crania  413
A •  ncephalocele  411
E •  cclusive cerebrovascular disease  419
O
• Anencephaly  411 • Encephalopathy  415 • Optic glioma  421
• Ataxic cerebral palsy  415 • Ependymoma  419 • Phenylketonuria (PKU)  416
• Bacterial meningitis  418 • Epilepsy  417 • Pica  418
• Brain stem glioma  421 • Fontanelle  409 • Retinoblastoma  422
• Cerebellar astrocytoma  419 • Lysosomal storage disease  416 • Reye syndrome  418
• Cerebral palsy  415 • Macewen sign (“cracked pot”sign)  415 • Spastic cerebral palsy  415
• Congenital hydrocephalus  414 • Medulloblastoma  419 • Spina bifida  413
• Craniopharyngioma  421 • Meningitis  418 • Spina bifida occulta  413
• Craniorachischisis totalis  411 • Meningocele  411 • Stroke  419
• Craniosynostosis  413 • Microcephaly  413 • Tay-Sachs disease (GM2
• Cyclopia  410 • Moyamoya disease  419 gangliosidosis)  416
• Dandy-Walker malformation • Myelodysplasia  410 • Type II Chiari malformation (Arnold-
(DWM)  414 • Myelomeningocele  412 Chiari malformation)  412
• Dystonic cerebral palsy  415 • Neuroblastoma  421 • Viral meningitis  418

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reducing childhood exposures to lead: recommendations of CDC’s Cancer 33(6):333–360, 2009.
Advisory Committee on Childhood Lead Poisoning Prevention, MMWR 55. Maris JM: Recent advances in neuroblastoma, N Engl J Med
Recommend Rep 56(RR-8):1–14, 16, 2007. Available at www.cdc.gov/mm 362(23):2202–2211, 2010.
wr/preview/mmwrhtml/rr5608a1.htm. 56. De Grandis E, et al: Long-term follow-up of neuroblastoma-associated
36. Centers for Disease Control and Prevention: Lead. Last updated July 27, opsoclonus-myoclonus-ataxia syndrome, Neuropediatrics 40(3):103–111,
2010. Available from www.cdc.gov/nceh/lead/Last updated July 27, 2010. 2009.
37. Centers for Disease Control and Prevention: Lead: prevention tips, 57. Knudson AG Jr: Mutation and cancer: a statistical study of retinoblas-
Updated June 1, 2009. Available at www.cdc.gov/nceh/lead/tips.htm. toma, Proc Natl Acad Sci U S A 68(4):820–823, 1971.
CHAPTER

17
Mechanisms of Hormonal Regulation
Valentina L. Brashers and Sue E. Huether

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
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• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Mechanisms of Hormonal Regulation, 426 Thyroid and Parathyroid Glands, 435
Regulation of Hormone Release, 426 Endocrine Pancreas, 437
Hormone Transport, 427 Adrenal Glands, 439
Mechanisms of Hormone Action, 428 Neuroendocrine Response to Stressors, 443
Structure and Function of the Endocrine Glands, 431 GERIATRIC CONSIDERATIONS: Aging & Its Effects on Specific
Hypothalamic-Pituitary System, 431 Endocrine Glands, 444
Pineal Gland, 435

The endocrine system is composed of various glands located throughout and (c) patterns that depend on levels of circulating substrates (e.g.,
the body (Figure 17-1). These glands can synthesize and release special calcium, sodium, potassium, or the hormones themselves). Diur-
chemical messengers called hormones. The endocrine system has five nal, pulsatile, and cyclic patterns of hormone release involve con-
general functions: (1) differentiation of the reproductive and central sistent patterns of secretion.
nervous systems in the developing fetus; (2) stimulation of sequential 2. Operate within feedback systems, either positive or negative, to
growth and development during childhood and adolescence; (3) coor- maintain an optimal internal environment.
dination of the male and female reproductive systems, which makes 3. Affect only target cells with specific receptors for the hormone and
sexual reproduction possible; (4) maintenance of an optimal internal then act on these cells to initiate specific cell functions or activities.
environment throughout life; and (5) initiation of corrective and adap- 4. Are excreted by the kidneys or are deactivated by the liver or cel-
tive responses when emergency demands occur. Hormones convey spe- lular mechanisms.
cific regulatory information among cells and organs and are integrated Hormones may be classified according to structure, gland of origin,
with the nervous system to maintain communication and control. The effects, or chemical composition. (Table 17-1 categorizes known hor-
mechanisms of communication include autocrine (within the cell), mones based on structure.) The secretion and mechanisms of action
paracrine (between local cells), and endocrine (between remote cells). of hormones represent an extremely complex system of integrated
responses. The endocrine and nervous systems work together to regu-
late responses to the internal and external environments.
MECHANISMS OF HORMONAL REGULATION
The endocrine glands respond to specific signals by synthesizing and Regulation of Hormone Release
releasing hormones into the circulation, which then trigger intracel- Hormones are released either in response to an altered cellular environ-
lular responses. All hormones share certain general characteristics: ment or in the maintenance of a regulated level of another hormone
1. Have specific rates and rhythms of secretion. Three basic secretion or substance. One or more of the following mechanisms regulates hor-
patterns are (a) diurnal patterns, (b) pulsatile and cyclic patterns, mone release: (1) chemical factors (such as blood glucose or calcium

426
 CHAPTER 17  Mechanisms of Hormonal Regulation 427

Hypothalamus
TABLE 17-1 STRUCTURAL CATEGORIES
Pituitary
Pineal OF HORMONES
STRUCTURAL CATEGORY EXAMPLES
Parathyroids Thyroid
Water Soluble
Thymus Peptides Growth hormone
Insulin
Leptin
Adrenals
Parathyroid hormone
Prolactin
Pancreas Glycoproteins Follicle-stimulating hormone
(islets)
Luteinizing hormone
Thyroid-stimulating hormone
Polypeptides Adrenocorticotropic hormone
Antidiuretic hormone
Calcitonin
Endorphins
Glucagon
Ovaries Hypothalamic hormones
(female) Lipotropins
Testes
(male) Melanocyte-stimulating hormone
Oxytocin
Somatostatin
Thymosin
Thyrotropin-releasing hormone
Amines Epinephrine
Norepinephrine

Lipid Soluble
Thyroxine (an amine but lipid soluble) Both thyroxine (T4) and
triiodothyronine (T3)
Steroids (cholesterol is a precursor for Estrogens
FIGURE 17-1  Principal Endocrine Glands. (From Patton KT, all steroids)
Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.) Glucocorticoids (cortisol)
Mineralocorticoids (aldosterone)
Progestins (progesterone)
Testosterone
levels), (2) endocrine factors (a hormone from one endocrine gland Derivatives of arachidonic acid (auto- Leukotrienes
controlling another endocrine gland), and (3) neural control. For crine or paracrine action)
example, insulin is secreted by the chemical stimulation of increased Prostacyclins
plasma glucose levels, cortisol from the adrenal cortex is an endocrine Prostaglandins
factor that regulates and stimulates insulin secretion, and direct stimu- Thromboxanes
lation of the insulin-secreting cells of the pancreas by the autonomic
nervous system is a form of neural control.
Feedback systems provide precise monitoring and control of the
cellular environment. The most common feedback system, negative Hormone Transport
feedback, occurs because the changing chemical, neural, or endocrine Once hormones are released into the circulatory system, they are dis-
response to a stimulus negates the initiating change that triggered the tributed throughout the body. The protein (peptide) hormones (see
release of the hormone. An example of hormone negative feedback is Table 17-1) are water soluble and generally circulate in free (unbound)
shown in Figure 17-2, A. Thyroid-stimulating hormone (TSH) secre- forms. This process immediately exposes these water-soluble hormones
tion from the anterior pituitary is stimulated by thyrotropin-releasing to circulating catabolizing enzymes, giving them an expected half-life
hormone (TRH) from the hypothalamus and by decreased serum lev- of seconds to minutes. Lipid-soluble hormones (see Table 17-1) are
els of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). transported bound to a carrier or transport protein. Lipid-soluble hor-
Secretion of TSH stimulates the synthesis and secretion of thyroid hor- mones can remain in the blood for hours to days. Water-soluble hor-
mones. Increasing levels of T4 and T3 then generate negative feedback mones mediate short-acting responses, and lipid-soluble hormones
on the pituitary and hypothalamus to inhibit TRH and TSH synthesis. mediate both rapid-acting and long-acting responses. Water-soluble
Negative feedback systems are important for maintaining hormone hormones bind to cell-surface receptors, and lipid-soluble hormones
levels within physiologic ranges. These negative feedback regulatory may bind to plasma membrane receptors or diffuse through the cel-
systems are diagrammed in Figure 17-2, B. lular plasma membrane and bind to cytosolic or nuclear receptors.1
The lack of negative feedback inhibition on hormonal release often Because an equilibrium exists between the concentrations of free
results in pathologic excessive hormone production (see Chapter 18). hormones and hormones bound to plasma proteins, a significant
428 CHAPTER 17  Mechanisms of Hormonal Regulation

change in the concentration of binding proteins can affect the con- Mechanisms of Hormone Action
centration of free hormones in the plasma (Table 17-2). Only free hor- Although a hormone is distributed throughout the body, only those
mones can signal a target cell. (Mechanisms of hormone binding are cells with appropriate receptors for that hormone are affected. Hormone
discussed in Chapter 1.) receptors of the target cell have two main functions: (1) to recognize

Central
nervous
system
(+)
(_ ) (_ ) or (+)
HYPOTHALAMUS

Hypothalamus

TRH Releasing hormones and factors

Release-inhibiting hormones and factors
( ) Short
( ) feedback
loop (_ ) (_ )
Ultra- ANTERIOR PITUITARY
Anterior Long
short
pituitary feedback
TSH feedback
loop loop
Tropic hormones

( ) (_ )
( )
TARGET ORGAN Short
feedback
Ultra- (_ ) loop
short
Hormone
feedback
loop
T3 T4
Thyroid
Physiologic effect
A B
FIGURE 17-2  Feedback Loops. A, Endocrine feedback loops involving the hypothalamus-pituitary gland
and end organs; in this example, the thyroid gland is illustrated (endocrine regulation). B, General model
for control and negative feedback to hypothalamic-pituitary target organ systems. Negative feedback reg-
ulation is possible at three levels: target organ (ultra-short feedback), anterior pituitary (short feedback),
and hypothalamus (long feedback). TRH, Thyroid-releasing hormone; TSH, thyroid-stimulating hormone;
T3, triiodothyronine; T4, tetraiodothyronine (thyroxine).

TABLE 17-2 BINDING PROTEINS, THEIR HORMONES, AND VARIABLES THAT AFFECT THEIR
CIRCULATING LEVELS
FACTORS THAT INCREASE BINDING FACTORS THAT DECREASE
BINDING PROTEIN HORMONE PROTEIN LEVELS BINDING PROTEIN LEVELS
Corticosteroid-binding globulin Cortisol Estrogen Liver disease
Progesterone
Sex hormone–binding globulin Dihydrotestosterone — Androgens
Testosterone Hypothyroidism
Estradiol Liver disease
Thyroid-binding globulin Thyroxine (T4) Estrogen Testosterone
Triiodothyronine (T3) Hyperthyroidism Glucocorticoids
Liver disease
Albumin All lipid-soluble hormones Estrogen Liver disease
Malnutrition
Renal disease
 CHAPTER 17  Mechanisms of Hormonal Regulation 429

and bind specifically and with high affinity to their particular hormones very high levels (i.e., achieved with exogenous administration), ADH
and (2) to initiate a signal to appropriate intracellular effectors. acts as a vasoconstrictor.
The sensitivity of the target cell to a particular hormone is related
to the total number of receptors per cell: the more receptors, the more Hormone Receptors
sensitive the cell. Low concentrations of hormone increase the num- Hormone receptors may be located in the plasma membrane or in
ber of receptors per cell; this is called up-regulation. High concen- the intracellular compartment of the target cell. Water-soluble (pep-
trations of hormone decrease the number of receptors; this is called tide) hormones, which include the protein hormones and the catechol-
down-regulation (Figure 17-3). Thus the cell can adjust its sensitivity amines, have a high molecular weight and cannot diffuse across the
to the concentration of the signaling hormone. The receptors on the cell membrane. They interact or bind with receptors located in or on
plasma membrane are continuously synthesized and degraded, so that the cell membrane. Fat-soluble steroid, vitamin D, retinoic acid, and
changes in receptor concentration may occur within hours. Various thyroid hormones diffuse freely across the plasma and nuclear mem-
physiochemical conditions can affect both the receptor number and branes and bind with cytosolic or nuclear receptors (Figure 17-4). The
the affinity of the hormone for its receptor. Some of these physiochem- hormone-receptor complex binds to a specific region in the deoxyri-
ical conditions are the fluidity and structure of the plasma membrane, bonucleic acid (DNA) and stimulates the expression of a specific gene.
pH, temperature, ion concentration, diet, and the presence of other Some fat-soluble hormones (i.e., estrogen [see Chapter 31) may also
chemicals (e.g., drugs). bind with plasma membrane receptors and can have rapid cellular
Hormones affect target cells directly or permissively. Direct effects effects.1-3
are the obvious changes in cell function that result specifically from
stimulation by a particular hormone. Permissive effects are less obvi- First and Second Messengers
ous hormone-induced changes that facilitate the maximal response Receptors for most water-soluble hormones and some steroid hor-
or functioning of a cell. For example, insulin via insulin receptors mones are located in the plasma membranes of cells. The hormone is
has a direct effect on skeletal muscle cells, causing increased glucose the first messenger and is secreted into the bloodstream and carries a
transport into these cells. Insulin also has a permissive effect on mam- message to the target cell. At the target cell it interacts with the receptor
mary cells, facilitating the response of these cells to the direct effects of on the plasma membrane. The interaction initiates a signal that gener-
prolactin. ates a second messenger inside the cell. Second messengers are small
Some hormones have biphasic effects that are dependent on the molecules, such as cyclic adenosine monophosphate (cAMP), cyclic
concentration of the hormone. For example, physiologic levels of guanosine monophosphate (cGMP), calcium, and inositol triphos-
antidiuretic hormone (ADH) released in response to dehydration phate (IP3), and the tyrosine kinase system (Table 17-3). The second
stimulate renal tubular reabsorption of sodium and water. However, at messenger transduces the signal from the receptor to the cytoplasm
and nucleus of the cell and mediates the effect of the hormone on
the target cell (e.g., membrane transport, contractile protein control,
Up-regulation enzyme activation, protein synthesis, or cellular growth).
Hormone When hormones, such as adrenocorticotropic hormone and thy-
roid-stimulating hormone, bind to a cell membrane receptor, intra-
cellular levels of cAMP increase. cAMP activates protein kinases,
leading to phosphorylation of cellular proteins. This either activates

Hormone
Target cell receptor

Fat-soluble Water-soluble
A Time hormone hormone (peptide)

Plasma
Down-regulation
membrane
Hormone

Membrane
Second messenger receptor
Hormone
Target cell receptor
Intracellular
receptor Protein kinase A or C
B Time
FIGURE 17-3  Regulation of Target Cell Sensitivity. A, Low hor-
Cellular response
mone level and up-regulation, or an increase in the number of recep-
tors. B, High hormone level and down-regulation, or a decrease in
the number of receptors. (From Patton KT, Thibodeau GA: Anatomy
& physiology, ed 7, St Louis, 2010, Mosby.) FIGURE 17-4  Hormone Binding at Target Cell.
430 CHAPTER 17  Mechanisms of Hormonal Regulation

or ­deactivates intracellular enzymes, thus directing the actions or

TABLE 17-3 SECOND MESSENGERS
products of specific cells (Figure 17-5).
IDENTIFIED FOR SPECIFIC cGMP functions as a second messenger for receptor binding by
HORMONES atrial natriuretic peptide and nitric oxide. These hormones play cru-
SECOND MESSENGER ASSOCIATED HORMONES cial roles in cardiovascular and pulmonary health and disease; thus
Cyclic AMP Adrenocorticotropic hormone (ACTH) drugs such as phosphodiesterase inhibitors that target cGMP are being
Luteinizing hormone (LH) explored.4,5
Human chorionic gonadotropin (hCG) Calcium and inositol triphosphate function as second messengers
Follicle-stimulating hormone (FSH) for non–steroid hormones, such as angiotensin II and antidiuretic
Thyroid-stimulating hormone (TSH) hormone. Hormone receptor binds through a plasma membrane
Antidiuretic hormone (ADH) G protein and results in generation of inositol triphosphate. Ino-
Thyrotropin-releasing hormone (TRH) sitol triphosphate triggers a release of intracellular calcium stores.
Parathyroid hormone (PTH) Increased intracellular calcium levels can lead to the formation of the
Glucagon calcium-calmodulin complex, which mediates the effects of calcium
Cyclic GMP Atrial natriuretic peptide on intracellular activities that are crucial for cell metabolism and
Calcium and IP3 Angiotensin II growth. For example, calmodulin-dependent protein kinases control
Gonadotropin-releasing hormone intracellular contractile components (myosin and actin, which cause
(GnRN) contraction), alter plasma membrane permeability to calcium, and
Antidiuretic hormone (ADH) regulate the intracellular enzyme activity that promotes hormone
Luteinizing hormone–releasing secretion.
­hormone (LHRH) Some hormones, such as insulin, growth hormone, and prolactin,
Tyrosine kinases Insulin bind to surface receptors that directly activate tyrosine kinases. These
Growth hormone tyrosine kinases include the Janus family of tyrosine kinases (JAK) and
Leptin signal transducers and activators of transcription (STAT). They regu-
Prolactin late a wide range of intracellular processes that contribute to cellular
metabolism and growth, and are being targeted in emerging treat-
AMP, Adenosine monophosphate; GMP, guanosine monophosphate; ments for diabetes and cancer.1,6,7
IP3, inositol triphosphate.

Non—steroid hormone
(first messenger)

FIGURE 17-5  Example of First- and 1

Second-Messenger Mechanisms.
A non–steroid hormone (first messen-
ger) binds to a fixed receptor in the
plasma membrane of the target cell (1). Adenylyl
The hormone-receptor complex acti- cyclase
4
vates the G protein (2). The activated G (second
G protein (G) reacts with guanosine messenger)
triphosphate (GTP), which in turn acti- 2
vates the membrane-bound enzyme
adenylyl cyclase (3). Adenylyl cyclase ATP cAMP
3 5
catalyzes the conversion of adenosine Receptor
triphosphate (ATP) to cyclic adenos- protein
ine monophosphate (cAMP) (second GTP
messenger) (4). cAMP activates pro-
Activates
tein kinase A (5). Protein kinases acti-
protein kinase
vate specific intracellular enzymes (6). Target cell
These activated enzymes then influ- 6
ence specific cellular reactions, thus
producing the target cell’s response to
the hormone (7). (From Thibodeau GA, Activates
Patton KT: Anatomy & physiology, ed specific enzyme
6, St Louis, 2007, Mosby.)
7

Cytosol Substrate Product

 CHAPTER 17  Mechanisms of Hormonal Regulation 431

by the pituitary stalk (Figure 17-8). The hypothalamus is connected to

Steroid (Lipid-Soluble) Hormone Receptors the anterior pituitary through hypophysial portal blood vessels (Fig-
The lipid-soluble hormones are steroid hormones and are synthesized ure 17-9) and to the posterior pituitary via a nerve tract referred to as
from cholesterol. They include androgens, estrogens, progestins, glu- the hypothalamohypophysial tract (Figure 17-10). These connections
cocorticoids, mineralocorticoids, thyroid hormones, vitamin D, and are vital to the functioning of the hypothalamus-pituitary system. The
retinoid. Because these are relatively small, lipophilic, hydrophobic special cells of the hypothalamus are like other neurons in that they
molecules, they can cross the lipid plasma membrane by simple diffu- have similar electrical properties, organelles, membranes, and syn-
sion (see Chapter 1). Receptors for steroid hormones are in the cytosol apses. Neurosecretory cells, however, can synthesize and secrete the
and nucleus and direct gene expression (Figure 17-6). Modulation of hypothalamic-releasing hormones that regulate the release of hor-
gene expression can take hours to days. Studies also reveal that ste- mones from the anterior pituitary; in addition, these cells synthesize
roid hormone receptors are in the plasma membrane and are asso- the hormones antidiuretic hormone (ADH) and oxytocin that are
ciated with rapid responses that may have genomic and nongenomic released from the posterior pituitary gland. These hormones are sum-
effects.8,9 marized in Table 17-4.
The pituitary gland is located in the sella turcica (a saddle-
shaped depression of the sphenoid bone at the base of the skull). It
4 QUICK CHECK 17-1 weighs approximately 0.5 g, except during pregnancy when its weight
approaches 1 g. It is composed of two distinctly different lobes:
1. What are hormones? By what mechanisms do they function?
2. What is meant by a negative feedback regulation of hormone release? (1) the anterior pituitary, or adenohypophysis, and (2) the posterior
3. How do first messengers differ from second messengers? pituitary, or neurohypophysis (see Figure 17-7). These two lobes differ
4. Where are the receptors for steroid (lipid-soluble) hormones located? in their embryonic origins, cell types, and functional relationship to
the hypothalamus.

The Anterior Pituitary

STRUCTURE AND FUNCTION OF THE ENDOCRINE The anterior pituitary (adenohypophysis) accounts for 75% of the
GLANDS total weight of the pituitary gland. It is composed of three regions:
(1) the pars distalis, (2) the pars tuberalis, and (3) the pars intermedia.
Hypothalamic-Pituitary System The pars distalis is the major component of the anterior pituitary and
The hypothalamic-pituitary axis (HPA) forms the structural and is the source of the anterior pituitary hormones. The pars tuberalis is
functional basis for central integration of the neurologic and endo- a thin layer of cells on the anterior and lateral portions of the pituitary
crine systems, creating what is called the neuroendocrine system. The stalk. The pars intermedia lies between the two. In the adult, the dis-
HPA produces several hormones that affect a number of diverse body tinct pars intermedia disappears and the individual cells are distributed
functions (Figure 17-7), including thyroid, adrenal, and reproductive diffusely throughout the pars distalis and pars nervosa (neural lobe) of
functions. the posterior pituitary.
The hypothalamus contains special neurosecretory cells and is The anterior pituitary is composed of two main cell types:
located at the base of the brain. It is connected to the pituitary gland (1) the chromophobes, which appear to be nonsecretory, and (2) the

Plasma
1 protein
Target cell carrier
molecule
2 FIGURE 17-6  Steroid Hormone Mechanism. Lipid-sol-
Steroid Blood uble steroid hormone molecules detach from the carrier
hormone vessel
Cytosol protein (1) and pass through the plasma membrane (2).
Hormone molecules then diffuse into the nucleus, where
Receptor A they bind to a receptor to form a hormone-receptor complex
molecule (3). This complex then binds to a specific site on a deoxyri-
Hormone-
receptor bonucleic acid (DNA) molecule (4), triggering transcription
complex B of the genetic information encoded there (5). The resulting
Activates Ribosome messenger ribonucleic acid (mRNA) molecule moves to
3 second messenger the cytosol, where it associates with a ribosome, initiating
4 Plasma
synthesis of a new protein (6). This new protein—usually
membrane
an enzyme or channel protein—produces specific effects
on the target cell (7). The classic genomic action is typically
slow (red arrows). Steroids also may exact rapid effects
6
5 (green arrows) by binding to receptors on the plasma mem-
brane (A) and activating an intercellular second messenger
DNA Extracellular (B). (Modified from Patton KT, Thibodeau GA: Anatomy &
fluid physiology, ed 7, St Louis, 2010, Mosby.)

mRNA 7
Nucleus Protein
432 CHAPTER 17  Mechanisms of Hormonal Regulation

Hypothalamic
neurosecretory cell

Bone

Anterior pituitary Posterior pituitary

Growth Kidney
hormone (GH) tubules
Antidiuretic
Adrenocorticotropic hormone
Adrenal (ADH)
cortex hormone (ACTH)

Thyroid-
stimulating
hormone (TSH) Oxytocin
(OT)
Gonadotropic
hormones
Thyroid Prolactin
(FSH and LH)
gland (PRL) Uterus
smooth
muscle

Testis
Mammary
Ovary Mammary glands
glands

FIGURE 17-7  Pituitary Hormones and Their Target Organs. FSH, Follicle-stimulating hormone;
ICSH, male analog of LH (interstitial cell–stimulating hormone); LH, luteinizing hormone. (Modified
from Patton KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)

Optic chiasm Third ventricle

Thalamus Hypothalamus

Optic
chiasm Pineal gland Mammillary body

Infundibulum Hypothalamus Pituitary stalk

Pituitary Brain stem
diaphragm
Neurohypophysis
Pituitary (posterior)
(hypophysis)
Sphenoid bone
Nasal cavity
Pars intermedia
Adenohypophysis
Pars anterior (anterior)
FIGURE 17-8  Location and Structure of the Pituitary Gland (Hypophysis). The pituitary gland is
located within the sella turcica of the skull’s sphenoid bone and is connected to the hypothalamus by a
stalklike infundibulum. The infundibulum passes through a gap in the portion of the dura mater that cov-
ers the pituitary (the pituitary diaphragm). The inset shows that the pituitary is divided into an anterior por-
tion, the adenohypophysis, and a posterior portion, the neurohypophysis. The adenohypophysis is further
subdivided into the pars anterior and pars intermedia. The pars intermedia is almost absent in the adult
pituitary. (Modified from Patton KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)
 CHAPTER 17  Mechanisms of Hormonal Regulation 433

chromophils, which are considered the secretory cells of the adeno- effects of the hormones secreted by target glands, and (3) direct effects
hypophysis. The chromophils are subdivided into seven secretory cell of other mediating neurotransmitters. (These are summarized in Fig-
types, and each cell type secretes a specific hormone or hormones. In ure 17-2.)
general, the anterior pituitary hormones are regulated by (1) secretion The anterior pituitary secretes tropic hormones that affect the
of hypothalamic peptide hormones or releasing factors, (2) feedback physiologic function of specific target organs (see Figure 17-7 and Table
17-5). Melanocyte-stimulating hormone (MSH) promotes the pitu-
itary secretion of melanin, which darkens skin color. The glycoprotein
hormones follicle-stimulating hormone (FSH) and luteinizing hor-
mone (LH) influence reproductive function and are discussed in Chap-
ter 31. Adrenocorticotropic hormone (ACTH) regulates the release
of cortisol from the adrenal cortex. Thyroid-stimulating hormone
(TSH) regulates the activity of the thyroid gland. The roles of ACTH
and TSH are discussed later in this chapter. Growth hormone (GH)

Hypothalamic
neurosecretory
cell

Thalamus
Supraoptic
nucleus
Superior Frontal
Releasing hormones Paraventricular nucleus
hypophysial lobe Hypothalamus
artery
Supraopticohypophysial tract

Optic
chiasm Mammillary
body
Pituitary stem
Tuberohypophysial
Pituitary stalk tract
Pars
Connective intermedia
Target cells in tissue (trabecula) Pars
adenohypophysis nervosa
Anterior Pars distalis
hypophysial vein
Posterior
FIGURE 17-9  Hypophysial Portal System. Neurons in the hypo- lobe
Anterior lobe Cleft
thalamus secrete releasing hormones into veins that carry the
releasing hormones directly to the vessels of the adenohypophy- FIGURE 17-10  Nerve Tracts From Hypothalamus to Posterior
sis, thus bypassing the normal circulatory route. (From Patton KT, Lobe of Pituitary Gland. Nerve tracts from hypothalamus to poste-
Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.) rior lobe of pituitary gland.

TABLE 17-4 HYPOTHALAMIC HORMONES (HYPOPHYSIOTROPIC HORMONES)

HORMONE TARGET TISSUE ACTION
Thyrotropin-releasing hormone (TRH) Anterior pituitary Stimulates release of thyroid-stimulating hormone (TSH)
Modulates prolactin secretion
Gonadotropin-releasing hormone (GnRH) Anterior pituitary Stimulates release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH)
Somatostatin Anterior pituitary Inhibits release of growth hormone (GH) and TSH
Growth hormone–releasing hormone (GHRH) Anterior pituitary Stimulates release of GH
Corticotropin-releasing hormone (CRH) Anterior pituitary Stimulates release of adrenocorticotropic hormone (ACTH) and β-endorphin
Substance P Anterior pituitary Inhibits synthesis and release of ACTH
Stimulates secretion of GH, FSH, LH, and prolactin
Prolactin-inhibiting factor (PIF, dopamine) Anterior pituitary Inhibits synthesis and secretion of prolactin
Prolactin-releasing factor (PRF) Anterior pituitary Stimulates secretion of prolactin
434 CHAPTER 17  Mechanisms of Hormonal Regulation

TABLE 17-5 TROPIC HORMONES OF THE ANTERIOR PITUITARY AND THEIR FUNCTIONS

HORMONE SECRETORY CELL TYPE TARGET ORGANS FUNCTIONS
Adrenocorticotropic hormone Corticotropic Adrenal gland (cortex) Increased steroidogenesis (cortisol and androgenic
(ACTH) hormones)
Synthesis of adrenal proteins contributing to maintenance
of adrenal gland
Melanocyte-stimulating Melanotropic Anterior pituitary Promotes secretion of melanin and lipotropin by anterior
hormone (MSH) pituitary; makes skin darker

Somatotropic Hormones
Growth hormone (GH) Somatotropic Muscle, bone, liver Regulates metabolic processes related to growth and
adaptation to physical and emotional stressors, muscle
growth, increased protein synthesis, increased liver
glycogenolysis, increased fat mobilization
Liver Induces formation of somatomedins, or insulin-like growth
factors (IGFs) that have actions similar to insulin
Prolactin Lactotropic Breast Milk production

Glycoprotein Hormones
Thyroid-stimulating Thyrotropic Thyroid gland Increased production and secretion of thyroid hormone
hormone (TSH) Increased iodide uptake
Promotes hypertrophy and hyperplasia of thymocytes
Luteinizing hormone (LH) Gonadotropic In women: granulosa cells Ovulation, progesterone production
In men: Leydig cells Testicular growth, testosterone production
Follicle-stimulating Gonadotropic In women: granulosa cells Follicle maturation, estrogen production
hormone (FSH) In men: Sertoli cells Spermatogenesis
β-Lipotropin Corticotropic Adipose cells Fat breakdown and release of fatty acids
β-Endorphins Corticotropic Adipose cells Analgesia; may regulate body temperature, food and water
Brain opioid receptors intake

and prolactin are called the somatotropic hormones and have diverse hypothalamus. It often is designated as part of the posterior pituitary
effects on body tissues. GH secretion is controlled by two hormones but contains at least 10 biologically active hypothalamic-releasing hor-
from the hypothalamus: growth hormone–releasing hormone mones, as well as the neurotransmitters dopamine, norepinephrine,
(GHRH), which increases GH secretion; and somatostatin, which serotonin, acetylcholine, and histamine. The pituitary stalk contains
inhibits GH secretion. GH is essential to normal tissue growth and the axons of neurons that originate in the supraoptic and paraventricu-
maturation and also impacts aging, sleep, nutritional status, stress, lar nuclei of the hypothalamus and connects the pituitary gland to the
and reproductive hormones. Many of the anabolic functions of GH brain. Axons originating in the hypothalamus terminate in the pars
are mediated, at least in part, by the insulin-like growth factors (IGFs), nervosa, which secretes the hormones of the posterior pituitary (see
which are also known as the somatomedins.10 There are two primary Figure 17-10).
forms of IGF: IGF-1 and IGF-2, of which IGF-1 is the most biologically The posterior pituitary secretes two polypeptide hormones:
active. They both circulate bound to a group of IGF binding proteins (1) antidiuretic hormone (ADH), also called arginine vasopressin,
(IGFBP). IGF-1 binds to both insulin receptors, providing an insulin- and (2) oxytocin. These hormones differ by only two amino acids.
like effect on skeletal muscle, and to IGF-1 receptor, which mediates They are synthesized—along with their binding proteins, the neuro-
the anabolic effects of GH. The IGF-2 receptor causes a negative effect physins—in the supraoptic and paraventricular nuclei of the hypo-
on tissue growth, thus balancing the activity of the IGF-1 receptor. thalamus (see Figure 17-10). They are packaged in secretory vesicles
Because of the anabolic effects of GH and IGF, they can be used to and are moved down the axons of the pituitary stalk to the pars ner-
treat growth disorders and increase muscle mass but their use has also vosa for storage. The posterior pituitary thus can be seen as a storage
been linked to increased rates of cancer.11-13 and releasing site for hormones synthesized in the hypothalamus. The
Prolactin primarily functions to induce milk production during release of ADH and oxytocin is mediated by cholinergic and adrener-
pregnancy and lactation and also has effects on ovulation and immune gic neurotransmitters. The major stimulus to both ADH and oxytocin
function. Synthesis is stimulated by vasoactive intestinal polypeptide, release is glutamate, whereas the major inhibitory input is through
serotonin, and growth factors with release inhibited by dopamine. gamma-aminobutyric acid (GABA).14 Before release into the circula-
tory system, ADH and oxytocin are split from the neurophysins and
The Posterior Pituitary are secreted in unbound form.
The embryonic posterior pituitary (neurohypophysis) is derived from Antidiuretic hormone. The major homeostatic function of the
the hypothalamus and is comprised of three parts: (1) the median posterior pituitary is the control of plasma osmolality as regulated by
eminence, located at the base of the hypothalamus; (2) the pituitary ADH, or arginine vasopressin (see Chapter 4). At physiologic levels,
stalk; and (3) the pars nervosa or neural lobe. The median eminence ADH increases the permeability of the distal renal tubules and col-
is composed largely of the nerve endings of axons from the ventral lecting ducts (see Chapter 28. This increased permeability leads to
 CHAPTER 17  Mechanisms of Hormonal Regulation 435

increased water reabsorption into the blood, thus reducing serum vessels, removing toxic oxygen free radicals, and decreasing insulin
osmolality and concentrating the urine. Hypercalcemia, prostaglandin secretion.17
E, and hypokalemia can inhibit this water reabsorption.
The secretion of ADH is regulated primarily by the osmorecep- Thyroid and Parathyroid Glands
tors of the hypothalamus, located near or in the supraoptic nuclei. As The thyroid gland, located in the neck just below the larynx, produces
plasma osmolality increases these osmoreceptors are stimulated, the hormones that control the rates of metabolic processes throughout the
rate of ADH secretion increases, more water is reabsorbed from the body. The four parathyroid glands are near the posterior side of the
kidney, and the plasma is diluted back to its set-point osmolality. ADH thyroid and function to control serum calcium levels (Figure 17-11).
has no direct effect on electrolyte levels, but by increasing water reab-
sorption, serum electrolyte concentrations may decrease because of a Thyroid Gland
dilutional effect. The two lobes of the thyroid gland lie on either side of the trachea,
ADH secretion also is increased by changes in intravascular vol- inferior to the thyroid cartilage and joined by the isthmus (see Figure
ume, which are monitored by baroreceptors in the left atrium, in 17-11). The normal thyroid gland is not visible on inspection, but it
the carotid arteries, and in the aortic arches. A volume loss of 7% to may be palpated on swallowing, which causes it to be displaced upward.
25% stimulates ADH secretion. Stress, trauma, pain, exercise, nausea, The thyroid gland consists of follicles that contain follicular cells
nicotine, exposure to heat, and drugs such as morphine also increase surrounding a viscous substance called colloid (Figure 17-12). The fol-
ADH secretion. ADH secretion decreases with decreased plasma licular cells synthesize and secrete the thyroid hormones. Neurons ter-
osmolality, increased intravascular volume, hypertension, and alco- minate on blood vessels within the thyroid gland and on the follicular
hol ingestion. cells themselves, so neurotransmitters (acetylcholine, catecholamines)
ADH was originally named vasopressin because in extremely high may directly affect the secretory activity of follicular cells.
levels it causes vasoconstriction and a resulting increase in arterial Also found in the thyroid are parafollicular cells, or C cells (see
blood pressure. This baroreceptor-mediated response is much less Figure 17-12). C cells secrete calcitonin and somatostatin. Calcitonin,
sensitive than the ADH response to changes in osmolality. Therefore also called thyrocalcitonin, lowers serum calcium levels by inhibition
physiologic levels of ADH do not significantly impact vessel tone. of bone-resorbing osteoclasts (Table 17-6). High levels of calcitonin
However, significant vasoconstriction may be achieved pharmacologi- are required for these effects; however, deficiencies of calcitonin do
cally. For example, high doses of ADH (given as the drug vasopressin) not lead to hypocalcemia. Consequently, the metabolic consequences
may be administered to achieve hemostasis during hemorrhage and to of calcitonin deficiency or excess do not appear to be significant in
raise blood pressure in shock states.15,16 humans. (Bone resorption is explained in Chapter 36.) Calcitonin and
Oxytocin. Oxytocin is responsible for contraction of the uterus parathyroid hormone together regulate calcium balance.
and milk ejection in lactating women and may affect sperm motility Regulation of thyroid hormone secretion. Thyroid hormone (TH)
in men. In both genders, oxytocin has an antidiuretic effect similar to is regulated through a negative feedback loop involving the hypothala-
that of ADH. mus, the anterior pituitary, and the thyroid gland (see Figure 17-2).
In women, oxytocin is secreted in response to suckling and mechan- Thyrotropin-releasing hormone (TRH), which is synthesized and
ical distention of the female reproductive tract. Oxytocin binds to its stored within the hypothalamus, initiates this loop. TRH is released
receptors on myoepithelial cells in the mammary tissues and causes into the hypothalamic-pituitary portal system and circulates to the
contraction of those cells, which increases intramammary pressure and anterior pituitary, where it stimulates the release of TSH. TRH levels
milk expression (“let-down” reflex). increase with exposure to cold or stress and from decreased levels of T4.
Oxytocin also acts on the uterus to stimulate contractions. Oxy- Thyroid-stimulating hormone (TSH) is a glycoprotein synthesized
tocin functions near the end of labor to enhance effectiveness of con- and stored within the anterior pituitary. When TSH is secreted by the
tractions, promote delivery of the placenta, and stimulate postpartum
uterine contractions, thereby preventing excessive bleeding. The func-
Epiglottis
tion of this hormone is discussed in detail in Chapter 31.
Hyoid bone

4 QUICK CHECK 17-2 Larynx

1. What is the relationship between the hypothalamus and the pituitary?
2. What is the action of antidiuretic hormone (ADH)? Superior
parathyroid gland

Pineal Gland Thyroid gland

The pineal gland is located near the center of the brain and is com-
posed of photoreceptive cells that secrete melatonin. It is innervated Inferior
by noradrenergic sympathetic nerve terminals controlled by pathways parathyroid
within the hypothalamus. Melatonin release is stimulated by expo- gland
sure to dark and inhibited by light exposure. It is synthesized from Trachea
tryptophan, which is first converted to serotonin and then to mela-
tonin. Melatonin regulates circadian rhythms and reproductive sys-
tems, including the secretion of the gonadotropin-releasing hormones FIGURE 17-11  Thyroid and Parathyroid Glands. Note the rela-
and the onset of puberty. It also plays an important role in immune tionship of the thyroid and parathyroid glands to each other, to the
regulation and is postulated to impact the aging process. Further larynx (voice box), and to the trachea. (From Patton KT, Thibodeau
effects of melatonin include increasing nitric oxide release from blood GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)
436 CHAPTER 17  Mechanisms of Hormonal Regulation

anterior pituitary, it circulates to bind with receptors on the plasma Synthesis of thyroid hormone. The first step in the synthesis of TH is
membrane of the thyroid follicular cells. The primary effect of TSH on the concentration of iodide by the thyroid gland. Iodide is the inorganic
the thyroid gland is to cause an immediate release of stored TH and or ionic form of iodine and is the form in which iodine enters the thy-
an increase in TH synthesis. Another effect of TSH is to affect growth roid gland. Because there is an iodide concentration gradient of about
of the thyroid gland by stimulating thymocyte hyperplasia and hyper- 30:1 to 40:1 between the thyroid gland and the blood, iodide is moved
trophy. As TH levels rise, there is a negative feedback effect on the by active transport from the extracellular fluid to the thyroid follicu-
HPA to inhibit TRH and TSH release, which then results in decreased lar cells (called the iodide trap). The iodide must then be oxidated to
TH synthesis and secretion. TH synthesis is also controlled by serum iodine by the enzyme thyroidal peroxidase inside the follicular cells.
iodide levels and by circulating selenium-dependent enzymes, called Thyroglobulin (TG), a large glycoprotein synthesized within the
deiodinases, which inactivate the precursor molecule thyroxine. Thy- follicular cell, is the precursor of TH. Uniodinated TG is released into
roid gland hormones and their regulation and function are summa- the colloid, and iodine combines with tyrosine in the TG to form iodo-
rized in Table 17-6.18,19 tyrosines. Coupling of iodotyrosines by the enzyme thyroperoxidase

Blood vessels
are found around
the follicles. A C cell can be
distinguished from
Colloid (retracted surrounding follicular
after fixation) cells by its pale
Follicular epithellum
In the inactive follicle, cytoplasm.
the follicular Two more effective
epithelium is simple identification
low cuboidal, or approaches are:
squamous. During 1. Immunocytochemistry,
their active secretory using an antibody to
phase, the cells calcitonin.
become columnar. 2. Electron microscopy,
to visualize calcitonin-
Area of colloid containing cytoplasmic
resorption granules.
FIGURE 17-12  Thyroid Follicle Cells.

TABLE 17-6 THYROID GLAND HORMONES AND THEIR REGULATION AND FUNCTIONS

HORMONE REGULATION FUNCTIONS
Thyroxine (T4) and T4 and T3 levels are controlled by TSH Regulates protein, fat, and carbohydrate catabolism in all cells
triiodothyronine (T3) Released in response to metabolic demand Regulates metabolic rate of all cells
Influences on amount secreted: Regulates body heat production
Gender Insulin antagonist
Pregnancy Maintains growth hormone secretion, skeletal maturation
Gonadal- and adrenocortical-increased steroids = ↑ levels Affects CNS development
Exposure to extreme cold = ↑ levels Necessary for muscle tone and vigor
Nutritional state Maintains cardiac rate, force, and output
Chemicals Maintains secretion of GI tract
GHIH = ↓ levels Affects respiratory rate and oxygen utilization
Dopamine = ↓ levels Maintains calcium mobilization
Catecholamines = ↑ levels Affects RBC production
Stimulates lipid turnover, free fatty acid release, and cholesterol synthesis
Calcitonin Elevated serum calcium level—major stimulant for calcitonin Lowers serum calcium level by opposing bone-resorbing effects of PTH,
Other stimulants: prostaglandins, and calciferols by inhibiting osteoclastic activity
Gastrin Lowers serum phosphate levels
Calcium-rich foods (regardless of serum Ca++ levels) Decreases calcium and phosphorus absorption in GI tract
Pregnancy
Lowered serum calcium level—suppresses calcitonin release

From Monohan FD et al: Phipps’ medical-surgical nursing: health and illness perspective, ed 8, St Louis, 2007, Mosby.
CNS, Central nervous system; GHIH, growth hormone–inhibiting hormone; GI, gastrointestinal; PTH, parathyroid hormone; RBC, red blood cell;
TSH, thyroid-stimulating hormone.
 CHAPTER 17  Mechanisms of Hormonal Regulation 437

forms TH. Triiodothyronine (T3) is formed from the coupling of

HEALTH ALERT
monoiodotyrosine (one iodine atom and tyrosine) and diiodotyrosine
(two iodine atoms and tyrosine). Thyroxine is tetraiodothyronine (T4) Vitamin D
and is formed from the coupling of two diiodotyrosines. Nearly 90% Vitamin D is essential for bone health and is widely used for the prevention
of TH is synthesized as T4; however, most of the T4 is then converted to and treatment of postmenopausal osteoporosis and renal osteodystrophy.
T3, which acts on the target cell. More recently, vitamin D deficiency has been found to affect more than 75%
TH is transported in the blood in bound and free forms. Most of of all Americans, and more than 90% of Americans with pigmented skin.
the TH is transported bound to thyroxine-binding globulin (TBG) Inadequate serum levels of vitamin D have been linked to infections, cancer,
and to a lesser extent by thyroxine-binding prealbumin or albumin. heart disease, dementia, diabetes, chronic pain syndromes, and autoimmune
The free form is generally considered to be biologically active, and the disorders. Recommendations for vitamin D supplementation include increased
bound form serves as a reservoir.20 intake of vitamin D–containing foods (seafood, vitamin D–fortified juices, and
Actions of thyroid hormone. TH affects many body tissues and has a milk products), increased exposure to sunlight, and vitamin D supplementation
significant effect on the growth and maturation of tissues. TH is essential with a goal of achieving a serum level of 35 to 50 ng/mL.
for normal growth and neurologic development in the fetus and infant
and affects neurologic functioning in adults. Similar to some steroid hor- Data from Holick MF et al: Evaluation, treatment, and prevention of
mones, TH binds to intracellular receptor complexes that then influence vitamin D deficiency: an Endocrine Society clinical practice guideline,
the genetic expression of specific proteins. TH also affects cell metabo- J Clin Endocrinol Metab 96(7):1911–1930, 2011. Bruner RL et al: Cal-
lism by altering protein, fat, and glucose metabolism and, as a result, cium, vitamin D supplementation and physical function in the Women’s
Health Initiative, J Am Dietetic Assoc 108:1472–1479, 2008; Dimeglio
heat production and oxygen consumption are increased. Thus these
LA: Pediatric endocrinology: vitamin D and cardiovascular disease
hormones are essential for maintaining healthy metabolic processes, and
risk in children, Nat Rev Endocrinol 6(1):12–13, 2010; Pearce SH,
their use is being explored for the therapy of many metabolic disorders.21 Cheetham TD: Diagnosis and management of vitamin D deficiency,
BMJ 340:b5664, 2010; Institute of Medicine: Dietary reference intakes
Parathyroid Glands for vitamin D and calcium, National Acadamies of Science, November
Normally two pairs of small parathyroid glands are present behind the 30, 2010. Available at http://www.iom.edu/Reports/2010/ 
upper and lower poles of the thyroid gland (see Figure 17-11). How- Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx.
ever, their number may range from two to six.
The parathyroid glands produce parathyroid hormone (PTH),
which is the single most important factor in the regulation of serum It houses the islets of Langerhans. The islets of Langerhans have four
calcium concentration. The overall effect of PTH secretion is to types of hormone-secreting cells: alpha cells, which secrete glucagon;
increase serum calcium concentration and decrease serum phosphate beta cells, which secrete insulin and amylin; delta cells, which secrete
level. A decrease in serum-ionized calcium level stimulates PTH secre- gastrin and somatostatin; and F (or PP) cells, which secrete pancreatic
tion. PTH acts directly on the bone to release calcium by stimulating polypeptide. These hormones regulate carbohydrate, fat, and protein
osteoclast activity. PTH also acts on the kidney to increase calcium metabolism. (The pancreas is illustrated in Figure 17-13.) Nerves from
reabsorption and to decrease phosphate reabsorption. The resultant both the sympathetic and parasympathetic divisions of the autonomic
increase in serum calcium concentration inhibits PTH secretion. nervous system innervate the pancreatic islets.
1,25-Dihydroxy-vitamin D3 (the active form of vitamin D) works as
a cofactor with PTH to promote calcium and phosphate absorption Insulin
in the gut and enhance bone mineralization. Vitamin D also plays an The beta cells of the pancreas synthesize insulin from the precursor
important role in metabolic processes and controlling inflammation. proinsulin, which is formed from a larger precursor molecule, prepro-
It has been found to be deficient in the majority of individuals in the insulin. Proinsulin is composed of A peptide and B peptide connected
United States (see Health Alert: Vitamin D). by a C peptide and two disulfide bonds. C peptide is cleaved by pro-
Phosphate and magnesium concentrations also affect PTH secre- teolytic enzymes, leaving the bonded A and B peptides as the insulin
tion. An increase in serum phosphate level decreases serum calcium molecule. C peptide level can be measured in the blood and used as an
level by causing calcium-phosphate precipitation into soft tissue and indirect measurement of serum insulin synthesis.23 Secretion of insulin
bone, which indirectly stimulates PTH secretion. Hypomagnesemia in is regulated by chemical, hormonal, and neural control. Insulin secre-
persons with normal calcium levels acts as a mild stimulant to PTH tion is promoted when blood levels of glucose, amino acids (arginine
secretion; however, in persons with hypocalcemia, hypomagnesemia and lysine), and gastrointestinal hormones (glucagon, gastrin, chole-
decreases PTH secretion.22 cystokinin, secretin) increase, and when the beta cells are stimulated
parasympathetically. Insulin secretion diminishes in response to low
4 QUICK CHECK 17-3
blood levels of glucose (hypoglycemia), high levels of insulin (through
negative feedback to the beta cells), and sympathetic stimulation of the
1. How does the anterior pituitary regulate the thyroid gland? alpha cells in the islets. Prostaglandins also inhibit insulin secretion.
2. What form of thyroid hormone is biologically active? At the target cell, insulin combines with an enzyme-linked plasma
3. What two organs are the sites of action of parathyroid hormone (PTH)? membrane receptor that contains tyrosine kinase on the cytosolic sur-
face. Insulin receptor binding activates tyrosine kinase autophosphor-
ylation and sends a cascade of signals to activate glucose transporters
Endocrine Pancreas (GLUT) for entry of glucose into the cell, and to phosphorylate protein
The pancreas is both an endocrine gland that produces hormones kinase.24 Protein kinase then activates or deactivates target enzymes for
and an exocrine gland that produces digestive enzymes. (The exocrine glucose metabolism (Figure 17-14).
function of the pancreas is discussed in Chapter 33.) The pancreas is The sensitivity of the insulin receptor is a key component in main-
located behind the stomach, between the spleen and the duodenum. taining normal cellular function; insulin resistance has been implicated
 Accessory
Common bile duct pancreatic duct Body of pancreas

Duodenum Tail of
pancreas

Lesser duodenal papilla

Hepato-pancreatic ampulla
Pancreatic duct
Greater duodenal papilla
Jejunum
Plicae circulares
Head of pancreas

A Alpha cells Beta cells

(secrete glucagon) (secrete insulin)

Pancreatic
islet
Acini cells
(secrete
enzymes)

Vein Pancreatic duct

B (to duodenum)

FIGURE 17-13  The Pancreas. A, Pancreas dissected to show main and accessory ducts. The main
duct may join the common bile duct, as shown here, to enter the duodenum by a single opening at the
major duodenal papilla, or the two ducts may have separate openings. The accessory pancreatic duct is
usually present and has a separate opening into the duodenum. B, Exocrine glandular cells (around small
pancreatic ducts) and endocrine glandular cells of the pancreatic islets (adjacent to blood capillaries).
Exocrine pancreatic cells secrete pancreatic juice, alpha endocrine cells secrete glucagon, and beta cells
secrete insulin. (From Thibodeau GA, Patton KT: Anatomy & physiology, ed 6, St Louis, 2007, Mosby.)

ss
Insulin
s s
s s
K+
PO4 Amino Receptor Plasma Glucose
Mg++ acids s s membrane
ss ss

*
Tyrosine kinase
P P
Autophosphorylation
Glucose Translocation
Protein synthesis

MAP kinase Insulin receptor

signaling cascade substrates 1-4 Transport
Phosphorylation protein (GLUT4)
cascades
GLUT4 vesicle
Cell growth and Glucose transport
differentiation, Fatty acid synthesis
gene expression Protein synthesis
Glycogen synthesis
Cell growth and survival
Amino acid and electrolyte transport

FIGURE 17-14  Insulin Action on Cells. Binding of insulin to its receptor causes autophosphorylation
of the receptor, which then itself acts as a tyrosine kinase that phosphorylates insulin receptor sub-
strate 1 (IRS-1). Numerous target enzymes, such as protein kinase B and MAP kinase, are activated
and these enzymes have a multitude of effects on cell function. The glucose transporter (GLUT4) is
recruited to the plasma membrane, where it facilitates glucose entry into the cell. The transport of
amino acids, potassium, magnesium, and phosphate into the cell is also facilitated. The synthesis
of various enzymes is induced or suppressed, and cell growth is regulated by signal molecules that
modulate gene expression. IREs, Insulin responsive elements; mRNA, messenger ribonucleic acid.
(Redrawn from Berne RM, Levy MN: Principles of physiology, ed 3, St Louis, 2000, Mosby.)
 CHAPTER 17  Mechanisms of Hormonal Regulation 439

in numerous cardiovascular diseases, including hypertension and dia- glucose level. The brain, red blood cells, kidney, and lens of the eye
betes. Adipocytes release a number of hormones that are altered in do not require insulin for glucose transport. Insulin also facilitates the
obesity and have an important impact on insulin sensitivity (see Health intracellular transport of potassium (K+), phosphate, and magnesium.
Alert: Hormones from Adipose Tissue—The Adipokines).
Amylin
Amylin (or islet amyloid polypeptide) is a hormone co-secreted with
HEALTH ALERT insulin in response to nutrient stimuli. It regulates blood glucose
Hormones from Adipose Tissue—The Adipokines concentration by delaying nutrient uptake and suppressing glucagon
secretion after meals. Amylin also has a satiety effect. Through these
Several hormones are released from adipose cells that affect many other tis- mechanisms, amylin has an antihyperglycemic effect.25
sues. The best known of these substances are leptin and adiponectin. Leptin
decreases appetite but in obese individuals levels of leptin are chronically ele- Glucagon
vated and lead to resistance to its appetite-suppressive functions. Chronically Glucagon is produced by the alpha cells of the pancreas and by cells lining
elevated levels of leptin also can result in many adverse effects on tissues and the gastrointestinal tract. Glucagon acts primarily in the liver and increases
contribute to vascular diseases, such as atherosclerosis and hypertension. In blood glucose concentration by stimulating glycogenolysis and gluconeo-
contrast, adiponectin is a protective hormone that is decreased in obesity. genesis in muscle and lipolysis in adipose tissue. Amino acids, such as
It normally helps maintain insulin sensitivity and protect vascular function. alanine, glycine, and asparagine, stimulate glucagon secretion. Glucagon
Finally, resistin is another less well-known adipokine that is increased in obe- release is inhibited by high glucose levels and stimulated by low glucose
sity and that decreases insulin sensitivity. These hormones also have been levels and sympathetic stimulation; thus it is antagonistic to insulin.26
implicated in bone diseases and cancer. The roles of these hormones in health
and disease are being intensively studied in the search for new therapeutic Pancreatic Somatostatin
modalities to treat obesity-related disorders. The somatostatin produced by delta cells of the pancreas is essential
Data from Kelesidis T et al: Narrative review: the role of leptin in
in carbohydrate, fat, and protein metabolism (homeostasis of ingested
human physiology: emerging clinical applications, Ann Intern Med nutrients). It is different from hypothalamic somatostatin, which inhib-
152(2):93–100, 2010; Maury E, Brichard SM: Adipokine dysregulation, its the release of growth hormone and TSH. Pancreatic somatostatin is
adipose tissue inflammation and metabolic syndrome, Mol Cell Endo- involved in regulating alpha-cell and beta-cell function within the islets
crinol 314(1):1–16, 2010; Oswal A, Yeo G: Leptin and the control of by inhibiting secretion of insulin, glucagon, and pancreatic polypeptide.26
body weight: a review of its diverse central targets, signaling mecha-
nisms, and role in the pathogenesis of obesity, Obesity 18(2):221–229, Gastrin, Grehlin, and Pancreatic Polypeptide
2010; Ouchi N, et al: Adipokines in inflammation and metabolic dis- The function of pancreatic gastrin has not been established. It is pos-
ease, Nat Rev Immunol 11(2):85–97, 2011; Cui J, Panse S, Falkner B: tulated that fetal pancreatic gastrin secretion is necessary for adequate
The role of adiponectin in metabolic and vascular disease: a review,
islet cell development. Grehlin stimulates GH secretion, controls
Clin Nephrol 75(1):26–33, 2011.
appetite, and plays a role in the regulation of insulin sensitivity. Pan-
creatic polypeptide is released by F cells in response to hypoglycemia
Insulin is an anabolic hormone that promotes glucose uptake and and protein-rich meals. It inhibits gallbladder contraction and exo-
the synthesis of proteins, carbohydrates, lipids, and nucleic acids and crine pancreas secretion and is frequently increased in individuals with
functions mainly in the liver, muscle, and adipose tissue. Table 17-7 pancreatic tumors or diabetes.25
summarizes the actions of insulin. The net effect of insulin in these
tissues is to stimulate protein and fat synthesis and decrease blood Adrenal Glands
The adrenal glands are paired, pyramid-shaped organs behind the
peritoneum and close to the upper pole of each kidney. Each gland
TABLE 17-7 INSULIN ACTIONS is surrounded by a capsule, embedded in fat, and well supplied with
SITES OF INSULIN ACTION blood from the phrenic and renal arteries and the aorta. Venous return
LIVER MUSCLE ADIPOSE from the left adrenal gland is to the renal vein and from the right adre-
ACTIONS CELLS CELLS CELLS nal gland is to the inferior vena cava.
Glucose uptake Increased Increased Increased Each adrenal gland consists of two separate portions—an inner
Glucose use — — Increased glyc- medulla and an outer cortex. These two portions have different embry-
erol phosphate onic origins, structures, and hormonal functions. In effect, each adrenal
Glycogenesis Increased Increased — gland functions like two separate glands, although there are interrela-
Glycogenolysis Decreased Decreased — tionships (Figure 17-15).
Glycolysis Increased Increased Increased The adrenal cortex, or outer region of the gland, accounts for 80%
Gluconeogenesis Increased — — of the weight of the adult gland. The cortex is histologically subdivided
Other Increased Increased amino Increased fat into the following three zones27:
fatty acid acid uptake esterification 1. The zona glomerulosa, the outer layer, constitutes about 15% of the
synthesis cortex and primarily produces the mineralocorticoid aldosterone.
Decreased Increased protein Decreased 2. The zona fasciculata, the middle layer, constitutes 78% of the
ketogenesis synthesis lipolysis cortex and secretes the glucocorticoids cortisol, cortisone, and
Decreased Decreased Increased fat corticosterone.
urea cycle ­proteolysis storage 3. The zona reticularis, the inner layer, constitutes 7% of the cortex
activity and secretes mineralocorticoids (aldosterone), adrenal androgens
and estrogens, and glucocorticoids.
440 CHAPTER 17  Mechanisms of Hormonal Regulation

Adrenal gland

Kidney Capsule
Capsule
Zona Zona
glomerulosa glomerulosa

Zona
fasciculata
Capsule

Cortex Zona
fasciculata
Medulla

Zona
reticularis Zona
reticularis
Medulla
A B Medulla
FIGURE 17-15  Structure of the Adrenal Gland Showing Cell Layers (Zonae) of the Cortex.
A, Zona glomerulosa secretes aldosterone. Zona fasciculata secretes abundant amounts of glucocorti-
coids, chiefly cortisol. Zona reticularis secretes minute amounts of sex hormones and glucocorticoids.  
B, A portion of the medulla is visible at the lower right in the photomicrograph (×35) and at the bottom
of the drawing. (A from Patton KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby;
B from Kierszenbaum A: Histology and cell biology, St Louis, 2002, Mosby.)

The adrenal medulla, which accounts for 20% of the gland’s total lymphocytes, primarily T-helper lymphocytes. There is a greater effect
weight, secretes the catecholamines epinephrine (adrenaline) and nor- on T-helper 1 (Th1) cytokine production (including antiviral inter-
epinephrine (noradrenaline). Both sympathetic and parasympathetic ferons) than there is T-helper 2 (Th2) cytokine production and there-
cholinergic fibers innervate the adrenal medulla. fore greater depression of cellular immunity than humoral immunity
(see Chapter 7). Glucocorticoids affect innate immunity through sev-
Adrenal Cortex eral pathways, including decreasing the activity of pattern receptors
The adrenal cortex secretes several steroid hormones, including the on the surface of macrophages (see Chapter 5). Glucocorticoids also
glucocorticoids, the mineralocorticoids, and the adrenal androgens have anti-inflammatory effects related to decreased function of natural
and estrogens. These hormones are all synthesized from cholesterol. killer cells, suppression of inflammatory cytokines, and stabilization
The cells of the adrenal cortex are stimulated by adrenocorticotropic of lysosomal membranes, which decreases the release of proteolytic
hormone (ACTH) from the pituitary gland.27 The best known pathway enzymes.27 This suppression of innate and adaptive immunity by glu-
of steroidogenesis involves the conversion of cholesterol to pregneno- cocorticoids means that infection and poor wound healing are some
lone, which is then converted to the major corticosteroids. The adrenal of the most problematic complications of the use of glucocorticoids in
cortex also contains a high concentration of ascorbic acid (vitamin C) the treatment of disease. Similarly, psychologic and physiologic stress
and vitamin A. increases glucocorticoid production, which provides a pathway for the
Glucocorticoids well-described decrease in immunity seen in both acute and chronic
Functions of the glucocorticoids. The glucocorticoids are ste- stress conditions (see Chapter 8).
roid hormones that have metabolic, anti-inflammatory, and growth- Other effects of glucocorticoids include inhibition of bone for-
suppressing effects and influence levels of awareness and sleep patterns. mation, inhibition of ADH secretion, and stimulation of gastric acid
(These functions are summarized in Box 17-1). Glucocorticoids have secretion. Glucocorticoids appear to potentiate the effects of catechol-
direct effects on carbohydrate metabolism. These hormones increase amines, including sensitizing the arterioles to the vasoconstrictive
blood glucose concentration by promoting gluconeogenesis in the liver effects of norepinephrine. Thyroid hormone and growth hormone
and by decreasing uptake of glucose into muscle cells, adipose cells, effects on adipose tissue are also potentiated by glucocorticoids.
and lymphatic cells. In extrahepatic tissues, they stimulate protein A metabolite of cortisol may act like a barbiturate and depress nerve
catabolism and inhibit amino acid uptake and protein synthesis. cell function in the brain, accounting for the noted effects on mood
The glucocorticoids act at several sites to influence immune and associated with steroid level fluctuation in disease or stress.
inflammatory reactions. One major immune suppressant effect Pathologically high levels of glucocorticoids increase the number
is the glucocorticoid-mediated decrease in the proliferation of T of circulating erythrocytes (leading to polycythemia), increase the
 CHAPTER 17  Mechanisms of Hormonal Regulation 441

levels follow a similar pattern); and (3) psychologic and physiologic (e.g.,
BOX 17-1 MAJOR FUNCTIONS
hypoxia, hypoglycemia, hyperthermia, exercise) stress increases ACTH
OF GLUCOCORTICOIDS secretion, leading to increased cortisol levels. (Neurologic mechanisms
Metabolic regulating sleep are discussed in Chapter 13.) A form of immunoreactive
Increase blood glucose concentration ACTH (ir ACTH) is produced by the cells of the immune system and may
Increase hepatic gluconeogenesis account, in part, for integration of the immune and endocrine systems.
Decease glucose use in muscle, adipose, and lymphatic tissue Once ACTH is secreted, it binds to specific plasma membrane recep-
Antagonize insulin tors on the cells of the adrenal cortex and on other extraadrenal tissues.
Stimulate protein catabolism and decrease protein synthesis Because both adrenal and extraadrenal tissues have ACTH receptors,
a number of effects result from stimulation by ACTH. In addition to
Inflammatory and Immune increasing adrenocortical secretion of cortisol, ACTH maintains the
Decrease cellular immunity size and synthetic functions of the adrenal cortex through activation of
Decrease T lymphocyte proliferation crucial enzymes and storage of cholesterol for metabolism into steroid
Decrease natural killer cell activity hormones. Extraadrenal effects of ACTH include stimulation of mela-
Decrease macrophage activity nocytes and activation of tissue lipase.
Anti-inflammatory Once ACTH stimulates the cells of the adrenal cortex, cortisol
Decrease number of eosinophils synthesis and secretion immediately occur. In the healthy person, the
Decrease number of fibroblasts secretory patterns of ACTH and cortisol are nearly identical. After
Decrease inflammatory cytokines (interleukins, bradykinin, serotonin, and secretion, some cortisol circulates in bound form attached to albumin
histamine) but primarily it is bound to the plasma protein transcortin. A smaller
Stimulate anti-inflammatory cytokines (interleukin-10, transforming growth amount circulates in the free form and diffuses into cells with specific
factor-beta) intracellular receptors for cortisol. ACTH is rapidly inactivated in the
Stabilize lysosomal membranes circulation, and the liver and kidneys remove the deactivated hormone.
Mineralocorticoids: aldosterone. Mineralocorticoid steroids
Other directly affect ion transport by epithelial cells, causing sodium reten-
Inhibit bone formation tion and potassium and hydrogen loss. Aldosterone is the most
Inhibit ADH and ACTH secretion potent naturally occurring mineralocorticoid and conserves sodium
Stimulate gastric acid secretion by increasing the activity of the sodium pump of epithelial cells. (The
Potentiate the effects of catecholamines, thyroid hormone, and growth sodium pump is described in Chapter 1.)
­hormone on adipose tissue The initial stages of aldosterone synthesis occur in the zona fas-
Affect nerve function in the brain (affects mood and sleep) ciculata and zona reticularis. The final conversion of corticosterone to
Data from Stewart PM, Krone NP: The adrenal cortex. In Melmed S, aldosterone is confined to the zona glomerulosa. Aldosterone synthesis
et al: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, and secretion are regulated primarily by the renin-angiotensin system
Saunders. (described in Chapter 28). The renin-angiotensin system is activated
by sodium and water depletion, increased potassium levels, and a
diminished effective blood volume (Figure 17-17). Angiotensin II is
appetite, promote fat deposition in the face and cervical areas, increase the primary stimulant of aldosterone synthesis and secretion; however,
uric acid excretion, decrease serum calcium levels (possibly by inhibit- sodium and potassium levels also may directly affect aldosterone secre-
ing gastrointestinal absorption of calcium), suppress the secretion and tion. ACTH may transiently stimulate aldosterone synthesis but does
synthesis of ACTH, and interfere with the action of growth hormone not appear to be a major regulator of secretion.
so that somatic growth is inhibited. When sodium and potassium levels are within normal limits, approx-
Cortisol. The most potent naturally occurring glucocorticoid is imately 50 to 250 mg of aldosterone is secreted daily. Of the secreted aldo-
cortisol. It is the main secretory product of the adrenal cortex and is sterone, 50% to 75% binds to plasma proteins. The large proportion of
needed to maintain life and protect the body from stress (see Figure unbound aldosterone contributes to its rapid metabolic turnover in the
8-1). Cortisol has a biologic half-life of approximately 90 minutes, with liver, its low plasma concentration, and its short half-life (about 15 min-
the liver primarily responsible for its deactivation. utes). Aldosterone is degraded in the liver and is excreted by the kidney.
Cortisol secretion is regulated primarily by the hypothalamus and Aldosterone maintains extracellular volume by acting on distal
the anterior pituitary gland (Figure 17-16). Corticotropin-releasing nephron epithelial cells to increase sodium reabsorption and potas-
hormone (CRH) is produced by several nuclei in the hypothala- sium and hydrogen excretion. This renal effect takes 90 minutes to 6
mus and stored in the median eminence. Once released, CRH trav- hours. Other effects of aldosterone include enhancement of cardiac
els through the portal vessels to stimulate the production of ACTH, muscle contraction, stimulation of ectopic ventricular activity through
β-lipotropin, γ-lipotropin, endorphins, and enkephalins by the ante- secondary cardiac pacemakers in the ventricles, stiffening of blood
rior pituitary. ACTH is the main regulator of cortisol secretion and vessels with increased vascular resistance, and decreased fibrinolysis.
adrenocortical growth. Pathologically elevated levels of aldosterone have been implicated in
ACTH is synthesized as part of a precursor called pro-opiomelanocor- the myocardial changes associated with heart failure, resistant hyper-
tin (POMC). Three factors appear to be primarily involved in regulating tension, insulin resistance, and systemic inflammation.28,29
the secretion of ACTH: (1) high circulating levels of cortisol and synthetic Adrenal estrogens and androgens. The healthy adrenal cortex secretes
glucocorticoids suppress both CRH and ACTH, whereas low cortisol lev- minimal amounts of estrogen and androgens. ACTH appears to be the
els stimulate their secretion; (2) diurnal rhythms affect ACTH and corti- major regulator. Some of the weakly androgenic substances secreted by
sol levels (in persons with regular sleep-wake patterns, ACTH peaks 3 to the cortex (dehydroepiandrosterone [DHEA], androstenedione) are con-
5 hours after sleep begins and declines throughout the day, and cortisol verted by peripheral tissues to stronger androgens, such as testosterone,
442 CHAPTER 17  Mechanisms of Hormonal Regulation

( ) Diurnal rhythms
Hypothalamus ( )

Stress Corticotropin-releasing
Hypoxia hormone (CRH)
Hypoglycemia
Hyperthermia ( )
Exercise ( )
( ) Anterior pituitary
Cortisol
insufficiency
Adrenocorticotropic hormone
(ACTH)

Adrenal cortex

Glucocorticoids
(especially cortisol)
FIGURE 17-16  Feedback Control of Glucocorticoid Synthesis and Secretion.

Stimulating variables:
Nitric oxide from
macula densa
cAMP
Decreased renal Diuretics
blood flow Epinephrine
( ) ( )
Norepinephrine
Early part of day
Erect posture

Inhibiting variables:
Renin released Adenosine from macula densa
( ) by juxtaglomerular ( ) Angiotensin II
Sympathetic
cells of nephron Adrenergic blocking agents
input
cleaves Aldosterone
angiotensinogen Recumbent posture
Later part of day

Angiotensinogen Angiotensin I Angiotensin II

Increased effective Angiotensin I−converting

blood volume enzyme in lung
to correct initial stimulus
to the system

Increased sodium and

water reabsorption by
↑ Aldosterone levels
nephron collecting duct

( ) ( ) ( )

Hyponatremia Hyperkalemia ACTH levels

FIGURE 17-17  The Feedback Mechanisms Regulating Aldosterone Secretion. ACTH, Adrenocorti-
cotropic hormone; cAMP, cyclic adenosine monophosphate.
 CHAPTER 17  Mechanisms of Hormonal Regulation 443

thus accounting for some androgenic effects initiated by the adrenal cor- Once released, the catecholamines remain in the plasma for only
tex. Peripheral conversion of adrenal androgens to estrogens is enhanced seconds to minutes. The catecholamines exert their biologic effects
in aging or obese persons as well as in those with liver disease or hyperthy- after binding to plasma membrane receptors (α1, α2, β1, β2, and β3) in
roidism.30 The biologic effects and metabolism of the adrenal sex steroids target cells. This binding activates the adenylyl cyclase system. Cate-
do not vary from those produced by the gonads (see Chapter 31). cholamines are rapidly removed from the plasma by being absorbed by
neurons for storage in new cytoplasmic granules, or they may be met-
Adrenal Medulla abolically inactivated and excreted in the urine. The catecholamines
The adrenal medulla, together with the sympathetic division of the directly inhibit their own secretion by decreasing the formation of the
autonomic nervous system, is embryonically derived from neural crest enzyme tyrosine hydroxylase (the rate-limiting step).
cells. Chromaffin cells (pheochromocytes) are the cells of the adrenal Catecholamines have diverse effects on the entire body. Their
medulla. The major products stored and secreted by the chromaffin release and the body’s response have been characterized as the fight-
cells are the catecholamines epinephrine (adrenaline) and norepineph- or-flight response (stress response) (see Figure 8-2 and Figure 8-3
rine, which are synthesized from the amino acid phenylalanine (Figure and Tables 8-3 and 8-4). Metabolic effects of catecholamines promote
17-18). Only 30% of circulating epinephrine comes from the adrenal hyperglycemia through a variety of mechanisms including interference
medulla; the other 70% is released from nerve terminals. The medulla with the usual glucose regulatory feedback mechanisms.
is only a minor source of norepinephrine. The adrenal medulla func-
tions as a sympathetic ganglion without postganglionic processes.
Sympathetic cholinergic preganglion fibers terminate on the chromaf- 4 QUICK CHECK 17-4
fin cells and secrete catecholamines directly into the bloodstream. The 1. What are the islets of Langerhans? Where are they located?
catecholamines are therefore hormones and not neurotransmitters. 2. Compare and contrast the actions of alpha, beta, delta, and F cells.
Physiologic stress to the body (e.g., traumatic injury, hypoxia, hypo- 3. What is the most potent naturally occurring glucocorticoid, and how is its
glycemia, and many others) triggers release of adrenal catecholamines secretion related to that of adrenocorticotropic hormone (ACTH)?
through acetylcholine (from the preganglionic sympathetic fibers), 4. How does aldosterone influence fluid and electrolyte balance?
which depolarizes the chromaffin cells. Depolarization causes exocyto- 5. What are catecholamines?
sis of the storage granules from the chromaffin cells with release of epi-
nephrine and norepinephrine into the bloodstream. Secretion of adrenal
catecholamines also is increased by ACTH and the glucocorticoids.31 Neuroendocrine Response to Stressors
The endocrine system acts together with the nervous and immune
systems to respond to stressors. Perception that an event is stressful
Adrenal medulla may be essential to the emotional arousal and initiation of the stress
response. Some events, such as bacterial invasion, can activate the stress
response without emotional arousal. Details of the stress response are
presented in Chapter 8. Methods of hormone measurement are given
CH2-CH-NH2 Phenylalanine in Box 17-2.
COOH
Phenylalanine
hydroxylase
(liver) BOX 17-2 METHODS OF HORMONE
CH2-CH-NH2 Rate limiting
MEASUREMENT
Tyrosine
HO COOH step
Tyrosine
Radioimmunoassay (RIA)
hydroxylase In this immunologic technique, known amounts of antibody and radiolabeled
hormone are placed in an assay tube with the unlabeled hormone. The radiola-
HO beled hormone competes chemically with the nonlabeled hormone molecules
CH2-CH-NH2 Dopa for binding sites on the antibodies. When increasing amounts of unlabeled
HO COOH
() hormones are added to the assay, the limited binding sites of the antibody can
L-Aromatic
bind less of the radiolabeled hormone. Therefore, the higher the concentration
amino acid
() of unlabeled hormone, the fewer the number of radioactive counts, or labeled
decarboxylase
HO hormone, that bind with the fixed concentration of antibody. A quantitative
HO CH2-CH2-NH2 Dopamine value is established by use of standard reference curves.

Dopamine- Enzyme-Linked Immunosorbent Assay (ELISA)

β-hydroxylase Used to determine circulating hormone levels. The method is similar to that of
HO RIA but is less expensive and easier to conduct. Instead of radiolabeled hor-
HO CH-CH2-NH2 Norepinephrine mones, an enzyme-labeled hormone is used. The enzyme activity in either the
OH bound or the unbound fraction is determined and related to the concentration
Phenylethanolamine of the unlabeled hormone.
N-methyltransferase
HO H Bioassay
HO CH-CH2-N Epinephrine This assay uses graded doses of hormone in a reference preparation and then
OH CH3 compares the results with an unknown sample. Bioassays are used more com-
monly in investigative endocrinology than in clinical laboratories.
FIGURE 17-18  Synthesis of Catecholamines.
444 CHAPTER 17  Mechanisms of Hormonal Regulation

GERIATRIC CONSIDERATIONS
Aging & Its Effects on Specific Endocrine Glands
General Endocrine Changes With Aging Pancreas
Atrophy and weight loss with vascular changes; decreased secretion and clear- Nearly half of older individuals have glucose intolerance or diabetes, and these
ance of hormones often occurs; variable change in receptor binding and intra- disorders frequently are undiagnosed in aging adults. Mechanisms include
cellular responses. decreased insulin receptor activity and decreased beta-cell secretion of
insulin.
Pituitary
Posterior: Decrease in size; reduced antidiuretic hormone (ADH) secretion. Adrenal
Anterior: Increased fibrosis and moderate increase in size of gland; decline in Decreased DHEA levels lead to decreased synthesis of androgen-derived estro-
growth hormone release. gen and testosterone; decreased metabolic clearance of glucocorticoids and
cortisol causes decreased cortisol secretion; there also are decreased levels
Thyroid of aldosterone. Circadian patterns of ACTH and cortisol secretion may change
Glandular atrophy, fibrosis, nodularity, and increased inflammatory infiltrates; with aging.
possible changes in thyroid hormone (TH) are difficult to determine because
of concurrent disease in elderly persons; may find decreased T4 secretion and Gonads
turnover, decline in T3 (especially in men), diminished thyroid-stimulating Postmenopausal women have decreased estrogen and progesterone, increased
hormone (TSH) secretion; reduced response of plasma TSH concentration to follicle-stimulating hormone, and relative increases in androgen levels; these
thyroid-releasing hormone (TRH) administration (especially in men). changes have numerous physiologic and pathophysiologic consequences (see
Chapter 31); in men there is a gradual decrease in serum testosterone levels,
Growth Hormone and Insulin-like Growth Factors leading to decreased sexual activity, decreased muscle strength, and decreased
The amounts of GH and IGF decline with aging, which contributes to decreases bone mineralization.
in muscle size and function, reduced fat and bone mass, and changes in repro-
ductive and cognitive function. Increased visceral fat, decreased lean body
mass, and decreased bone density are common in older adults.

DID YOU UNDERSTAND?

Mechanisms of Hormonal Regulation Structure and Function of the Endocrine Glands
1. The endocrine system has diverse functions, including sexual differentia- 1. The pituitary gland, consisting of anterior and posterior portions, is con-
tion, growth and development, and continuous maintenance of the body’s nected to the central nervous system through the hypothalamus.
internal environment. 2. The hypothalamus regulates anterior pituitary function by secreting releas-
2. Hormones are chemical messengers synthesized by endocrine glands and ing or inhibiting hormones and factors into the portal circulation.
released into the circulation. 3. Hypothalamic hormones include prolactin-releasing factor (PRF), which
3. Hormones have specific negative and positive feedback mechanisms. Most stimulates secretion of prolactin; prolactin-inhibiting factor (PIF, dopamine),
hormone levels are regulated by negative feedback, in which hormone which inhibits prolactin secretion; thyrotropin-releasing hormone (TRH),
secretion raises the level of a specific hormone, ultimately causing secre- which affects release of thyroid hormones; growth hormone–releasing
tion to subside. hormone (GHRH), which stimulates the release of growth hormone (GH);
4. Endocrine feedback is described in terms of short, long, and ultra-short somatostatin, which inhibits the release of GH; gonadotropin-releasing
feedback loops. hormone (GnRH), which facilitates the release of follicle-stimulating hor-
5. Water-soluble hormones circulate throughout the body in unbound form, mone (FSH) and luteinizing hormone (LH); corticotropin-releasing hormone
whereas lipid-soluble hormones (e.g., steroid and thyroid hormones) circu- (CRH), which facilitates the release of adrenocorticotropic hormone (ACTH)
late throughout the body bound to carrier proteins. and endorphins; and substance P, which inhibits ACTH release and stimu-
6. Hormones affect only target cells with appropriate receptors and then act lates the release of a variety of other hormones.
on these cells to initiate specific cell functions or activities. 4. The posterior pituitary secretes antidiuretic hormone (ADH), which also is
7. Hormones have two general types of effects on cells: (a) direct effects, or called vasopressin, and oxytocin.
obvious changes in cell function, and (b) permissive effects, or less obvious 5. Hormones of the anterior pituitary are regulated by (a) secretion of hypotha-
changes that facilitate cell function. lamic-releasing hormones or factors, (b) negative feedback from hormones
8. Receptors for hormones may be located on the plasma membrane or in the secreted by target organs, and (c) mediating effects of neurotransmitters.
intracellular compartment of a target cell. 6. Hormones of the anterior pituitary include ACTH, melanocyte-stimulating
9. Water-soluble hormones act as first messengers, binding to receptors on the hormone (MSH), somatotropic hormones (growth hormone [GH], prolactin),
cell’s plasma membrane. The signals initiated by hormone-receptor binding and glycoprotein hormones—follicle-stimulating hormone (FSH), luteiniz-
are then transmitted into the cell by the action of second messengers. ing hormone (LH), and thyroid-stimulating hormone (TSH).
10. Lipid-soluble hormones (including steroid and thyroid hormones) cross the 7. ADH controls serum osmolality, increases permeability of the renal
plasma membrane by diffusion. These hormones diffuse directly into the tubules to water, and causes vasoconstriction when administered phar-
cell nucleus and bind to nuclear receptors. Rapid responses of steroid hor- macologically in high doses. ADH also may regulate some central nervous
mones may be mediated by plasma membrane receptors. system functions.
 CHAPTER 17  Mechanisms of Hormonal Regulation 445

DID YOU UNDERSTAND?—cont’d

8. O xytocin causes uterine contraction and lactation in women and may have 28. T he steroid hormones secreted by the adrenal cortex are synthesized from
a role in sperm motility in men. In both men and women, oxytocin has an cholesterol. These hormones include glucocorticoids, mineralocorticoids,
antidiuretic effect similar to that of ADH. and adrenal androgens and estrogens.
9. The two-lobed thyroid gland contains follicles, which secrete some of the 29. Glucocorticoids directly affect carbohydrate metabolism by increasing blood
thyroid hormones, and C cells, which secrete calcitonin and somatostatin. glucose concentration through gluconeogenesis in the liver and by decreasing
10. Regulation of thyroid hormone (TH) levels is complex and involves the use of glucose. Glucocorticoids inhibit immune and inflammatory responses.
hypothalamus, anterior pituitary, thyroid gland, and numerous biochemical 30. The most potent naturally occurring glucocorticoid is cortisol, which is nec-
variables. essary for the maintenance of life and for protection from stress. Secretion
11. Thyroid hormone (TH) secretion is regulated by thyroid-releasing hormone of cortisol is regulated by the hypothalamus and anterior pituitary.
(TRH) through a negative feedback loop that involves the anterior pituitary 31. Cortisol secretion is related to secretion of adrenocorticotropic hormone
and hypothalamus. (ACTH), which is stimulated by corticotropin-releasing hormone (CRH).
12. Thyroid-stimulating hormone (TSH), which is synthesized and stored in the ACTH binds with receptors of the adrenal cortex, which activates intracel-
anterior pituitary, stimulates secretion of TH by activating intracellular pro- lular mechanisms (specifically cyclic AMP) and leads to cortisol release.
cesses, including uptake of iodine necessary for the synthesis of TH. 32. Mineralocorticoids are steroid hormones that directly affect ion transport
13. Once secreted, TH acts on the thyroid gland, the anterior pituitary, and the by renal tubular epithelial cells, causing sodium retention and potassium
median eminence to regulate further TH production. and hydrogen loss.
14. Synthesis of TH depends on the glycoprotein thyroglobulin (TG), which con- 33. Aldosterone is the most potent of the naturally occurring mineralocorti-
tains a precursor of TH, tyrosine. Tyrosine then combines with iodine to coids. Its primary role is to conserve sodium.
form precursor molecules of the thyroid hormones thyroxine (T4) and triio- 34. Aldosterone secretion is regulated primarily by the renin-angiotensin sys-
dothyronine (T3). tem and by the serum sodium concentration.
15. When released into the circulation, T3 and T4 are bound by carrier proteins 35. Aldosterone acts by binding to a site on the cell nucleus and altering protein
in the plasma, which store these hormones and provide a buffer for rapid production within the cell. Its principal site of action is the kidney, where it
changes in hormone levels. The free form is the active form. causes sodium reabsorption and potassium and hydrogen excretion.
16. Thyroid hormones alter protein synthesis and have a wide range of meta- 36. Androgens and estrogens secreted by the adrenal cortex act in the same
bolic effects on proteins, carbohydrates, lipids, and vitamins. TH also way as those secreted by the gonads.
affects heat production and cardiac function. 37. The adrenal medulla secretes the catecholamines epinephrine and nor-
17. The paired parathyroid glands normally are located behind the upper and epinephrine. Epinephrine is 10 times more potent than norepinephrine in
lower poles of the thyroid. These glands secrete parathyroid hormone exerting metabolic effects. Their release is stimulated by sympathetic ner-
(PTH), an important regulator of serum calcium levels. vous system stimulation, ACTH, and glucocorticoids.
18. PTH secretion is regulated by levels of ionized calcium in the plasma and by 38. Catecholamines bind with various target cells and are taken up by neurons
cyclic adenosine monophosphate (cAMP) within the cell. or excreted in the urine. They cause a range of metabolic effects character-
19. In bone, PTH causes bone breakdown and resorption. In the kidney, PTH ized as the fight-or-flight response and include hyperglycemia and immune
increases reabsorption of calcium and decreases reabsorption of phospho- suppression.
rus and bicarbonate. 39. The endocrine system acts together with the nervous system to respond to
20. The endocrine pancreas contains the islets of Langerhans, which secrete stressors.
hormones responsible for much of the carbohydrate metabolism in the body. 40. The response to stressors involves (a) activation of the sympathetic division
21. The islets of Langerhans consist of alpha cells, beta cells, delta cells, and of the autonomic nervous system and (b) activation of the endocrine system.
F cells. 41. Other hormones that are secreted in response to stress include growth
22. Alpha cells produce glucagon, which is secreted inversely to blood glucose hormone (GH), prolactin, testosterone, antidiuretic hormone (ADH), and
concentrations. insulin.
23. Delta cells secrete somatostatin, which inhibits glucagon and insulin 42. The adrenal glands and the sympathetic neurons that innervate these
secretion. glands form the sympathoadrenal axis.
24. Beta cells secrete preproinsulin, which is ultimately converted to insulin.
25. F cells secrete pancreatic polypeptide. GERIATRIC CONSIDERATIONS: Aging & Its Effects on
26. Insulin is a hormone that regulates blood glucose concentrations and over- Specific Endocrine Glands
all body metabolism of fat, protein, and carbohydrates. 1. The general changes in the endocrine glands that occur with older age
27. The paired adrenal glands are situated above the kidneys. Each gland con- include atrophy and weight loss with vascular changes, decreased secre-
sists of an adrenal medulla, which secretes catecholamines, and an adre- tion and clearance of hormones, and variable change in receptor binding
nal cortex, which secretes steroid hormones. and intracellular responses

 KEY TERMS
•  drenal cortex  439
A •  lpha cell  437
A •  alcitonin  435
C
• Adrenal gland  439 • Amylin  439 • Chromophil  433
• Adrenal medulla  440 • Anterior pituitary  431 • Chromophobe  431
• Adrenocorticotropic hormone • Antidiuretic hormone (ADH)  434 • Corticotropin-releasing hormone
(ACTH)  433 • Beta cell  437 (CRH)  441
• Aldosterone  441 • C cell  435 • Cortisol  441
Continued
446 CHAPTER 17  Mechanisms of Hormonal Regulation

 KEY TERMS—cont’d
•  elta cell  437
D • L uteinizing hormone (LH)  433 •  rolactin  434
P
• 1,25-Dihydroxy-vitamin D3  437 • Median eminence  434 • Second messenger  429
• Direct effect  429 • Melanocyte-stimulating hormone • Somatostatin  439
• Down-regulation  429 (MSH)  433 • Target cell  428
• F (or PP) cell  437 • Melatonin  435 • Thyroglobulin (TG)  436
• First messenger  429 • Mineralocorticoid  441 • Thyroid gland  435
• Follicle  435 • Negative feedback  427 • Thyroid hormone (TH)  435
• Follicle-stimulating hormone (FSH)  433 • Oxytocin  435 • Thyroid-stimulating hormone
• Gastrin  439 • Pancreas  437 (TSH)  433
• Glucagon  439 • Pancreatic polypeptide  439 • Thyrotropin-releasing hormone
• Glucocorticoid  440 • Parathyroid hormone (PTH)  437 (TRH)  427
• Grehlin  439 • Pars distalis  431 • Thyroxine-binding globulin (TBG)  437
• Growth hormone  433 • Pars intermedia  431 • Tropic hormone  433
• Hormone  426 • Pars nervosa (neural tube)  434 • Up-regulation  429
• Hormone receptor  429 • Pars tuberalis  431 • Zona fasciculata  439
• Hypothalamus  431 • Permissive effect  429 • Zona glomerulosa  439
• Insulin  437 • Pituitary gland  431 • Zona reticularis  439
• Islet of Langerhans  437 • Pituitary stalk  434
• Isthmus  435 • Posterior pituitary  434

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15. Kampmeier TG, et al: Vasopressin in sepsis and septic shock, Minerva 31. Young WF: Endocrine hypertension. In Melmed S, et al: Williams textbook
Anestesiol 76(10):844–850, 2010. of endocrinology, ed 12, Philadelphia, 2011, Saunders.
 CHAPTER

18
Alterations of Hormonal Regulation
Robert E. Jones, Valentina L. Brashers, and Sue E. Huether

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Mechanisms of Hormonal Alterations, 447 Dysfunction of the Endocrine Pancreas:
Alterations of the Hypothalamic-Pituitary System, 448 Diabetes Mellitus, 458
Diseases of the Posterior Pituitary, 448 Types of Diabetes Mellitus, 459
Diseases of the Anterior Pituitary, 450 Acute Complications of Diabetes Mellitus, 465
Alterations of Thyroid Function, 453 Chronic Complications of Diabetes Mellitus, 465
Hyperthyroidism, 453 Alterations of Adrenal Function, 469
Hypothyroidism, 456 Disorders of the Adrenal Cortex, 469
Thyroid Carcinoma, 457 Disorders of the Adrenal Medulla, 472
Alterations of Parathyroid Function, 457
Hyperparathyroidism, 457
Hypoparathyroidism, 458
 

Functions of the endocrine system involve complex interrelationships inappropriate signals. Once hormones are released into the circulation,
and interactions that maintain dynamic steady states and provide they may be degraded at an altered rate or be inactivated before reach-
growth and reproductive capabilities. Endocrine system dysfunction ing the target cell by antibodies that function as circulating hormone
includes excessive or insufficient function of the endocrine gland with inhibitors. Other causes of decreased hormone delivery to the target
alterations in hormone levels. These alterations are caused by either cell include an inadequate blood supply to the gland or target tissues
hypersecretion or hyposecretion of the various hormones, leading to or an insufficient amount of the appropriate carrier proteins in the
abnormal hormone concentrations in the blood. Dysfunction also may serum. Ectopic sources of hormones (hormones produced by nonen-
result from abnormal cell receptor function or from altered intracel- docrine tissues) may cause abnormally elevated hormone levels with-
lular response to the hormone-receptor complex. out the benefit of the normal feedback system for hormone control; in
this case, the ectopic hormone production is said to be autonomous.
Target cells may not respond appropriately to hormonal stimula-
MECHANISMS OF HORMONAL ALTERATIONS tion for a number of reasons. The following are the two general types
Significantly elevated or significantly depressed hormone levels may of target cell insensitivity to hormones:
result from various causes (Table 18-1). Dysfunction of an endocrine 1. Cell surface receptor–associated disorders. These disorders have been
gland may involve its failure to produce adequate amounts of bio- identified primarily in water-soluble hormones, such as insulin.
logically free or active hormone, or a gland may synthesize or release They may involve a decrease in the number of receptors, leading to
too much hormone. Feedback systems that recognize the need for a decreased or defective hormone-receptor binding; impaired recep-
particular hormone may fail to function properly or may respond to tor function, resulting in insensitivity to the hormone; presence of

447
448 CHAPTER 18  Alterations of Hormonal Regulation

TABLE 18-1 MECHANISMS OF HORMONE ALTERATIONS

INAPPROPRIATE AMOUNTS OF HORMONE DELIVERED
TO TARGET CELL INAPPROPRIATE RESPONSE BY TARGET CELL
Inadequate Hormone Synthesis Cell Surface Receptor–Associated Disorders
1. Inadequate quantity of hormone precursors 1. Decrease in the number of receptors
2. Secretory cell unable to convert precursors to active hormone 2. Impaired receptor function (altered affinity
for hormones)
Failure of Feedback Systems 3. Presence of antibodies against specific
1. Do not recognize positive feedback, leading to inadequate hormone synthesis receptors
2. Do not recognize negative feedback, leading to excessive hormone synthesis 4. Unusual expression of receptor function

Inactive Hormones Intracellular Disorders

1. Inadequate biologically free hormone 1. Acquired defects in postreceptor signaling cascades
2. Hormone degraded at an altered rate 2. Inadequate synthesis of a second messenger
3. Circulating inhibitors 3. Intracellular enzymes or proteins are altered
4. Alterations in nuclear co-regulators
Dysfunctional Delivery System 5. Altered protein synthesis
1. Inadequate blood supply
2. Inadequate carrier proteins
3. Ectopic production of hormones

antibodies against specific receptors that either reduce available

binding sites or mimic hormone action, suppressing or exaggerat- Decreased hypothalamic function
ing, respectively, the target cell response; or unusual expression of
receptor function, for example, tumor cells with abnormal receptor
activity.
2. Intracellular disorders. These disorders involve acquired defects in GnRH TRH CRH PIF GHRH
postreceptor signaling cascades or inadequate synthesis of a sec-
ond messenger, such as cyclic adenosine monophosphate (cAMP),
needed to transduce the hormonal signal into intracellular events.
Anterior pituitary
The target cell for water-soluble hormones may have a faulty
response to hormone-receptor binding and thus fail to generate the
required second messenger, or the cell may respond abnormally to
the second messenger if levels of intracellular enzymes or proteins FSH LH TSH ACTH Prolactin Growth
are altered. (Second messengers for various hormones are listed in hormone
Table 17-3.) As a result, the target cell fails to express the usual hor-
monal effect. FIGURE 18-1  Loss of Hypothalamic Hormones. GnRH, Gonad-
Pathogenic mechanisms affecting target cell response for lipid-­ otropin-releasing hormone; TRH, thyrotropin-releasing hormone;
soluble hormones are recognized less often than those affecting water- CRH, corticotropin-releasing hormone; PIF, prolactin inhibitory fac-
soluble hormones. When they do occur, the mechanisms are similar to tor (probably dopamine); GHRH, growth hormone–releasing hor-
mone; FSH, follicle-stimulating hormone; LH, luteinizing hormone;
those for water-soluble hormones, including changes in the number
TSH, thyroid-stimulating hormone; ACTH, adrenocorticotropic
and binding affinity of intracellular receptors or altered generation of hormone.
new messenger ribonucleic acid (RNA) and substrates for new protein
synthesis.
of growth hormone–releasing hormone (GHRH) result in growth
ALTERATIONS OF THE HYPOTHALAMIC- hormone (GH) deficiency and growth failure in children. Hyperpro-
lactinemia is caused by an absence of the usual inhibitory control of
PITUITARY SYSTEM
prolactin secretion (dopamine).
Perhaps the most common cause of apparent hypothalamic dysfunc-
tion is interruption of the pituitary stalk caused by destructive lesions, Diseases of the Posterior Pituitary
rupture after head injury, surgical transection, or tumor. In these cases, Diseases of the posterior pituitary that cause clinically significant
interruption of the physical connections between the hypothalamus alterations in hormone function usually are related to abnormal secre-
and the pituitary gland causes apparent pituitary disease. For example, tion of antidiuretic hormone (ADH, arginine vasopressin). An excess
without hypothalamic hormones (Figure 18-1), women cease to men- amount of this hormone results in water retention and a hypoosmolar
struate and men experience hypogonadism and impaired spermato- state, whereas deficiencies in the amount or response to ADH result
genesis. Adrenocorticotropic hormone (ACTH) response to low serum in serum hyperosmolarity. These complex pathophysiologic states not
cortisol levels is decreased because of the absence of corticotropin- only have significant clinical effects on the modulation of body flu-
releasing hormone (CRH). Hypothalamic hypothyroidism is caused ids and electrolytes but also affect cognitive and emotional responses
by the absence of thyrotropin-releasing hormone (TRH). Low levels to stress.
 CHAPTER 18  Alterations of Hormonal Regulation 449

correction of hyponatremia and salt wasting. Demeclocycline, which

Syndrome of Inappropriate Antidiuretic Hormone Secretion causes the renal tubules to develop resistance to ADH, may be used to
Syndrome of inappropriate ADH secretion (SIADH), also known treat resistant or chronic SIADH. ADH receptor antagonists have been
as vasopressin dysregulation, is characterized by high levels of ADH used in selective instances of ADH excess.6
without normal physiologic stimuli for its release.
The most common cause of SIADH is the ectopic production of ADH Diabetes Insipidus
by tumors such as small cell carcinoma of the duodenum, stomach, and Diabetes insipidus (DI) is a disorder of insufficient activity of ADH,
pancreas; cancers of the bladder, prostate, and endometrium; lympho- leading to polyuria (frequent urination) and polydipsia (frequent
mas; and sarcomas. Pulmonary disorders associated with SIADH include drinking). The two forms of DI are as follows:
bronchogenic carcinoma, pneumonia (e.g., tuberculosis), asthma, cystic 1. Neurogenic or central DI. Caused by the insufficient secretion of
fibrosis, and respiratory failure requiring mechanical ventilation.1,2 Cen- ADH, it occurs when any organic lesion of the hypothalamus, pitu-
tral nervous system disorders that may cause SIADH include encephali- itary stalk, or posterior pituitary interferes with ADH synthesis,
tis, meningitis, intracranial hemorrhage, tumors, and trauma.3 transport, or release. Causative lesions include primary brain tumors,
Any surgery can result in increased ADH secretion for as long as 5 hypophysectomy, aneurysms, thrombosis, infections, and immu-
to 7 days after surgery. The precise mechanism is uncertain but is likely nologic disorders. Central DI is a well-recognized complication of
related to fluid and volume changes following surgery, the amount closed-head injury. It can also be caused by hereditary disorders that
and type of intravenous fluids given, and the use of narcotic analge- affect ADH genes or result in structural changes in the pituitary gland.
sics. Transient SIADH also may follow pituitary surgery because stored 2. Nephrogenic DI. Caused by inadequate response of the renal tubules
ADH is released in an unregulated fashion. to ADH, which is usually acquired or may be genetic. Acquired neph-
Medications are an important cause of SIADH, especially in the rogenic DI is generally related to disorders and drugs that damage
elderly. These include hypoglycemic medications (e.g., chlorprop- the renal tubules or inhibit the generation of cAMP in the tubules.
amide), narcotics, general anesthetics, chemotherapeutic agents, non- These disorders include pyelonephritis, amyloidosis, destructive
steroidal anti-inflammatory drugs, and synthetic ADH analogs. Finally, uropathies, and polycystic kidney disease, all of which lead to irre-
SIADH may be associated with psychiatric disease treated with antide- versible diabetes insipidus. Drugs that may induce a reversible form
pressants or antipsychotics.4 of nephrogenic diabetes insipidus include lithium carbonate, col-
chicines, amphotericin B, loop diuretics, general anesthetics (such
PATHOPHYSIOLOGY  The cardinal features of SIADH are the result as methoxyflurane), and demeclocycline. Several genetic causes of
of enhanced renal water retention. ADH increases renal collecting duct nephrogenic DI have been identified.7 One of the best described is
permeability to water by inducing the insertion of aquaporin-2, a water a mutation in the gene that codes for aquaporin-2, which is one of
channel protein, into the tubular luminal membrane, which increases the four water transport channels in the renal tubule.8
water reabsorption by the kidneys. (Renal function is discussed in Psychogenic polydipsia may be confused with diabetes insipidus.
Chapter 28.) This results in an expansion of extracellular fluid volume It is caused by the chronic ingestion of extremely large quantities of
that leads to dilutional hyponatremia (low serum sodium concentra- fluid that wash out the renal medullary concentration gradient, which
tion), hypoosmolarity, and urine that is inappropriately concentrated results in a partial resistance to ADH. This condition resolves with
with respect to serum osmolarity.3 decreased fluid ingestion. Psychogenic polydipsia must be differenti-
ated from true DI because administering an ADH analog to an indi-
CLINICAL MANIFESTATIONS  The symptoms of SIADH result from vidual with psychogenic DI will result in severe hypoosmolality.
hyponatremia and are determined by its severity and rapidity of onset.
Thirst, impaired taste, anorexia, dyspnea on exertion, fatigue, and PATHOPHYSIOLOGY  Individuals with diabetes insipidus have a
dulled sensorium occur when the serum sodium level decreases rapidly partial to total inability to concentrate urine. Insufficient ADH activity
from 140 to 130 mEq/L. Peripheral edema is absent. Severe gastroin- causes excretion of large volumes of dilute urine, leading to increased
testinal symptoms, including vomiting and abdominal cramps, occur plasma osmolality. In conscious individuals, the thirst mechanism is
with a drop in sodium concentration from 130 to 120 mEq/L. Even if stimulated and induces polydipsia—usually a craving for cold drinks.
hyponatremia develops slowly, serum sodium levels below 110 to 115 The urine output is varied but can increase from the normal output of
mEq/L cause confusion, lethargy, muscle twitching, and convulsions; 1 to 2 L/day to as much as 8 to 12 L/day and the urine specific gravity is
severe and sometimes irreversible neurologic damage may occur. low. Dehydration develops rapidly without ongoing fluid replacement.
Symptoms usually resolve with correction of hyponatremia. If the individual with DI cannot conserve as much water as is lost in the
urine, serum hypernatremia and hyperosmolality occur. Other serum
EVALUATION AND TREATMENT  A diagnosis of SIADH requires electrolytes generally are not affected.
the following manifestations: (1) serum hypoosmolality and hypona-
tremia, (2) urine hyperosmolarity (i.e., urine osmolality is greater than CLINICAL MANIFESTATIONS  The clinical manifestations of dia-
expected for the concomitant serum osmolality), (3) urine sodium betes insipidus include polyuria, nocturia, continuous thirst, and
excretion that matches sodium intake, (4) normal adrenal and thyroid polydipsia. Individuals with long-standing diabetes insipidus develop
function, and (5) absence of conditions that can alter volume status a large bladder capacity and hydronephrosis (see Chapter 28).9 Neu-
(e.g., congestive heart failure, hypovolemia from any cause, or renal rogenic diabetes insipidus usually has an abrupt onset and many
insufficiency).5 individuals can specifically recall the date of onset of their symptoms.
The treatment of SIADH involves the correction of any underly- Nephrogenic DI usually has a more gradual onset.
ing causal problems and fluid restriction with careful monitoring.
In severe SIADH, emergency correction of severe hyponatremia by EVALUATION AND TREATMENT  Diabetes insipidus must be distin-
careful administration of hypertonic saline may be required. Resolu- guished from other polyuric states, including diabetes mellitus, osmot-
tion usually occurs within 3 days, with a 2- to 3-kg weight loss and ically induced diuresis, and psychogenic polydipsia. The criteria for the
450 CHAPTER 18  Alterations of Hormonal Regulation

TABLE 18-2 SIGNS AND SYMPTOMS OF DIABETES INSIPIDUS (DI) AND SYNDROME

OF INAPPROPRIATE ANTIDIURETIC HORMONE (SIADH) SECRETION
SIGNS AND SYMPTOMS DI SIADH
Urine output High Low (no hypovolemia)
Urine osmolality Low (<100-200 mOsm/L) High (>800 mOsm/L)
Urine specific gravity Low (<1.010) High (>1.020)
Serum sodium Hypernatremia (>145 mEq/L) Hyponatremia (<135 mEq/L)
Serum osmolality Hyperosmolar (>300 mOsm/L) Hypoosmolar (<285 mOsm/L)
Symptoms Polyuria, thirst Nausea, vomiting, mental changes

diagnosis of DI include low urine specific gravity, low urine osmolality, of pituitary tissue and the symptoms of hypopituitarism develop.12,13
hypernatremia, high serum osmolality, and continued diuresis despite Adenomas and aneurysms may compress otherwise normal secreting
a serum sodium concentration of 145 mEq/L or greater. The diagnosis pituitary cells and lead to compromised hormonal output.15
of DI is generally confirmed through water deprivation testing. Psy-
chogenic polydipsia can be differentiated from nephrogenic DI based CLINICAL MANIFESTATIONS  The signs and symptoms of hypo-
on plasma ADH levels. ADH levels are low in psychogenic polydipsia function of the anterior pituitary are variable and depend on which
and normal or high in nephrogenic DI. hormones are affected. In panhypopituitarism, all hormones are defi-
Treatment of neurogenic DI is based on the extent of the ADH cient and the individual suffers from multiple complications including
deficiency and on age, endocrine and cardiovascular status, and life- cortisol deficiency from lack of ACTH, thyroid deficiency from lack of
style. Some individuals require ADH replacement, but oral hydration thyroid-stimulating hormone (TSH), and loss of secondary sex char-
often is adequate. ADH replacement therapy for symptomatic central acteristics because of the lack of follicle-stimulating hormone (FSH)
or neurogenic diabetes insipidus includes intravascular or, more com- and luteinizing hormone (LH). Low levels of growth hormone (GH)
monly, oral or intranasal administration of the synthetic vasopressin and insulin-like growth factor 1 (IGF-1) affect growth in children and
analog DDAVP (desmopressin).10 Management of nephrogenic DI can cause physiologic and psychologic symptoms in adults. In addi-
requires treatment of any reversible underlying disorders, discontinu- tion, postpartum women cannot lactate because of decreased or absent
ation of etiologic medications, and correction of associated electrolyte prolactin.
disorders. Surprisingly, thiazide diuretics may improve renal tubular ACTH deficiency with associated loss of cortisol is a potentially life-
salt and water retention in individuals with moderate nephrogenic DI. threatening disorder. ACTH deficiency usually is encountered with
Drugs that potentiate the action of otherwise insufficient amounts of generalized pituitary hypofunction; it rarely occurs as an isolated event.
endogenous ADH, such as chlorpropamide, carbamazepine, and clo- Within 2 weeks of the complete absence of ACTH, symptoms of corti-
fibrate, may be used in individuals with incomplete ADH deficiency.11 sol insufficiency develop, including nausea, vomiting, anorexia, fatigue,
Table 18-2 compares the signs and symptoms of DI and SIADH. and weakness. Hypoglycemia results from increased insulin sensitivity,
decreased glycogen reserves, and decreased gluconeogenesis associated
Diseases of the Anterior Pituitary with hypocortisolism. ACTH deficiency also limits maximal aldosterone
Hypopituitarism secretion, although the renin-angiotensin system can stimulate some
Hypopituitarism can be characterized by the absence of selective pitu- aldosterone secretion. The glomerular filtration rate decreases, causing
itary hormones or the complete failure of all pituitary hormone func- decreased urine output. (Renal function is described in Chapter 28.)
tions. Hypopituitarism results from either an inadequate supply of TSH deficiency is rarely seen in isolation but often occurs with
hypothalamic-releasing hormones, because of damage to the pituitary other pituitary hormone deficiencies. Symptoms develop 4 to 8 weeks
stalk, or an inability of the gland to produce hormones.12 The most after hypothyrotropinemia occurs and include cold intolerance, skin
common causes of hypopituitarism lie within the pituitary gland itself dryness, mild myxedema, lethargy, and decreased metabolic rate. The
and result from pituitary infarction or space-occupying lesions, such symptoms usually are less severe than those of primary hypothyroidism.
as pituitary adenomas or aneurysms. Other causes of hypopituitarism The onset of FSH and LH deficiencies in women of reproductive
include removal or destruction of the gland, head trauma, infections age is associated with amenorrhea and an atrophic vagina, uterus, and
(e.g., meningitis, syphilis, tuberculosis), autoimmune hypophysitis, breasts. In postpubertal males, testicles atrophy and beard growth is
certain drugs (e.g., bexarotene, carbamazepine), or mutation of the stunted. Both men and women experience decreased body hair and
prophet of pituitary transcription factor (PROP-1) gene involved in diminished libido.
early embryonic pituitary development.13,14 GH deficiency occurs in both children and adults. Several genetic
defects have been identified in the growth hormone axis in children
PATHOPHYSIOLOGY  The pituitary gland is highly vascular and including a recessive mutation in the GH gene, resulting in a failure
relies heavily upon portal blood flow from the hypothalamus. It is, of growth hormone secretion.16 Mutations also may involve the GH
therefore, vulnerable to ischemia and infarction. Pituitary infarction receptor, IGF-1 biosynthesis, IGF-1 receptors, or defects in GH sig-
may be seen with Sheehan syndrome (postpartum pituitary necrosis), nal transduction. In adults, GH deficiency is most often caused by
pituitary apoplexy, traumatic brain injury, shock, sickle cell disease, structural or functional abnormalities of the pituitary. GH deficiency
and diabetes mellitus. Infarction results in tissue necrosis and edema in children is manifested by growth failure and a condition known as
with swelling of the gland. Expansion of the pituitary within the fixed hypopituitary dwarfism (Figure 18-2); however, not all children with
compartment of the sella turcica further impedes blood supply to the short stature have growth hormone deficiency. Symptoms of adult GH
pituitary. Over time the pituitary undergoes shrinkage and fibrosis deficiency syndrome are vague and include social withdrawal, fatigue,
 CHAPTER 18  Alterations of Hormonal Regulation 451

are hormonally silent and do not pose significant hazards to the indi-
vidual. More significant adenomas are associated with morbidity and
mortality attributable to alterations in hormone secretion or to inva-
sion or impingement of surrounding structures.

PATHOPHYSIOLOGY  Local expansion of the adenoma may impinge

on the optic chiasma and cause various visual disturbances, depend-
ing on the portion of the nerve compressed. If the tumor is locally
aggressive, invasion of the cavernous sinuses may occur, resulting in
compromise of the oculomotor, trochlear, abducens, and trigeminal
nerves with attending symptoms. Extension to the hypothalamus dis-
turbs control of wakefulness, thirst, appetite, and temperature.
Hormonal effects of adenomas include hypersecretion from the
adenoma itself and hyposecretion from surrounding pituitary cells.
The adenomatous tissue secretes the hormone of the cell type from
which it arose, without regard to the needs of the body and without
benefit of regulatory feedback mechanisms. Because of the pressure
exerted by the tumor in the unexpandable bony sella turcica, hypose-
cretion from those cells that are most sensitive to pressure is common
(GH-, FSH-, and LH-secreting cells).

CLINICAL MANIFESTATIONS  The clinical manifestations of pitu-

itary adenomas are related to tumor growth and hormone hypersecre-
tion or hyposecretion. Increased tumor size causes headache, fatigue,
neck pain or stiffness, and seizures. Visual changes include visual field
impairments (often beginning in one eye and progressing to the other)
and temporary blindness. If the tumor infiltrates other cranial nerves,
neuromuscular function is affected.
FIGURE 18-2  Hypopituitary Dwarfism. A 4-year-old boy whose
height is 25 inches. Girl is also 4 years old and has a normal height Pituitary adenomas are most often associated with increased secre-
of 39 inches. Boy (dwarf) has a normal face, as well as head, trunk, tion of growth hormone and prolactin (see Hypersecretion of Growth
and limbs of approximately normal proportions. (From Brashear HR, Hormone: Acromegaly and Prolactinoma sections in this chapter).18
Raney RB: Handbook of orthopaedic surgery, ed 10, St Louis, 1986, Gonadotropic hyposecretion results in menstrual irregularity in women,
Mosby.) decreased libido, and receding secondary sex characteristics in both men
and women. If the tumor exerts sufficient pressure, thyroid and adrenal
hypofunction may occur because of lack of TSH and ACTH, resulting
loss of motivation, and a diminished feeling of well-being. Osteoporo- in the symptoms of hypothyroidism and hypocortisolism, respectively.
sis and alterations in body composition (i.e., reduced lean body mass)
are typical concomitant symptoms of adult GH deficiency.17 EVALUATION AND TREATMENT  Diagnosis of pituitary adenoma
involves physical and laboratory evaluations, including pertinent
EVALUATION AND TREATMENT  The diagnostic evaluation of hormone assays and radiographic examination of the skull (MRI
suspected pituitary disease is often challenging and must be carefully [preferred] or contrast-enhanced CT). The goal of treatment is to pro-
interpreted together with the individual’s signs and symptoms. Simul- tect the individual from the effects of tumor growth and to control
taneous measurements of the tropic hormones from the pituitary and hormone hypersecretion while minimizing damage to appropriately
target endocrine glands are crucial and dynamic testing of the various secreting portions of the pituitary. Depending on tumor size and type,
axes may be indicated. Imaging of the pituitary (magnetic resonance individuals may be treated by administration of specific medications to
imaging [MRI] or computed tomography [CT] scans) is critical to suppress tumor growth, transsphenoidal tumor resection, or radiation
assess for anatomic lesions, such as tumors. therapy including stereotactic treatments.19
Management of hypopituitarism requires correction of the under-
lying disorder as quickly as possible. Replacement of target gland hor-
mones that are deficient because of lack of tropic anterior pituitary 4 QUICK CHECK 18-1
hormones is essential (such as cortisol, thyroid hormone, growth hor- 1. What is the mechanism of receptor-associated hormonal disorder?
mone, and gender-specific steroid hormones). In cases of circulatory 2. Why do individuals with the syndrome of inappropriate antidiuretic hor-
collapse, immediate therapy with glucocorticoids and intravenous flu- mone (SIADH) secrete concentrated urine?
ids is critical. 3. Why may individuals with a pituitary adenoma develop visual disturbances?

Hyperpituitarism: Primary Adenoma

Pituitary adenomas usually are benign, slow-growing tumors that Hypersecretion of Growth Hormone: Acromegaly
arise from cells of the anterior pituitary. The cause of pituitary adeno- Acromegaly results from continuous exposure to high levels of growth
mas is not known. Most are microscopic (microadenomas) and are hormone (GH) and insulin-like growth factor 1 (IGF-1); it almost
found only on postmortem examinations or incidentally discovered always is caused by a GH-secreting pituitary adenoma (it rarely results
on MRI examinations. The vast majority of pituitary microadenomas from the ectopic production of GHRH).20,21
452 CHAPTER 18  Alterations of Hormonal Regulation

Acromegaly usually occurs in adults in the 40- to 59-year-old on the renal tubules to increase phosphate reabsorption, leading to
age group, although it is often present for years before diagnosis. It mild hyperphosphatemia. Because the adenoma becomes increasingly
is a slowly progressive disease and, if untreated, is associated with a a space-occupying lesion, hypopituitarism may occur because of com-
decreased life expectancy. Deaths from acromegaly are caused by heart pression of surrounding hormone-secreting cells.
disease secondary to hypertension and atherosclerosis, diabetes mel-
litus, or malignancy (colon or lung cancers).21 CLINICAL MANIFESTATIONS  With connective tissue prolifera-
tion, individuals with acromegaly have an enlarged tongue, interstitial
PATHOPHYSIOLOGY  With a GH-secreting adenoma, the usual GH edema, enlarged and overactive sebaceous and sweat glands (leading
baseline secretion pattern and sleep-related GH peaks are lost, and a to increased body odor), and coarse skin and body hair. Bony pro-
totally unpredictable secretory pattern ensues. However, GH levels in liferation involves periosteal vertebral growth and enlargement of the
acromegalics are never completely suppressed. Only slight elevations bones of the face, hands, and feet (see Figure 18-4). The lower jaw and
of GH and IGF-1 stimulate growth. In children and adolescents whose forehead also protrude.
epiphyseal plates have not yet closed, the effect of increased GH lev- Increased IGF-1 levels cause ribs to elongate at the bone-cartilage
els is termed giantism (Figure 18-3). Skeletal growth is excessive, with junction, leading to a barrel-chested appearance, and increased pro-
some individuals becoming 8 or 9 feet tall. In the adult, epiphyseal clo- liferation of cartilage in joints, which causes backache and arthralgias.
sure has occurred, and increased amounts of GH and IGF-1 cause con- With bony and soft tissue overgrowth, nerve entrapment occurs, lead-
nective tissue proliferation and increased cytoplasmic matrix, as well ing to peripheral nerve damage manifested by weakness, muscular
as bony proliferation that results in the characteristic appearance of atrophy, footdrop, and sensory changes in the hands.
acromegaly (Figure 18-4).21 Symptoms of diabetes, such as polyuria and polydipsia, may occur.
GH also has significant effects on glucose, lipid, and protein metab- Acromegaly-associated hypertension is usually asymptomatic until heart
olism.22 Hyperglycemia results from GH’s inhibition of peripheral failure symptoms develop. Increased tumor size results in central ner-
glucose uptake and increased hepatic glucose production, followed by vous system symptoms of headache, seizure activity, visual disturbances,
compensatory hyperinsulinism and, finally, insulin resistance. Diabetes and papilledema. If compression hypopituitarism occurs, gonadotropin
mellitus occurs when the pancreas cannot secrete enough insulin to secretion may be affected, causing amenorrhea in women and sexual
offset the effects of GH. Excessive levels of GH and IGF-1 also affect dysfunction in men. Approximately 20% of growth hormone–secreting
the cardiovascular system. Although the associated pathophysiologic tumors also secrete prolactin, resulting in hypogonadism.
mechanism is not clearly understood at present, hypertension and left
ventricular heart failure are seen in one third to one half of individu- EVALUATION AND TREATMENT  Diagnosis is confirmed by clinical
als with acromegaly. Cardiomyopathy associated with progressive and features of the disease, MRI scans, and elevated levels of GH that are
unrestrained myocardial growth is a significant factor.21 GH also acts not suppressed by oral glucose intake. IGF-1 levels also are elevated.
The goals of treatment are to normalize or reduce GH secretion and
relieve or prevent complications related to tumor expansion. The treat-
ment of choice in acromegaly is transsphenoidal surgical removal of
the GH-secreting adenoma. Radiation therapy may be effective when
rapid control of GH levels is not essential, when the individual is not a
good surgical candidate, or when hyperfunction persists after subtotal

FIGURE 18-3  Giantism. A pituitary giant and dwarf contrasted

with normal-size men. Excessive secretion of growth hormone by
the anterior lobe of the pituitary gland during the early years of life FIGURE 18-4  Acromegaly. Chronologic sequence of photographs
produces giants of this type, whereas deficient secretion of this showing slow development of acromegaly. (From Belchetz P, Ham-
substance produces well-formed dwarfs. (From Thibodeau GA, Pat- mond P: Mosby’s color atlas and text of diabetes and endocrinol-
ton KT: Anatomy & physiology, ed 6, St Louis, 2007, Mosby.) ogy, Edinburgh, 2003, Mosby.)
 CHAPTER 18  Alterations of Hormonal Regulation 453

resection. Somatostatin analogs, such as octreotide, octreotide LAR, and

ALTERATIONS OF THYROID FUNCTION
lanreotide, normalize IGF-1 levels and lower growth hormone levels.
Dopaminergic agonists, such as cabergoline, also may be helpful, espe- Disorders of thyroid function develop as a result of primary dysfunc-
cially if the tumor also secretes prolactin. Pegvisomant is an effective drug tion or disease of the thyroid gland or, secondarily, as a result of pitu-
that induces tissue insensitivity to GH by blocking the GH receptor.23 itary or hypothalamic alterations. Primary thyroid disorders result
in alterations of thyroid hormone (TH) levels with secondary feed-
Prolactinoma back effects on pituitary thyroid-stimulating hormone (TSH). For
Pituitary tumors that secrete prolactin, prolactinomas, are the most example, when there are primary elevations in TH level, TSH level will
common hormonally active pituitary tumors.24 Other conditions or secondarily decrease because of negative feedback. When TH level is
medications can elevate prolactin levels in the absence of pituitary decreased because of a condition affecting the thyroid gland, TSH level
pathologic condition. For example, renal failure, polycystic ovarian will be elevated. Thyroid disease also can present with minimal or no
disease, primary hypothyroidism, breast stimulation, or even veni- symptoms but with abnormal laboratory values, known as subclinical
puncture can increase prolactin levels. Prolactin is under tonic inhibi- thyroid disease (see Health Alert: Subclinical Thyroid Dysfunction).
tory hypothalamic control through the secretion of dopamine. Thus Central (secondary) thyroid disorders are related to disorders of pitu-
medications that block the effects of dopamine can increase prolactin itary gland TSH production. When there is excessive TSH production,
level and stimulate proliferation of prolactin-secreting cells (lacto- TH level is elevated secondary to the primary elevation of TSH concen-
trophs). These include antipsychotics (risperidone, chlorpromazine), tration. The reverse is true with inadequate TSH production.
metoclopramide, tricyclic antidepressants, and methyldopa. Estrogens
increase prolactin concentration by stimulating hyperplasia of pro-
lactin-secreting cells. Any process that interferes with the delivery of HEALTH ALERT
dopamine from the hypothalamus to the lactotrophs (pituitary stalk Subclinical Thyroid Dysfunction
tumor, pituitary stalk transection, or compressive pituitary tumor) also
results in hyperprolactinemia. Because thyrotropin-releasing hormone Subclinical hypothyroidism is defined as a condition in which thyroid hormone
(TRH) stimulates prolactin secretion, in addition to enhancing TSH levels are within normal limits but serum TSH level is mildly elevated. This
release, prolactin concentration may be elevated in individuals with condition occurs in 3% to 8% of the population overall, and in 10% of indi-
primary hypothyroidism. viduals over the age of 60. Risk factors for the spontaneous form of this con-
dition include female gender, aging, and the presence of thyroid antibodies.
PATHOPHYSIOLOGY  The hallmark of a prolactinoma is sustained Subclinical hypothyroidism can also occur in neonates and children with cer-
increases in the levels of serum prolactin. The physiologic actions of tain genetic disorders and in individuals being inadequately treated for other
prolactin include breast development during pregnancy, postpartum hypothyroid conditions. Although the most common complication is the high
milk production, and suppression of ovarian function in nursing likelihood of progression to clinical hypothyroidism, some studies suggest an
women. Pathologic elevation of prolactin levels in women results in associated increase in risk for dyslipidemia, atherosclerosis, and left ventricu-
amenorrhea, nonpuerperal milk production (galactorrhea), hirsutism, lar dysfunction.
and osteopenia resulting from estrogen deficiency. Hyperprolactinemia Subclinical hyperthyroidism is defined as a condition in which thyroid hor-
in men causes hypogonadism and erectile dysfunction. mone levels are within normal limits but serum TSH level is mildly decreased.
Because the adenoma becomes an increasingly space-occupying This condition affects between 2% and 6% of the population, women more
lesion, hypopituitarism may occur because of the compression of sur- commonly than men. The recognized complications of subclinical hyperthyroid-
rounding hormone secreting cells. Central nervous system symptoms ism include osteoporosis, diminished arterial elasticity, reduced cognitive per-
may develop because of growth and pressure of the adenoma within formance, diminished muscle strength, and increased risk of atrial fibrillation.
the sella turcica. Monitoring and treatment of subclinical thyroid dysfunction is controversial
although some studies link treatment with a reduced risk of complications.
CLINICAL MANIFESTATIONS  Women with hyperprolactinemia Data from Biondi B: Cardiovascular mortality in subclinical hyperthyroid-
generally present with galactorrhea (nonpuerperal milk produc- ism: an ongoing dilemma, Eur J Endocrinol 162(3):587–589, 2010; Diez
tion) and menstrual disturbances including amenorrhea. In suscep- JJ, Iglesias P: An analysis of the natural course of subclinical hyperthy-
tible women, hirsutism develops because of estrogen deficiency. If not roidism, Am J Med Sci 337(4):225–232, 2009; Fatourechi V: Subclinical
detected until after many years, this estrogen deficiency also may result hypothyroidism: an update for primary care physicians, Mayo Clin Proc
in osteoporosis. Men often present late with symptoms related to the 84(1):65–71, 2009; Kim SK et al: Regression of the increased common
increasing size of the adenoma (i.e., headache or visual impairment).24 carotid artery-intima media thickness in subclinical hypothyroidism
after thyroid hormone replacement, Endocr J 56(6):753–758, 2009;
O’Grady MJ, Cody D: Subclinical hypothyroidism in childhood, Arch
EVALUATION AND TREATMENT  The diagnostic evaluation of hyper-
Dis Child 96(3):280–284, 2011; Karmisholt J, et al: Variation in thyroid
prolactinemia includes a careful history to exclude medications that may
function in subclinical hypothyroidism: importance of clinical follow-up
cause elevations in prolactin concentration. Symptoms of hypothyroid- and therapy. Eur J Endocrinol 164(3):317–323, 2011.
ism should be elicited, and screening with a serum TSH level is manda-
tory. MRI scanning of the pituitary is indicated to determine the size and
location of an adenoma. If serum prolactin level is less than 50 ng/ml, a Hyperthyroidism
careful search for a nonpituitary cause should be pursued. Thyrotoxicosis
Dopaminergic agonists (bromocriptine and cabergoline) are the Thyrotoxicosis is a condition that results from increased levels of thy-
treatment of choice for prolactinomas.24 Restoration of fertility in roid hormones (TH). Hyperthyroidism is a form of thyrotoxicosis in
previously anovulatory women is common. In individuals resistant or which excess amounts of TH are secreted from the thyroid gland. The
intolerant to these medications, transsphenoidal surgery and radio- terms thyrotoxicosis and hyperthyroidism are often used interchange-
therapy are options.25 ably. Common diseases that cause primary hyperthyroidism include
454 CHAPTER 18  Alterations of Hormonal Regulation

Graves disease (TSH

receptor antibodies) HYPOFUNCTION HYPERFUNCTION

Loss of hair
TSH receptor Thin hair
Coarse, brittle
hair
TSH Exophthalmos
Periorbital edema
IgG Puffy face
Enlarged thyroid:
• Diffuse ("warm
Normal or small on palpation")
thyroid • Nodular
4 • Solitary "toxic"
nodule
Heart
failure Heart failure
Low TSH (tachycardia)
1 Thyroid (bradycardia)
pill

Weight loss
Constipation Diarrhea

Cold
Nodular 2
intolerance
goiter
3
Warm skin,
sweaty palms

T3, T4 Adenoma

Muscle weakness
FIGURE 18-5  Common Causes of Hyperthyroidism. Hyperthy-
roidism may have several causes, among them: 1, Graves disease; Hyperreflexia
2, toxic multinodular goiter; 3, follicular adenoma; 4, thyroid medi-
cation. (From Damjanov I: Pathology for the health professions,
ed 3, St Louis, 2006, Saunders.)

Pretibial
Graves disease, toxic multinodular goiter, and solitary toxic adenoma Edema of the edema
(Figure 18-5). Central (secondary) hyperthyroidism is less common extremities
and is caused by TSH-secreting pituitary adenomas. Thyrotoxicosis
not associated with hyperthyroidism includes subacute thyroiditis,
ectopic thyroid tissue, and ingestion of excessive TH. Each condition
is associated with a specific pathophysiology and manifestations; how-
ever, all forms of thyrotoxicosis share some common characteristics.

CLINICAL MANIFESTATIONS  The clinical features of thyrotoxico- FIGURE 18-6  Clinical Manifestations of Hyperthyroidism and
sis are attributable to the metabolic effects of increased circulating lev- Hypothyroidism. (From Damjanov I: Pathology for the health pro-
els of thyroid hormones. This usually results in an increased metabolic fessions, ed 4, St Louis, 2012, Saunders.)
rate with heat intolerance and increased tissue sensitivity to stimula-
tion by the sympathetic division of the autonomic nervous system. The
major manifestations are summarized in Figure 18-6. Enlargement antithyroid drug therapy, radioactive iodine therapy, and surgery.26 A
of the thyroid gland (goiter) is common in hyperthyroid conditions major complication of all forms of treatment for hyperthyroidism is
caused by stimulation of TSH receptors. excessive ablation of the gland leading to hypothyroidism.

EVALUATION AND TREATMENT  Elevated serum thyroxine (T4) and Hyperthyroid Conditions
triiodothyronine (T3) and suppressed serum TSH levels are diagnostic Graves disease. Graves disease is the underlying cause of 50% to
for primary hyperthyroidism. By contrast, central (secondary) hyper- 80% of cases of hyperthyroidism with a prevalence of approximately
thyroidism caused by TSH-secreting pituitary tumors is characterized 0.5% in the U.S. population. It occurs more commonly in women.
by normal to increased TSH levels despite elevated thyroid hormone Although the cause of Graves disease is not known, genetic factors
concentrations. Radioactive iodine is used to test for increased uptake interacting with environmental triggers play an important role in
in primary hyperthyroidism (Figure 18-7). Treatment is directed at the pathogenesis of this autoimmune thyroid disease. Graves disease
controlling excessive TH production, secretion, or action and employs results from a form of type II hypersensitivity (see Chapter 7) in which
 CHAPTER 18  Alterations of Hormonal Regulation 455

HYPERTHYROIDISM
Elevated TH and
suppressed TSH

Radioactive iodine
Uptake and scan

A B
FIGURE 18-8  Thyrotoxicosis (Graves Disease). A, Exophthalmos
Low uptake Normal or elevated uptake* (large and protruding eyeballs often in association with a large goi-
ter); B, Pretibial myxedema associated with Graves disease; note
lumpy and swollen appearance from accumulation of connective
tissue and pinkish purple discoloration. (A from Belchetz P, Ham-
mond P: Mosby’s color atlas and text of diabetes and endocrinol-
ogy, Edinburgh, 2003, Mosby; B from Habif T: Clinical dermatology,
Thyroiditis Graves disease ed 5, 2009.)
-Postpartum Toxic multinodular goiter
-Painless Toxic adenoma
-de Quervain (viral)
recruited T lymphocytes.29 These manifestations occasionally appear
Exogenous thyroid hormone
on the hands, giving the appearance of clubbing of the fingers (thyroid
*Isotope scan aids in
acropachy).
differentiation of causes
Hyperthyroidism resulting from nodular thyroid disease. The thy-
FIGURE 18-7  Evaluation of Hyperthyroidism. Radioactive iodine roid gland normally enlarges in response to the increased demand for
is used in the differential diagnosis of hyperthyroidism.
TH that occurs in puberty, pregnancy, and iodine-deficient states as
well as in individuals with immunologic, viral, or genetic disorders.
there is stimulation of the thyroid by autoantibodies directed against When the condition requiring increased TH resolves, TSH secretion
the TSH receptor. These autoantibodies, called thyroid-stimulating normally subsides and the thyroid gland returns to its original size.
immunoglobulins (TSIs), override the normal regulatory mechanisms. Irreversible changes may have occurred in some follicular cells so
The TSI stimulation of TSH receptors in the gland results in hyperpla- these cells function autonomously and produce excessive amounts of
sia of the gland (goiter) and increased synthesis of TH, especially of TH. On the other hand, some follicular cells may cease to function.
triiodo-l-thyronine (T3). Increased levels of TH result in the classic The balance between the amount of TH produced by hyperfunctioning
signs and symptoms of hyperthyroidism illustrated in Figure 18-6. TSI nodules and that produced by the remainder of the gland determines
stimulation of the gland also causes diffuse thyroid enlargement (goi- whether an individual develops hyperthyroidism. Toxic multinodular
ter). TSH production by the pituitary is inhibited through the usual goiter occurs when there are several hyperfunctioning nodules lead-
negative feedback loop.27 ing to hyperthyroidism. If only one nodule is hyperfunctioning, it is
TSI also contributes to the two major distinguishing clinical termed toxic adenoma. The classic clinical manifestations of hyperthy-
manifestations of Graves disease (ophthalmopathy and, perhaps, roidism (see Figure 18-6) usually develop slowly, and exophthalmos
dermopathy [pretibial myxedema]). Two categories of ophthalmop- and pretibial myxedema do not occur. Nodules may be palpable on
athy associated with Graves disease (Figure 18-8) are (1) functional physical examination. The incidence of malignancy in toxic nodular
abnormalities resulting from hyperactivity of the sympathetic division goiter is estimated to be as high as 9%, so most individuals should
of the autonomic nervous system (lag of the globe on upward gaze undergo a fine needle aspiration biopsy of suspicious nodules before
and of the upper lid on downward gaze) and (2) infiltrative changes treatment. Treatment consists of a combination of radioactive iodine,
involving the orbital contents with enlargement of the ocular muscles. surgery, and antithyroid medications.30
These changes affect more than half of individuals with Graves dis- Thyrotoxic crisis. Thyrotoxic crisis (thyroid storm) is a rare but
ease. Orbital fat accumulation, inflammation, and edema of the orbital dangerous worsening of the thyrotoxic state in which death can occur
contents result in exophthalmos (protrusion of the eyeball), periorbital within 48 hours without treatment. The condition may develop spon-
edema, and extraocular muscle weakness, leading to diplopia (double taneously, but it usually occurs in individuals who have undiagnosed
vision).28 The individual may experience irritation, pain, lacrimation, or partially treated Graves disease and are subjected to excessive stress,
photophobia, blurred vision, decreased visual acuity, papilledema, such as infection, pulmonary or cardiovascular disorders, trauma, sei-
visual field impairment, exposure keratosis, and corneal ulceration. zures, emotional distress, dialysis, plasmapheresis, or inadequate prep-
A small number of individuals with Graves disease and very high aration for thyroid surgery.
levels of TSI experience pretibial myxedema (Graves dermopathy), The systemic symptoms of thyrotoxic crisis include hyperthermia;
characterized by subcutaneous swelling on the anterior portions of tachycardia, especially atrial tachydysrhythmias; high-output heart
the legs and by indurated and erythematous skin. Graves dermopa- failure; agitation or delirium; and nausea, vomiting, or diarrhea con-
thy is associated with thyrotropin receptor antigens on fibroblasts and tributing to fluid volume depletion. The symptoms may be attributed
456 CHAPTER 18  Alterations of Hormonal Regulation

to increased β-adrenergic receptors and catecholamines. Treatment The characteristic sign of severe or long-standing hypothyroidism
includes (1) the use of drugs that block TH synthesis (i.e., propyl- is myxedema, which results from the altered composition of the der-
thiouracil or methimazole), (2) the use of beta-blockers for control mis and other tissues. The connective tissue fibers are separated by large
of cardiovascular symptoms, the administration of (3) steroids or (4) amounts of protein and mucopolysaccharide. This complex binds water,
iodine (e.g., saturated solution of potassium iodide [SSKI]), and (5) producing nonpitting, boggy edema, especially around the eyes, hands,
supportive care. and feet and in the supraclavicular fossae (Figure 18-10). The tongue and
laryngeal and pharyngeal mucous membranes thicken, producing thick,
Hypothyroidism slurred speech and hoarseness. Myxedema coma, a medical emergency,
Deficient production of TH by the thyroid gland results in the clinical is a diminished level of consciousness associated with severe hypothy-
state termed hypothyroidism. Hypothyroidism is the most common roidism. Signs and symptoms include hypothermia without shivering,
disorder of thyroid function, affects between 1% and 2% of the U.S. hypoventilation, hypotension, hypoglycemia, and lactic acidosis. Older
population, and occurs more commonly in women. It may be primary individuals with severe vascular disease and with moderate or untreated
or central. Primary hypothyroidism accounts for 99% of all cases. hypothyroidism are particularly at risk for developing myxedema coma.
Causes of central (secondary) hypothyroidism are less common and It also may occur after overuse of narcotics or sedatives or after an acute
are related to either pituitary or hypothalamic failure. illness in hypothyroid individuals.33 Symptoms of hypothyroidism
in older adults should not be attributed to normal aging changes.
PATHOPHYSIOLOGY  In primary hypothyroidism, loss of thyroid
function leads to decreased production of TH and increased secretion EVALUATION AND TREATMENT  The diagnosis of primary hypo-
of TSH and TRH (Figure 18-9). The most common causes of primary thyroidism is made by documentation of the clinical symptoms of
hypothyroidism in adults include autoimmune thyroiditis (Hashimoto hypothyroidism, and measurement of increased levels of TSH and
disease), iatrogenic loss of thyroid tissue after surgical or radioactive decreased levels of TH (total T3 and both total and free T4). When
treatment for hyperthyroidism or after head and neck radiation ther- hypothyroidism is caused by pituitary deficiencies, serum TSH lev-
apy, medications, and endemic iodine deficiency.31 Infants and chil- els and basal metabolic rate (BMR) decrease. Hormone replacement
dren may present with hypothyroidism because of congenital defects. therapy with the hormone levothyroxine is the treatment of choice.
Central (secondary) hypothyroidism is caused by the pituitary’s fail- The restoration of normal TH levels should be timed appropriately;
ure to synthesize adequate amounts of TSH or a lack of TRH. Pituitary a regimen of hormonal therapy depends on the individual’s age, the
tumors that compress surrounding pituitary cells or the consequences duration and severity of the hypothyroidism, and the presence of other
of their treatment are the most common causes of central hypothy- disorders, particularly cardiovascular disorders.34
roidism. Other causes include traumatic brain injury, subarachnoid
hemorrhage, or pituitary infarction. Hypothalamic dysfunction results Hypothyroid Conditions
in low levels of TH, TSH, and TRH.32 Primary hypothyroidism. The most common cause of hypothy-
roidism in the United States is autoimmune thyroiditis (Hashimoto
CLINICAL MANIFESTATIONS  Hypothyroidism generally affects disease, chronic lymphocytic thyroiditis), which results in gradual
all body systems and occurs insidiously over months or years. The
decrease in TH level lowers energy metabolism and heat production.
The individual develops a low basal metabolic rate, cold intolerance,
lethargy, and slightly lowered basal body temperature (see Figure
18-6). The decrease in the level of TH can lead to excessive TSH pro-
duction, which stimulates thyroid tissue and causes goiter.

Mechanisms of hypothyroidism

Secondary causes

Primary thyroid Pituitary Hypothalamic

malfunction malfunction malfunction

Lack of TH negative Lack of negative Decreased

feedback on pituitary feedback to TRH
TSH secretion and hypothalamic release
hypothalamic of TRH by TSH and
TRH secretion thyroid TH

Low levels of TH Low levels of TSH Low levels of

and high levels of and TH and high TRH, TSH,
TSH and TRH levels of TRH and TH
FIGURE 18-10  Myxedema. Note edema around eyes and facial
FIGURE 18-9  Mechanisms  of  Primary  and  Secondary  Hypo­ puffiness. The hair is dry. (From Bolognia: Dermatology, ed 2, 2008,
thyroidism. Mosby.)
 CHAPTER 18  Alterations of Hormonal Regulation 457

inflammatory destruction of thyroid tissue by infiltration of lympho- bone. Changes in voice and swallowing and difficulty breathing are
cytes and circulating thyroid autoantibodies (antithyroid peroxidase related to tumor growth impinging on the trachea or esophagus. The
and antithyroglobulin antibodies).35 This disorder is linked with sev- diagnosis of thyroid cancer is generally made by fine needle aspira-
eral genetic risk factors and is commonly associated with other autoim- tion of a thyroid nodule. Ultrasonographic characteristics may be
mune conditions.36 Infiltration of thyroid autoantibodies, autoreactive suggestive of malignancy, but radioisotope scanning is rarely help-
T lymphocytes, natural killer cells, and inflammatory cytokines and ful in a euthyroid individual. Treatment may include partial or total
induction of apoptosis are involved in the tissue destruction seen in thyroidectomy, TSH suppression therapy (levothyroxine), radioactive
Hashimoto thyroiditis.37 iodine therapy (in iodine-concentrating tumors), postoperative radia-
Spontaneous recovery of thyroid function is seen in three condi- tion therapy, and chemotherapy (especially in anaplastic carcinoma).
tions: subacute thyroiditis, painless thyroiditis, and postpartum thy- New insights into the molecular pathogenesis of thyroid carcinoma are
roiditis. Subacute thyroiditis is a nonbacterial inflammation of the leading to new therapies.41
thyroid gland often preceded by a viral infection. It is accompanied by
fever, tenderness, and enlargement of the thyroid gland. The inflam-
matory process initially results in elevated levels of thyroid hormone 4 QUICK CHECK 18-2
through the release of stored thyroglobulin, which then is associ- 1. Compare the clinical manifestations of hyperthyroidism and hypothyroidism.
ated with transient hypothyroidism before the gland recovers nor- 2. What is Graves disease?
mal activity. Symptoms may last for 2 to 4 months, and nonsteroidal 3. What is myxedema?
anti-inflammatory drugs or corticosteroids usually resolve symptoms.
Painless thyroiditis has a course similar to that of subacute thyroiditis
but is pathologically identical to Hashimoto disease. Postpartum thy- ALTERATIONS OF PARATHYROID FUNCTION
roiditis is pathologically related to Hashimoto disease and generally
occurs up to 6 months after delivery with a course similar to that seen Hyperparathyroidism
in subacute thyroiditis. Thus a hyperthyroid phase (with a low thyroid Hyperparathyroidism is characterized by greater than normal secre-
radioiodine uptake) precedes the hypothyroid phase in typical cases tion of parathyroid hormone (PTH) and hypercalcemia. Hyperpara-
of subacute, painless, or postpartum thyroiditis. Spontaneous recovery thyroidism is classified as primary or secondary. Calcium levels are
occurs in 95% of these conditions. either low or normal in secondary hyperparathyroidism.
Congenital hypothyroidism. Hypothyroidism in infants occurs
when thyroid tissue is absent (thyroid dysgenesis) or with hereditary PATHOPHYSIOLOGY  Primary hyperparathyroidism is character-
defects in TH synthesis. Thyroid dysgenesis occurs more often in ized by inappropriate excess secretion of PTH by one or more of the
female infants, with permanent abnormalities in 1 of every 4000 live parathyroid glands. It is one of the most common endocrine disor-
births. Because TH is essential for embryonic growth, particularly of ders. Approximately 80% to 85% of cases are caused by parathyroid
brain tissue, the infant will be cognitively disabled if there is no thyrox- adenomas, another 10% to 15% result from parathyroid hyperpla-
ine during fetal life.38 Hypothyroidism at birth presents clinically with sia, and approximately 1% is caused by parathyroid carcinoma. In
high birthweight, hypothermia, delay in passing meconium, and neo- addition, primary hyperparathyroidism may be caused by a variety
natal jaundice. Cord blood can be examined in the first days of life for of genetic causes, especially the genes that cause multiple endocrine
T4 and TSH levels. The probability of normal growth and intellectual neoplasia.42
function is high if treatment with levothyroxine is started before the In primary hyperparathyroidism, PTH secretion is increased and is
child is 3 or 4 months old. The earlier thyroid hormone replacement is not under the usual feedback control mechanisms. The calcium level
initiated, the better the child’s outcome.39 in the blood increases because of increased bone resorption and gas-
Without early screening, hypothyroidism may not be evident until trointestinal absorption of calcium, but fails to inhibit PTH secretion
after 4 months of age. Symptoms include difficulty eating, hoarse cry, by the parathyroid gland.
and protruding tongue caused by myxedema of oral tissues and vocal Secondary hyperparathyroidism is a compensatory response of
cords; hypotonic muscles of the abdomen with constipation, abdomi- the parathyroid glands to chronic hypocalcemia, which can be associ-
nal protrusion, and umbilical hernia; subnormal temperature; leth- ated with decreased renal activation of vitamin D (renal failure) (see
argy; excessive sleeping; slow pulse rate; and cold, mottled skin. Skeletal Chapter 29. Secretion of PTH is elevated, but PTH cannot achieve nor-
growth is stunted because of impaired protein synthesis, poor absorp- mal calcium levels because of insufficient levels of activated vitamin
tion of nutrients, and lack of bone mineralization. The child will be D. Other causes of secondary hyperparathyroidism include dietary
dwarfed with short limbs, if not treated. Dentition is often delayed. deficiency in vitamin D or calcium; decreased intestinal absorption of
Cognitive disability varies with the severity of hypothyroidism and the vitamin D or calcium; and ingestion of drugs, such as phenytoin, phe-
length of delay before treatment is initiated. nobarbital, and laxatives, which either accelerates the metabolism of
vitamin D or decreases intestinal absorption of calcium.
Thyroid Carcinoma
Thyroid carcinoma is the most common endocrine malignancy and CLINICAL MANIFESTATIONS  Hypercalcemia and hypophosphate-
accounts for 4% of all cancer cases in women in the United States.40 mia are the hallmarks of primary hyperparathyroidism. Hypercalcemia
Exposure to ionizing radiation, especially during childhood, is the and hypophosphatemia may be asymptomatic or affected individuals
most consistent causal factor. Papillary and follicular thyroid carcino- may present with symptoms related to the muscular, nervous, and gas-
mas are the most frequent and medullary and anaplastic thyroid carci- trointestinal systems, including fatigue, headache, depression, anorexia,
nomas are less common. Most tumors are well differentiated. and nausea and vomiting. Excessive osteoclastic and osteocytic activity
Most individuals with thyroid carcinoma have normal T3 and T4 resulting in bone resorption may cause pathologic fractures, kyphosis
levels and are therefore euthyroid. The cancer is typically discovered of the dorsal spine, and compression fractures of the vertebral bodies.
as a small thyroid nodule or metastatic tumor in the lungs, brain, or (Bone resorption is discussed in Chapter 37.)
458 CHAPTER 18  Alterations of Hormonal Regulation

The increased renal filtration load of calcium leads to hypercal- The effects of hypomagnesemia on the peripheral metabolism and
ciuria. Hypercalcemia also affects proximal renal tubular function, clearance of PTH are not clearly understood. Once serum magnesium
causing metabolic acidosis and production of an abnormally alkaline levels return to normal, however, PTH secretion returns to normal,
urine.43 PTH hypersecretion enhances renal phosphate excretion and as does the responsiveness of peripheral tissues to PTH. Hypomag-
results in hypophosphatemia and hyperphosphaturia (see Chapter nesemia may be related to chronic alcoholism, malnutrition, malab-
4). The combination of these three variables—hypercalciuria, alka- sorption, increased renal clearance of magnesium caused by the use
line urine, and hyperphosphaturia—predisposes the individual to the of aminoglycoside antibiotics or certain chemotherapeutic agents, or
formation of calcium stones, particularly in the renal pelvis or renal prolonged magnesium-deficient parenteral nutritional therapy.
collecting ducts. These may be associated with infections. Both kidney
stones and renal infection can lead to impaired renal function. Hyper- CLINICAL MANIFESTATIONS  Symptoms associated with hypo-
calcemia also impairs the concentrating ability of the renal tubule by parathyroidism are primarily those of hypocalcemia. Hypocalcemia
decreasing its response to ADH. Chronic hypercalcemia of hyperpara- causes a lowered threshold for nerve and muscle excitation so that a
thyroidism is associated with mild insulin resistance, necessitating nerve impulse may be initiated by a slight stimulus anywhere along the
increased insulin secretion to maintain normal glucose levels. length of a nerve or muscle fiber. This creates tetany, a condition char-
Secondary hyperparathyroidism caused by renal disease presents acterized by muscle spasms, hyperreflexia, clonic-tonic convulsions,
clinically not only with bone resorption but also with the symptoms of laryngeal spasms, and, in severe cases, death by asphyxiation. Chvostek
hypocalcemia and hyperphosphatemia. Hypocalcemia can cause many and Trousseau signs may be used to evaluate for neuromuscular irri-
significant clinical problems (see Chapter 4 and hyperphosphatemia tability. Chvostek sign is elicited by tapping the cheek, resulting in
can cause deleterious effects on the cardiovascular system. twitching of the upper lip. Trousseau sign is elicited by sustained infla-
tion of a sphygmomanometer placed on the upper arm to a level above
EVALUATION AND TREATMENT  The concurrent findings of the systolic blood pressure with resultant painful carpal spasm. Other
increased ionized calcium concentration despite elevated PTH concen- symptoms of hypocalcemia include dry skin, loss of body and scalp
tration are suggestive of primary hyperparathyroidism. Imaging pro- hair, hypoplasia of developing teeth, horizontal ridges on the nails,
cedures are used to localize adenomas before surgery. Observation of cataracts, basal ganglia calcifications (which may be associated with a
asymptomatic individuals with mild hypercalcemia is recommended; parkinsonian syndrome), and bone deformities, including brachydac-
these individuals are advised to avoid dehydration and limit dietary tyly and bowing of the long bones.
calcium intake. Definitive treatment of severe primary hyperparathy- Phosphate retention caused by increased renal reabsorption of
roidism involves surgical removal of the solitary adenoma or, in the phosphate is also associated with hypoparathyroidism. Hyperphos-
case of hyperplasia, complete removal of three and partial removal of phatemia results from PTH deficiency and, in turn, hyperphosphate-
the fourth hyperplastic parathyroid glands. In those individuals who mia further lowers calcium concentration by inhibiting the activation
fail surgery, other treatments such as bisphosphonates and calcimi- of vitamin D, thereby lowering the gastrointestinal absorption of
metics (e.g., cinacalcet, a new class of calcium-lowering drugs) may calcium.
be considered.
If serum calcium concentration is low but PTH level is elevated, EVALUATION AND TREATMENT  A low serum calcium concentra-
secondary hyperparathyroidism is likely. Evaluation for renal function tion and a high phosphorus level in the absence of renal failure, intesti-
may indicate chronic renal disease. Treatment for secondary hyper- nal disorders, or nutritional deficiencies suggest hypoparathyroidism.
parathyroidism in chronic renal disease requires calcium replacement, PTH levels are low in hypoparathyroidism and measurement of serum
dietary phosphate restriction and phosphate binders, and vitamin D magnesium level and urinary calcium excretion also can help in diag-
replacement. Treatment also may include calcimimetics, which work nosis. Treatment is directed toward alleviation of the hypocalcemia.45
to increase parathyroid calcium receptor sensitivity, thus lowering PTH In acute states, this involves parenteral administration of calcium,
levels.44 which corrects serum calcium concentration within minutes. Mainte-
nance of serum calcium level is achieved with pharmacologic doses of
Hypoparathyroidism an active form of vitamin D and oral calcium. Hypoplastic dentition,
Hypoparathyroidism (abnormally low PTH levels) is most com- cataracts, bone deformities, and basal ganglia calcifications do not
monly caused by damage to the parathyroid glands during thyroid respond to the correction of hypocalcemia, but the other symptoms of
surgery. This occurs because of the anatomic proximity of the para- hypocalcemia are reversible.
thyroid glands to the thyroid. Hypoparathyroidism also is associated
with genetic syndromes, including familial hypoparathyroidism and
DiGeorge syndrome (velocardiofacial syndrome). Hypomagnesemia 4 QUICK CHECK 18-3
also can cause a decrease in both PTH secretion and PTH function. An 1. How does excessive parathyroid hormone (PTH) affect bones?
idiopathic or autoimmune form of hypoparathyroidism also is recog- 2. What are the results of a lack of circulating PTH?
nized.45 There is an inherited condition associated with hypocalcemia
but with normal to elevated levels of PTH called pseudohypoparathy-
roidism; it is caused by a postreceptor defect in PTH action. DYSFUNCTION OF THE ENDOCRINE PANCREAS:
PATHOPHYSIOLOGY  A lack of circulating PTH causes depressed
DIABETES MELLITUS
serum calcium levels and increased serum phosphate levels. In the Diabetes mellitus is a group of metabolic diseases characterized by
absence of PTH, resorption of calcium from bone and regulation of hyperglycemia resulting from defects in insulin secretion, insulin
calcium reabsorption from the renal tubules are impaired. Phosphate action, or both. 25.8 million people, or 8.3% of the U.S. population,
reabsorption by the renal tubules is therefore increased, causing hyper- have diabetes and another 7 million are estimated to be undiagnosed.
phosphatemia (PTH causes a phosphaturia). It is the seventh cause of death and costs $174 billion dollars per year in
 CHAPTER 18  Alterations of Hormonal Regulation 459

TABLE 18-3 CLASSIFICATION AND CHARACTERISTICS OF DIABETES MELLITUS

NAME CHARACTERISTICS
Type 1 (beta-cell destruction leading to Cellular-mediated autoimmune destruction of pancreatic beta cells
absolute insulin deficiency) Individual prone to ketoacidosis
Immune-mediated diabetes common form Little or no insulin secretion
(≈90%) Insulin dependent
75% of individuals develop before 30 yr of age; can occur up to the tenth decade
Usually not obese
Idiopathic (≈10%) No defined etiologies; absolute requirement for insulin replacement therapy in affected individuals may vary
Type 2 diabetes (may range from pre- Usually not insulin dependent but may be insulin requiring
dominantly insulin resistance with rela- Individual not ketosis prone (but may form ketones under stress)
tive insulin deficiency to predominantly Obesity common in abdominal region
secretory defect with insulin resistance) Generally occurs in those older than 40 yr, but frequency is rapidly increasing in children
Strong genetic predisposition
Often associated with hypertension and dyslipidemia

Other Specific Types

Genetic defects of beta-cell function Genetic abnormalities that decrease ability of beta-cell to secrete insulin:
1. Maturity-onset of youth (MODY) includes six specific autosomal dominant mutations including genes for
­hepatocyte nuclear factor-1α (HNF-1α; MODY 3 ), glucokinase (MODY 2), HNF-4α (MODY 1), insulin ­promoter
factor-1 (IPF-1; MODY 4 ), HNF-1β (MODY 5), and NeuroD1 (MODY 6)
2. Defects in mitochondrial deoxyribonucleic acid (DNA)
3. Other (including inability to convert proinsulin to insulin)
Genetic defects in insulin action Mutations in insulin receptor with hyperinsulinism or hyperglycemia or severe diabetes
Diseases of exocrine pancreas Any process that diffusely injures the pancreas, including pancreatitis, neoplasia, and cystic fibrosis
Endocrinopathies Endocrine disorders including acromegaly, Cushing syndrome, glucagonoma, pheochromocytoma, hyperthyroid-
ism, somatostatinoma, and aldosteronoma
Drug- or chemical-induced beta-cell Commonly associated drugs include glucocorticoids and thiazide diuretics, although many others may be
dysfunction implicated
Infections Beta-cell destruction by viruses including cytomegalovirus, congenital rubella
Uncommon forms of immune-mediated Anti–insulin receptor antibodies
diabetes mellitus Reported with “stiff man syndrome” and individuals receiving interferon-α
Other genetic syndromes sometimes as- Down, Klinefelter, Turner, and Wolfram syndromes
sociated with diabetes mellitus

Gestational Diabetes Mellitus (GDM)

Any degree of glucose intolerance Insulin resistance combined with inadequate insulin secretion in relation to hyperglycemia
with ­onset of first recognition during Women who are obese, older than 25 yr, have a family history of diabetes, have a history of previous GDM, or
­pregnancy are of certain ethnic groups (Hispanic, Native Americans, Asians, or blacks) are at increased risk of developing
GDM
Metabolic stress of pregnancy may uncover a genetic tendency for type 2 diabetes mellitus
From American Diabetes Association: Diagnosis and classification of diabetes mellitus, Diabetes Care 33:S62–S69, 2010.

the United States.45a The American Diabetes Association (ADA) classi- cell (approximately 120 days). This test is critically dependent upon
fies four categories of diabetes mellitus46 (Table 18-3): the method of measurement and must be related to established stan-
1. Type 1 (beta-cell destruction, usually leading to absolute insulin dards. The ADA classification “categories at increased risk for diabetes”
deficiency) describes nondiabetic elevations of HbA1C, FPG, or the 2-hour plasma
2. Type 2 (ranging from predominantly insulin resistance with rela- glucose value during OGTT (see Box 18-1). This classification includes
tive insulin deficiency to predominantly an insulin secretory defect impaired glucose tolerance (IGT), which results from diminished insu-
with insulin resistance) lin secretion, and impaired fasting glucose (IFG), which is caused by
3. Other specific types enhanced hepatic glucose output. Individuals with IGT and IFG are at
4. Gestational diabetes increased risk of cardiovascular disease and premature death and carry
The diagnosis of diabetes mellitus is based on glycosylated hemo- a 3% to 7% yearly risk of developing diabetes.46
globin (HbA1C) levels; fasting plasma glucose (FPG) levels; 2-hour
plasma glucose levels during oral glucose tolerance testing (OGTT) Types of Diabetes Mellitus
using a 75-g oral glucose load; or random glucose levels in an indi- Type 1 Diabetes Mellitus
vidual with symptoms (Box 18-1). Glycosylated hemoglobin refers to Type 1 diabetes mellitus is the most common pediatric chronic disease
the permanent attachment of glucose to hemoglobin molecules and and affects 0.17% of U.S. children and the incidence is increasing.47,47a
reflects the average plasma glucose exposure over the life of a red blood Between 10% and 13% of individuals with newly diagnosed type 1
460 CHAPTER 18  Alterations of Hormonal Regulation

BOX 18-1 DIAGNOSTIC CRITERIA FOR DIABETES MELLITUS

1. HbA1C (as measured in a DCCT-referenced assay) ≥6.5%* 4. In an individual with classic symptoms of hyperglycemia or hyperglycemic
OR crisis, a random plasma glucose ≥200 mg/dl (11.1 mmol/L)
2. FPG ≥126 mg/dl (7.0 mmol/L); fasting is defined as no caloric intake for at
least 8 hr* Categories of Increased Risk for Diabetes
OR 1. FPG 100 to 125 mg/dl
3. 2-hr plasma glucose ≥200 mg/dl (11.1 mmol/L) during OGTT* 2. 2-hr PG 75 to 199 mg/dl during OGTT
OR 3. HbA1C 5.7% to 6.4%

The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression
of long-term complications in insulin-dependent diabetes mellitus, N Engl J Med 329(14):977–986, 1993.
*In the absence of unequivocal hyperglycemia, criteria 1 through 3 should be confirmed by repeat testing.
From American Diabetes Association: Diagnosis and classification of diabetes mellitus, Diabetes Care 33:S62–S69, 2010.
FPG, Fasting plasma glucose; HbA1C (hemoglobin A1C), glycosylated hemoglobin; DCCT, Diabetes Control and Complications Trial; OGTT, oral
glucose tolerance testing; PG, plasma glucose.

TABLE 18-4 EPIDEMIOLOGY AND ETIOLOGY OF DIABETES MELLITUS

IN THE UNITED STATES
TYPE 1 DIABETES: PRIMARY BETA-CELL TYPE 2 DIABETES: INSULIN RESISTANCE WITH
DEFECT OR FAILURE INADEQUATE INSULIN SECRETION
Incidence
Frequency One of most common childhood diseases (5-10% of all cases Accounts for most cases (≈90%-95%)
of diabetes mellitus) Prevalence rate for ages 45-64 yr is 10.5%, for ages 65-74 yr is
Prevalence rate is 0.17% 18.4%
Change in incidences No documented increase in incidence in United States Incidence in all age groups has doubled since 1980

Characteristics
Age at onset Peak onset at age 11-13 yr (slightly earlier for girls than for Risk of developing diabetes increases after age 40 yr; in general,
boys) incidence increases with age into 70s; among Pima Indians,
Rare in children younger than 1 yr and adults older than 30 yr incidence peaks between ages 40 and 50 yr, then falls
Gender Similar in males and females Similar in males and females overall, although black females
have highest incidence and prevalence of all groups
Racial distribution Rates for whites 1.5-2 times higher than for nonwhites Risk is highest for blacks and Native Americans
Higher rates for those of Scandinavian descent than for those
of Central or Southern European descent
Obesity Generally normal or underweight Frequent contributing factor to precipitate type 2 diabetes among
those susceptible; a major factor in populations recently
exposed to westernized environment
Increased risk related to duration, degree, and distribution of obesity

Etiology
Common theory Autoimmune: genetic and environmental factors, resulting in Disease results from genetic susceptibility (polygenic) combined
gradual process of autoimmune destruction in genetically with environmental determinants and other risk factors;
susceptible individuals inherited defects in beta-cell mass and function combined with
Nonautoimmune: Unknown peripheral tissue insulin resistance
Strong association with HLA-DQA and HLA-DQB genes Associated with long-duration obesity
Heredity Risk to sibling: 5%-10%; risk to offspring: 2-5% Risk to first-degree relative (child or sibling): 10%-15%
Presence of antibody Islet cell autoantibodies (ICAs) and/or autoantibodies to Islet cell antibodies not present
insulin, and autoantibodies to glutamic acid decarboxylase
(GAD65) and tyrosine phosphatases IA-2 and IA-2β are pres-
ent in 85%-90% of individuals when fasting hyperglycemia
is initially detected
Insulin resistance Insulin resistance at diagnosis is unusual, but insulin resis- Insulin resistance is generally caused by altered cellular metabo-
tance may occur as individual ages and gains weight lism and intracellular postreceptor defect
Insulin secretion Severe insulin deficiency or no insulin secretion at all Typically increased at time of diagnosis, but progressively
declines over course of illness

Data from American Diabetes Association: Diabetic Care 30(suppl 1): S42–S47, 2007; National Diabetes Clearinghouse: National Diabetes
­Statistics, 2011, NIH Publication No. 11–3892, February 2011. Available at http://diabetes.niddk.nih.gov/dm/pubs/statistics/#fast.
 CHAPTER 18  Alterations of Hormonal Regulation 461

diabetes have a first-degree relative (parent or sibling) with type 1 dia-

betes. There is a 50% concordance rate in twins.48 Diagnosis is rare CLINICAL MANIFESTATIONS  Historically, type 1 diabetes melli-
during the first 9 months of life and peaks at 12 years of age. Two dis- tus was believed to have an abrupt onset. It is now known, however,
tinct types of type 1 diabetes have been identified: autoimmune and that the natural history involves a long preclinical period with gradual
nonimmune.49 Autoimmune type 1 diabetes is called type 1A. Nonim- destruction of beta cells, eventually leading to insulin deficiency and
mune type 1 diabetes is far less common than immune. It occurs sec- hyperglycemia. Generally, this latent period is longer in older individ-
ondary to other diseases, such as pancreatitis, or to a more fulminant uals with type 1 diabetes and often results in misclassification of those
disorder termed idiopathic (type 1B) diabetes. Type 1B diabetes occurs affected as having type 2 diabetes.
mostly in people of Asian or African descent and affected individuals Type 1 diabetes mellitus affects the metabolism of fat, protein,
have varying degrees of insulin deficiency. Table 18-4 summarizes the and carbohydrates. Glucose accumulates in the blood and appears in
epidemiology of diabetes mellitus. the urine as the renal threshold for glucose is exceeded, producing an
osmotic diuresis and symptoms of polyuria and thirst (Table 18-5).
PATHOPHYSIOLOGY  Type 1A diabetes mellitus is a slowly progres- Wide fluctuations in blood glucose levels occur. In addition, protein
sive autoimmune T cell–mediated disease that destroys beta cells of and fat breakdown occurs because of the lack of insulin, resulting in
the pancreas. Destruction of beta cells is related to genetic suscepti- weight loss. Increased metabolism of fats and proteins leads to high
bility and environmental factors. The strongest genetic association is levels of circulating ketones, causing a condition known as diabetic
with histocompatibility leukocyte antigen (HLA) class II alleles HLA- ketoacidosis (DKA) (see p. 465).
DQ and HLA-DR. The HLA-DR marker is associated with other auto-
immune disorders, such as celiac, Graves, Hashimoto, and Addison EVALUATION AND TREATMENT  The criteria for diagnosis of type
diseases.50 Environmental factors that have been implicated include 1 diabetes are the same as those for type 2 diabetes (see Box 18-1). The
exposure to certain drugs, foods, and viruses. These gene-environment diagnosis of diabetes is not difficult when the symptoms of polydipsia,
interactions result in the formation of autoantigens that are expressed
on the surface of pancreatic beta cells and circulate in the bloodstream
TABLE 18-5 CLINICAL MANIFESTATIONS
and lymphatics (Figure 18-11). Cellular immunity (T cytotoxic cells
and macrophages) and humoral immunity (autoantibodies) are stim-
AND MECHANISMS FOR TYPE
ulated, resulting in beta-cell destruction and apoptosis.51,52 Over time, 1 DIABETES MELLITUS
insulin synthesis declines and hyperglycemia develops. MANIFESTATION RATIONALE
Insulin, amylin, and glucagon. For insulin synthesis to decline Polydipsia Because of elevated blood glucose levels, wa-
enough such that hyperglycemia occurs, 80% to 90% of the insu- ter is osmotically attracted from body cells,
lin-secreting beta cells of the islet of Langerhans must be destroyed. resulting in intracellular dehydration and
Insulin normally suppresses secretion of glucagon and, thus, hypoin- stimulation of thirst in hypothalamus
sulinemia leads to a marked increase in glucagon secretion. Glucagon, Polyuria Hyperglycemia acts as an osmotic diuretic;
a hormone produced by the alpha cells of the islets, acts in the liver amount of glucose filtered by glomeruli of kid-
to increase blood glucose level by stimulating glycogenolysis and glu- ney exceeds that which can be reabsorbed by
coneogenesis. In addition to the decline in insulin secretion, there is renal tubules; glycosuria results, accompanied
decreased secretion of amylin, another beta-cell hormone. One of the by large amounts of water lost in urine
critical actions of amylin is to suppress glucagon release from the alpha Polyphagia Depletion of cellular stores of carbohydrates,
cells.53 Thus both alpha-cell and beta-cell functions are abnormal and fats, and protein results in cellular starvation
both a lack of insulin and a relative excess of glucagon contribute to and a corresponding increase in hunger
hyperglycemia in type 1 diabetes. Weight loss Weight loss occurs because of fluid loss in
osmotic diuresis and loss of body tissue as
fats and proteins are used for energy
Genetic predisposition Environmental factors Fatigue Metabolic changes result in poor use of food
products, contributing to lethargy and fatigue
Recurrent infections Growth of microorganisms is stimulated by
(e.g., boils and increased glucose levels and diabetes is as-
Autoantigens form on insulin-producing beta cells ­carbuncles) sociated with some immunocompromise
and circulate in the bloodstream and lymphatics Prolonged wound healing Impaired blood supply hinders healing
Genital pruritus Hyperglycemia and glycosuria favor fungal
growth; candidal infections, resulting in pruritus,
are a common presenting symptom in women
Activation of cellular immunity (macrophages Visual changes Blurred vision occurs as water balance in eye
and T cytotoxic cells) and humoral immunity fluctuates because of elevated blood glucose
(autoantibodies) toward beta cells levels; diabetic retinopathy may ensue
Paresthesias Paresthesias are common manifestations of
diabetic neuropathies
Cardiovascular Diabetes contributes to formation of ath-
Destruction of beta cells with symptoms (e.g., chest erosclerotic plaques that involve coronary,
decreased insulin secretion pain, extremity pain peripheral, and cerebrovascular circulations
and neurologic deficits)
FIGURE 18-11  Pathophysiology of Type 1 Diabetes Mellitus.
462 CHAPTER 18  Alterations of Hormonal Regulation

polyuria, polyphagia, weight loss, and hyperglycemia are present in including immunosuppression with antirejection drugs.56 Finally, islet
fasting and postprandial states. C-peptide, a component of proinsulin cell and whole pancreas transplantation has been successful in selected
released during insulin production, can be measured in the serum as a individuals.57
surrogate for insulin levels and is indicative of residual beta-cell mass
and function. Other important aspects of evaluation include looking Type 2 Diabetes Mellitus
for evidence of the chronic complications of type 1 diabetes, including Type 2 diabetes mellitus (non–insulin-dependent diabetes mellitus)
renal, nervous system, cardiac, peripheral vascular, retinal, and bony is much more common than type 1 and has been rising in incidence
tissue damage. since 1940. In the United States, type 2 diabetes affects 10.5% of those
Nearly 50% of children ages 4 years and younger and nearly 25% ages 45 to 64 years and 18.4% of those ages 65 to 74 years and has
of those between the ages of 5 and 15 with type 1 diabetes are first doubled in all adult age groups in the past two decades.58 Prevalence
diagnosed when they present with the signs and symptoms of DKA.54 varies by ethnic group and gender and is highest in black women with
In DKA, acetone (a volatile form of ketones) is exhaled by hyperventi- an overall prevalence of 34% in those ages 65 to 74. There also is an
lation and gives the breath a sweet or “fruity” odor. Occasionally, dia- increased prevalence of type 2 diabetes in children, especially in Native
betic coma is the initial symptom of the disease. American and obese children (see Table 18-4).
Currently, treatment regimens are designed to achieve optimal glu- A genetic-environmental interaction appears to be responsible for
cose level control (as measured by the HbA1C value) without causing type 2 diabetes. The most well-recognized risk factors are age, obesity,
episodes of significant hypoglycemia. Management requires individual hypertension, physical inactivity, and family history. The metabolic
planning according to type of disease, age, and activity level, but all syndrome is a constellation of disorders (central obesity, dyslipidemia,
individuals require some combination of insulin therapy, meal plan- prehypertension, and an elevated fasting blood glucose level) that
ning, and exercise regimen. There are several different types of insulin together confer a high risk of developing type 2 diabetes and associated
preparations available and there are new technologies for more physi- cardiovascular complications (Box 18-2). The metabolic syndrome
ologic insulin delivery systems.55 Many different kinds of therapies develops during childhood and is highly prevalent among overweight
are being tested to prevent the autoimmune destruction of beta cells, children and adolescents, affecting approximately 55 million Ameri-
cans. These individuals should be screened on a regular basis for dia-
betes mellitus. Early recognition and treatment, including vigorous
lifestyle changes, are critical to reducing cardiovascular events and
BOX 18-2 CRITERIA FOR THE DIAGNOSIS improving clinical outcomes.59,60
OF METABOLIC SYNDROME
PATHOPHYSIOLOGY  Many genes have been identified that are
Three of the following five traits: associated with type 2 diabetes, including those that code for beta-cell
• Increased waist circumference (>40 inches in men; >35 inches in women) mass, beta-cell function (ability to sense blood glucose levels, insu-
• Plasma triglycerides ≥150 mg/dl lin synthesis, and insulin secretion), proinsulin and insulin molecular
• Plasma high-density lipoprotein (HDL) cholesterol <40 mg/dl (men) structures, insulin receptors, hepatic synthesis of glucose, glucagon
or <50 mg/dl (women) synthesis, and cellular responsiveness to insulin stimulation. These
• Blood pressure ≥130/85 mm Hg genetic abnormalities combined with environmental influences, such
• Fasting plasma glucose ≥100 mg/dl* as obesity, result in the basic pathophysiologic mechanisms of type
From Third Report of the National Cholesterol Education Program
2 diabetes: insulin resistance and decreased insulin secretion by beta
(NCEP) expert panel on detection, evaluation, and treatment of high cells (Figure 18-12).
blood cholesterol in adults (Adult Treatment Panel III): final report, Insulin resistance is defined as a suboptimal response of insulin-
Circulation 106:3143–3421, 2002. sensitive tissues (especially liver, muscle, and adipose tissue) to insulin
*Criterion decreased from 110 to 100 mg/dl based on 2010 diagnostic and is associated with obesity. Cellular insulin resistance and obe-
category for persons at risk for diabetes mellitus (see Box 18-1). sity are present in 60% to 80% of those with type 2 diabetes. Obesity

Genetic predisposition Obesity Diet, inactivity

Adipokines, free fatty acids

inflammatory cytokines
Activity of amylin Activity of ghrelin

Beta-cell mass and function Insulin resistance

Activity of incretins Demand for insulin synthesis

Hypoinsulinemia Hyperinsulinemia

Glucagon Tissue effects and Tissue effects without

hyperglycemia hyperglycemia (insulin
(type 2 diabetes) resistance without diabetes)
FIGURE 18-12  Pathophysiology of Type 2 Diabetes Mellitus.
 CHAPTER 18  Alterations of Hormonal Regulation 463

contributes to the development of insulin resistance and diabetes

HEALTH ALERT
through several important mechanisms:
1. Adipokines (leptin and adiponectin) are hormones produced in Incretin Hormones for Type 2 Diabetes Mellitus
adipose tissue. Obesity results in increased serum levels of leptin Therapy
and decreased levels of adiponectin. These changes are associated
The incretin hormones are secreted from endocrine intestinal cells in the presence
with inflammation and decreased insulin sensitivity.61
of carbohydrates, proteins, and fats. The major incretin hormone is glucagon-
2. Elevated levels of serum free fatty acids (FFAs) and intracellular
like peptide-1 (GLP-1) and it controls postprandial glucose levels by promoting
deposits of triglycerides and cholesterol are also found in obese
glucose-dependent insulin secretion, inhibiting glucagon synthesis, and delaying
individuals. These changes interfere with intracellular insulin sig-
gastric emptying. It may also enhance beta-cell mass and replenish intracellular
naling and thus decrease tissue responses to insulin and contribute
stores of insulin. These many positive effects on glucose metabolism without
to beta-cell apoptosis, a process known as lipotoxicity.62
hypoglycemia have led to the use of incretin hormones and incretin enhancers for
3. Inflammatory cytokines (tumor necrosis factor-alpha [TNF-α],
the treatment of type 2 diabetes. In addition to improving glucose control, many
interleukin-1-beta [IL-1β], and interleukin-6 [IL-6]) are released
people taking these medications experience weight loss and improvements in
from intra-abdominal adipocytes or adipocyte-associated mono-
measurements of blood pressure, serum lipids, and myocardial function.
nuclear cells; they induce insulin resistance and are cytotoxic to
beta cells.63,64 Data from Majumdar ID, Weber HC: Gastrointestinal regulatory
4. Obesity is correlated with hyperinsulinemia and decreased insulin peptides and their effects on fat tissue, Curr Opin Endocrinol Diabetes
receptor density. Obes 17(1):51–56, 2010; Mudaliar S, Henry RR: Effects of incretin hor-
Compensatory hyperinsulinemia prevents the clinical appearance mones on beta-cell mass and function, body weight, and hepatic and
of diabetes for many years. Eventually, however, beta-cell dysfunction myocardial function, Am J Med 123(3 Suppl):S19–S27, 2010; Peters A:
Incretin-based therapies: review of current clinical trial data, Am J Med
develops and leads to a relative deficiency of insulin activity. The islet dys-
123(3 Suppl):S28–S37, 2010; Jellinger PS: Focus on incretin-based
function is caused by a combination of a decrease in beta-cell mass and therapies: targeting the core defects of type 2 diabetes, Postgrad Med
a reduction in normal beta-cell function. A progressive decrease in the 123(1):53–65, 2011; Nauck MA: Incretin-based therapies for type 2
weight and number of beta cells occurs and many of the remaining cells diabetes mellitus: properties, functions, and clinical implications, Am J
develop “exhaustion” from increased demand for insulin biosynthesis.65 Med 124(1 Suppl):S3–S18, 2011.
Glucagon concentration is increased in type 2 diabetes because
pancreatic alpha cells become less responsive to glucose inhibition,
resulting in an increase in glucagon secretion. These abnormally high EVALUATION AND TREATMENT  The diagnostic criteria for type 2
levels of glucagon increase blood glucose level by stimulating glycoge- diabetes are the same as those for type 1 (see Box 18-1). As with type 1
nolysis and gluconeogenesis. As was discussed under type 1 diabetes, diabetes, the goal of treatment for individuals with type 2 diabetes is the
type 2 diabetes also is associated with a deficiency in amylin, further restoration of near-euglycemia (a normal blood glucose level) and cor-
increasing glucagon levels. Drugs aimed at improving amylin function rection of related metabolic disorders. Dietary measures and exercise
are being evaluated.62 are of primary importance in both the prevention and the treatment
Hormones released from the gastrointestinal (GI) tract play a role of type 2 diabetes.69 As the obese individual loses weight, the body’s
in insulin resistance, beta-cell function, and diabetes. Ghrelin is a resistance to insulin often diminishes so that weight loss results in
peptide produced in the stomach and pancreatic islets that stimulates improved glucose tolerance. In those individuals with morbid obesity
growth hormone release. Decreased levels of circulating ghrelin have unresponsive to diet and exercise interventions, bariatric surgery may
been associated with insulin resistance and increased fasting insulin be indicated. Recent studies suggest that gastric bypass surgery is asso-
levels.66 The incretins are a class of peptides that are released from the ciated with a decrease in the incidence of type 2 diabetes and marked
GI tract in response to food intake and function to increase the sensi- improvements in glycemic control in those with established diabetes.70
tivity of beta cells to circulating glucose levels, thus improving insulin Although the first approach to treatment of the individual with type 2
responsiveness to meals. Incretins also suppress glucagon secretion, diabetes is maintaining an appropriate diet and exercise program, medi-
delay gastric emptying, suppress appetite, reduce beta-cell apoptosis, cations are usually needed for optimal management. Oral hypoglycemic
and induce pancreatic acinar cells to differentiate into new beta cells. agents are useful in many individuals with type 2 diabetes (Table 18-6).
Between meals they are inactivated by the enzyme dipeptidyl peptidase Insulin therapy may be needed in the later stage of type 2 diabetes because
IV (DPP-IV). Incretin analogs and DPP-IV inhibitors are being used of loss of beta-cell function, which is progressive over time.69,71
for the treatment of type 2 diabetes67 (see Health Alert: Incretin Hor-
mones for Type 2 Diabetes Mellitus Therapy). Other Specific Types of Diabetes Mellitus and Gestational
Diabetes Mellitus
CLINICAL MANIFESTATIONS  The clinical manifestations of type As listed in Table 18-3, the American Diabetes Association classifica-
2 diabetes are nonspecific. Although many more children and ado- tion of diabetes mellitus not only includes the most common forms of
lescents are now developing type 2 diabetes, it generally affects those diabetes (type 1 and type 2) but also encompasses “other specific types
older than 30 years of age.68 The affected individual is often over- of diabetes mellitus” and “gestational diabetes mellitus.” Other specific
weight, dyslipidemic, hyperinsulinemic, and hypertensive. The indi- types of diabetes include genetic defects in beta-cell function, genetic
vidual with type 2 diabetes may show some classic symptoms of defects in insulin action, diseases of the exocrine pancreas, endocri-
diabetes, such as polyuria and polydipsia, but more often will have nopathies, drug- or chemical-induced beta-cell dysfunction, infec-
nonspecific symptoms such as fatigue, pruritus, recurrent infections, tions, and other uncommon autoimmune and inherited disorders that
visual changes, or symptoms of neuropathy (paresthesias or weak- are associated with diabetes. The best-described of these other specific
ness). In those whose diabetes has progressed without treatment, types of diabetes is termed maturity-onset diabetes of youth (MODY).
symptoms related to coronary artery, peripheral artery, and cerebro- MODY includes six specific autosomal dominant mutations that affect
vascular disease may develop. critical enzymes involved in beta-cell function or insulin action. It is
464 CHAPTER 18  Alterations of Hormonal Regulation

estimated that only 2% to 5% of cases of diabetes are monogenic and,

TABLE 18-6 TYPES OF ORAL
therefore, are classified as MODY. Diagnosis and management are sim-
HYPOGLYCEMIC DRUGS ilar to those used for type 2 diabetes.72
DRUG TYPE MECHANISM OF ACTION Gestational diabetes mellitus (GDM) has been defined as any
α-Glucosidase inhibitor Delays carbohydrate absorption in GI tract by degree of glucose intolerance with onset or first recognition during
inhibiting disaccharidases pregnancy. However, this definition meant that many women with
Biguanide (metformin) Decreases hepatic glucose production previously undiagnosed type 1 or type 2 diabetes were diagnosed with
Meglitinides GDM, and many of them had progressive disease after delivery. There-
Amino acid derivatives Stimulate insulin release from pancreatic fore the ADA recently recommended that high-risk women found to
beta cells have diabetes at their initial prenatal visit receive a diagnosis of type
Sulfonylureas Stimulate insulin release from pancreatic 1 or type 2 diabetes, not gestational diabetes.73 GDM complicates
beta cells approximately 7% of all pregnancies. Diagnosis of GDM is based on
Thiazolidinediones Increase insulin sensitivity, particularly in the presence of risk factors (older age, family history, history of glu-
adipose tissue cose intolerance, membership in certain ethnic or racial group, and
DPP-IV inhibitors Increase GLP-1 levels, increasing insulin history of poor obstetric outcomes in the past), plus the measurement
secretion (see Health Alert, p. 463) of an elevated fasting or casual FPG level. OGTT is often required to
GLP-1 agonists Mimic GLP-1, which increases insulin sensi- confirm the diagnosis. Careful glucose control prenatally, during preg-
tivity and promotes weight loss (see Health nancy, and after delivery is essential to the short- and long-term health
Alert, p. 463) of both mother and baby.69,74 Women who have GDM have a 35% to
60% chance of developing DM in the next 10-20 years. Making contin-
ued evaluation is important.45a

TABLE 18-7 COMMON ACUTE COMPLICATIONS OF DIABETES MELLITUS

HYPERGLYCEMIC NONKETOTIC
HYPOGLYCEMIA IN PERSONS WITH DM DIABETIC KETOACIDOSIS SYNDROMES
Synonyms
Insulin shock, insulin reaction Diabetic coma syndrome Hyperosmolar hyperglycemia nonketotic coma

Persons at Risk
Individuals taking insulin Individuals with type 1 diabetes Older adults or very young individuals with type
Individuals with rapidly fluctuating blood glucose Individuals with nondiagnosed diabetes 2 diabetes, nondiabetics with predisposing
levels factors, such as pancreatitis; individuals with
Individuals with type 2 diabetes taking ­sulfonylurea undiagnosed diabetes
agents

Predisposing Factors
Excessive insulin or sulfonylurea agent intake, lack of Stressful situation such as infection, accident, Infection, medications that antagonize insulin,
sufficient food intake, excessive physical exercise, trauma, emotional stress; omission of insu- comorbid condition
abrupt decline in insulin needs (e.g., renal failure, lin; medications that antagonize insulin
immediately postpartum), simultaneous use of
insulin-potentiating agents or beta-blocking agents
that mask symptoms

Typical Onset
Rapid Slow Slowest

Presenting Symptoms
Adrenergic reaction: pallor, sweating, tachycardia, Malaise, dry mouth, headache, polyuria, Polyuria, polydipsia, hypovolemia, dehydration
palpitations, hunger, restlessness, anxiety, tremors polydipsia, weight loss, nausea, vomiting, (parched lips, poor skin turgor), hypotension,
Neurogenic reaction: fatigue, irritability, headache, pruritus, abdominal pain, lethargy, shortness tachycardia, hypoperfusion, weight loss,
loss of concentration, visual disturbances, dizzi- of breath, Kussmaul respirations, fruity or weakness, nausea, vomiting, abdominal pain,
ness, hunger, confusion, transient sensory or motor acetone odor to breath hypothermia, stupor, coma, seizures
defects, convulsions, coma, death

Laboratory Analysis
Serum glucose <30 mg/dl in newborn (first 2-3 days) Glucose levels >250 mg/dl, reduction in Glucose levels >600 mg/dl, lack of ketosis, se-
and <55-60 mg/dl in adults bicarbonate concentration, increased rum osmolarity >320 mOsm/L, elevated blood
anion gap, increased plasma levels of β- urea nitrogen and creatinine levels
hydroxybutyrate, acetoacetate, and acetone
 CHAPTER 18  Alterations of Hormonal Regulation 465

Acute Complications of Diabetes Mellitus Hyperosmolar hyperglycemic nonketotic syndrome (HHNKS) is

The major acute complications of diabetes mellitus are hypoglycemia, an uncommon but significant complication of type 2 diabetes mellitus
diabetic ketoacidosis, and hyperosmolar hyperglycemic nonketotic with a high overall mortality. It occurs more often in elderly individ-
syndrome (see comparison in Table 18-7). Somogyi phenomenon and uals who have other comorbidities, including infections or cardio-
dawn phenomenon also may be seen. vascular or renal disease. HHNKS differs from DKA in the degree of
Hypoglycemia in diabetes is sometimes called insulin shock or insu- insulin deficiency (which is more profound in DKA) and the degree of
lin reaction. Individuals with type 2 diabetes are at less risk for hypo- fluid deficiency (which is more marked in HHNKS) (see Table 18-6).
glycemia than those with type 1 diabetes because they retain relatively The clinical features of HHNKS include a serum glucose level >600
intact glucose counterregulatory mechanisms. However, hypoglycemia mg/dl, a serum pH >7.30, a serum bicarbonate level >15 mg/dl, a
does occur in type 2 diabetes when treatment involves insulin secreto- serum osmolarity >320 mOsm/L, and either absent or small numbers
gogues (e.g., sulfonylureas) or exogenous insulin. Symptoms include of ketones in the urine and serum.75 Glucose levels are considerably
pallor, tremor, anxiety, tachycardia, palpitations, diaphoresis, head- higher in HHNKS than in DKA because of volume depletion. Because
ache, dizziness, irritability, fatigue, poor judgment, confusion, visual the amount of insulin required to inhibit fat breakdown is less than
disturbances, hunger, seizures, and coma. Treatment requires immedi- that needed for effective glucose transport, insulin levels are sufficient
ate replacement of glucose either orally or intravenously. Prevention to prevent excessive lipolysis and ketosis (see Figure 18-13). Clinical
is achieved with individualized management of medications and diet, manifestations include severe dehydration; loss of electrolytes, includ-
blood glucose monitoring, and education. ing potassium; and neurologic changes, such as stupor.
Diabetic ketoacidosis (DKA) is a serious complication related to The Somogyi effect is a unique combination of hypoglycemia fol-
a deficiency of insulin and an increase in the levels of insulin coun- lowed by rebound hyperglycemia. The rise in blood glucose concentra-
terregulatory hormones (catecholamines, cortisol, glucagon, growth tion occurs because of counterregulatory hormones (epinephrine, GH,
hormone) (Figure 18-13). The American Diabetes Association criteria corticosteroids), which are stimulated by hypoglycemia. They produce
for the diagnosis of DKA are (1) a serum glucose level >250 mg/dl, gluconeogenesis. Excessive carbohydrate intake may contribute to the
(2) a serum bicarbonate level <18 mg/dl, (3) a serum pH <7.30, rebound hyperglycemia. The clinical occurrence of Somogyi effect is
(4) the presence of an anion gap, and (5) the presence of urine and controversial.
serum ketones.75 DKA is much more common in type 1 diabetes because The dawn phenomenon is an early morning rise in blood glucose
insulin is more deficient (see Table 18-7). Insulin normally stimulates concentration with no hypoglycemia during the night. It is related to
lipogenesis and inhibits lipolysis, thus preventing fat catabolism. With nocturnal elevations of GH, which decrease metabolism of glucose
insulin deficiency, lipolysis is enhanced and there is an increase in the by muscle and fat. Increased clearance of plasma insulin also may be
amount of nonesterified fatty acids delivered to the liver. The conse- involved. Altering the time and dose of insulin administration manages
quence is increased glyconeogenesis contributing to hyperglycemia the problem.
and production of ketone bodies (acetoacetate, hydroxybutyrate, and
acetone) by the mitochondria of the liver at a rate that exceeds periph- Chronic Complications of Diabetes Mellitus
eral use. Accumulation of ketone bodies causes a drop in pH, result- A number of serious complications are associated with any type of
ing in metabolic acidosis. Symptoms of diabetic ketoacidosis include long-term diabetes mellitus, including microvascular (retinopathies,
Kussmaul respirations (hyperventilation in an attempt to compensate nephropathies, and neuropathies) and macrovascular (coronary
for the acidosis), postural dizziness, central nervous system depression, artery, peripheral vascular, and cerebral vascular) disease (Table 18-8).
ketonuria, anorexia, nausea, abdominal pain, thirst, and polyuria. Most complications are associated with chronic hyperglycemia (also

Relative insulin insufficiency Precipitating factor

Profound Mild to moderate Increased stress hormones

(glucagon, catecholamines, cortisol
and growth hormone)
Lipolysis
Decreased insulin use and
increased glucose production
Formation of beta-hydroxybutyric Hyperglycemia
and acetoacetic acids

Solute diuresis

Polyuria

Ketones Diabetic
in urine ketoacidosis (DKA) Dehydration
Hyperosmolality Hyperosmolar hyperglycemic
nonketotic syndrome (HHNKS)
Kussmal Thirst
respirations
Central nervous
Polydipsia system depression
FIGURE 18-13  Pathophysiology of DKA and HHNKS in Diabetes Mellitus.
466 CHAPTER 18  Alterations of Hormonal Regulation

TABLE 18-8 CHRONIC COMPLICATIONS OF DIABETES MELLITUS

COMPLICATIONS PATHOLOGIC MECHANISMS ASSOCIATED SYMPTOMS
Microvascular
Retinopathy
Nonproliferative Microaneurysms, capillary dilation, soft and hard May have no visual changes
exudates, dot and flame hemorrhages, arteriove-
nous shunts
Proliferative Formation of new blood vessels, vitreal hemorrhage, Loss of visual acuity
scarring, retinal detachment
Maculopathy Macular edema Loss of central vision
Hyperglycemic lens edema Shunting of glucose to polyol pathway: hyperosmolar Blurring of vision
fluid in lens
Cataract formation Chronic hyperglycemia Decreasing visual acuity
Nephropathy Glomerular basement membrane thickening, mesan- Microalbuminuria and hypertension slowly progressing to end-stage
gial expansion, glomerulosclerosis, focal tubular kidney failure
atrophy; hyperperfusion and hyperfiltration
Neuropathy Oxidative stress, poor perfusion and ischemia, loss of Nerve dysfunction and degeneration
nerve growth factor
Peripheral neuropathy Same as above Distal symmetric sensorimotor polyneuropathy with glove and stock-
ing loss of sensation (pain, vibration, temperature, proprioception);
loss of motor nerve function with clawed toes and small muscle
wasting in hands and flexor muscles; Charcot joints (loss of sensa-
tion results in joint and ligament degeneration, particularly of foot)
Acute painful neuropathy with burning pain in legs and feet
Autonomic neuropathy Same as above Heart rate variability and postural hypotension
Gastroparesis (delayed gastric emptying) and diarrhea
Loss of bladder tone, urinary retention, and risk for bladder infection
Erectile dysfunction and impotence in men
Skin and foot lesions Loss of sensation, poor perfusion, suppressed im- High risk for pressure ulcers and delayed wound healing; abscess
munity, and increased risk of infection formation; development of necrosis and gangrene, particularly of
toes and foot; infection and osteomyelitis

Macrovascular
Cardiovascular Endothelial dysfunction, hyperlipidemia, accelerated Hypertension, coronary artery disease, cardiomyopathy, and heart
atherosclerosis, coagulopathies failure
Cerebrovascular Same as above Increased risk for ischemic and thrombotic stroke
Peripheral vascular Same as above Claudication, nonhealing ulcers, gangrene
Infection Impaired immunity, decreased perfusion, recurrent Wound infections, urinary tract infections, increased risk for sepsis
trauma, delayed wound healing, urinary retention

known as glucose toxicity). Strict control of blood glucose level reduces of sorbitol (a six-carbon sugar alcohol, or polyol) through the action
some complications, particularly non-fatal myocardial infarction, but of the enzyme aldose reductase. The accumulated sorbitol increases
increases 5-year mortality. Strict control is not recommended for intracellular osmotic pressure and attracts water in tissue; for exam-
high-risk individuals with type 2 DM.76 Several complex metabolic ple, sorbitol buildup in the lens of the eye causes swelling and visual
pathways have been associated with persistent hyperglycemia and the changes and predisposition to cataracts. In nerves sorbitol interferes
chronic complications of diabetes mellitus. They include shunting of with ion pumps, damages Schwann cells, and disrupts nerve conduc-
glucose into the polyol pathway, activation of protein kinase C, pro- tion. RBCs become swollen and stiff, which interferes with perfusion.
duction of advanced glycation end products, increased activation of Activation of the polyol pathway also reduces the level of glutathione,
the hexosamine pathway, and overproduction of reactive oxygen spe- an important antioxidant, and consequently there is oxidative injury
cies (oxidative stress). in cells and tissues. Aldose reductase inhibitors are being evaluated for
treatment of these complications.77
Metabolic Mechanisms of Chronic Complications Hyperglycemia and protein kinase C. Protein kinase C (PKC)
Hyperglycemia and the polyol pathway. Tissues that do not require is a family of intracellular signaling proteins that can become inap-
insulin for glucose transport, such as kidney, red blood cells (RBCs), propriately activated in different tissues by hyperglycemia.78 Various
blood vessels, eye lens, and nerves, cannot down-regulate the cellular consequences have been observed, including insulin resistance and
uptake of glucose; consequently, intracellular glucose is shunted into an production of extracellular matrix and proinflammatory cytokines;
alternate metabolic pathway, known as the polyol pathway. Overacti- vascular endothelial proliferation and enhanced contractility and
vation of the polyol pathway results in two processes that may contrib- increased permeability. These effects contribute to the microvascular
ute to the complications of diabetes. One is the excessive accumulation complications of diabetes.
 CHAPTER 18  Alterations of Hormonal Regulation 467

Hyperglycemia and nonenzymatic glycation. Nonenzymatic gly- or hemorrhage into the vitreous humor. Macular edema is the lead-
cation is a normal process that involves the reversible attachment of ing cause of decreased vision among persons with diabetes. Blurring of
glucose to proteins, lipids, and nucleic acids without the action of vision also can be a consequence of hyperglycemia and sorbitol accu-
enzymes. With recurrent or persistent hyperglycemia, glucose becomes mulation in the lens. Dehydration of the lens, aqueous humor, and
irreversibly bound to proteins in blood vessel walls, interstitial tissue, vitreous humor also reduces visual acuity.
and cells, forming advanced glycation end products (AGEs). When Diabetic nephropathy. Diabetes is the most common cause of end-
AGEs attach to their receptor (RAGE) or act independently they have a stage kidney disease.83 Hyperglycemia, AGEs, activation of the polyol
number of properties that may cause tissue injury or pathologic condi- pathway, protein kinase C all contribute to kidney tissue injury; yet
tions associated with the chronic complications of diabetes.79,79a These the exact process responsible for destruction of kidneys in diabetes is
include the following: unknown. The glomeruli are injured by protein denaturation from
1. Cross-linking and trapping of proteins, including albumin, low- high glucose levels, by hyperglycemia with high renal blood flow
density lipoprotein (LDL), immunoglobulin, and complement, (hyperfiltration), and by intraglomerular hypertension exacerbated
with thickening of the basement membrane or increased perme- by systemic hypertension. Renal glomerular changes occur early in
ability in small blood vessels and nerves diabetes mellitus, occasionally preceding the overt manifestation of
2. Binding to cell receptors, such as macrophages, and inducing release the disease. Progressive changes include glomerular enlargement and
of cytokines and growth factors that stimulate cellular proliferation glomerular basement membrane thickening with proliferation of
in the glomeruli and smooth muscle of blood vessels mesangial cells and mesangial matrix. This results in diffuse and nodu-
3. Induction of lipid oxidation, oxidative stress, and inflammation lar glomerulosclerosis and progressively decreased glomerular blood
4. Inactivation of nitric oxide with loss of vasodilation flow and glomerular filtration. Alterations in glomerular membrane
5. Procoagulant changes on endothelial cells and promotion of plate- permeability occur with loss of negative charge and albuminuria. Ulti-
let adhesion mately, there also is tubular and interstitial fibrosis contributing to loss
Pharmacologic agents that inhibit AGE formation or block their of function.84
receptor (RAGE) are being evaluated.80 Microalbuminuria is the first manifestation of kidney dysfunction.
Hyperglycemia and the hexosamine pathway. Chronic hyperglyce- Continuous proteinuria generally heralds a life expectancy of less than
mia causes shunting of excess intracellular glucose into the hexosamine 10 years. Before proteinuria, no clinical signs or symptoms of progres-
pathway and leads to O-linked glycosylation (attachment of groups of sive glomerulosclerosis are likely to be evident. Later, hypoproteinemia,
oligosaccharides directly to proteins) of several enzymes and proteins reduction in plasma oncotic pressure, fluid overload, anasarca (gener-
with alteration in signal transduction pathways and oxidative stress. alized body edema), and hypertension may occur. As renal function
These reactions are associated with insulin resistance and cardiovascu- continues to deteriorate, individuals with type 1 diabetes may expe-
lar complications of diabetes mellitus.81 rience hypoglycemia (because of loss of renal insulin metabolism),
which necessitates a decrease in insulin therapy. As the glomerular
Microvascular Disease filtration rate drops below 10 ml/min, uremic signs, such as nausea,
Diabetic microvascular complications (disease in capillaries) are a lead- lethargy, acidosis, anemia, and uncontrolled hypertension, occur (see
ing cause of blindness, end-stage kidney failure, and various neuropa- Chapter 29 for a discussion of renal failure). Death from kidney failure
thies. Thickening of the capillary basement membrane, endothelial is much more common in individuals with type 1 diabetes mellitus
hyperplasia, thrombosis, and pericyte degeneration are characteristic than in those with type 2 diabetes because the appearance of protein-
of diabetic microangiopathy. The frequency and severity of lesions uria in these individuals is strongly correlated with death from cardio-
appear to be proportional to the duration of the disease (more or less vascular disease.85 Control of hypertension and hyperglycemia delays
than 10 years) and the status of glycemic control. Hypoxia and isch- the onset of end-stage kidney disease.
emia accompany microangiopathy, especially in the eye, kidney, and Diabetic neuropathies. Diabetic neuropathy is the most com-
nerves. Many individuals with type 2 diabetes will present with micro- mon cause of neuropathy in the Western world and is the most com-
vascular complications because of the long duration of asymptomatic mon complication of diabetes. The underlying pathologic mechanism
hyperglycemia that generally precedes diagnosis. This underscores the includes both metabolic and vascular factors related to chronic hyper-
need to screen for diabetes. glycemia with ischemia and demyelination contributing to neural
Diabetic retinopathy. Diabetic retinopathy is a leading cause changes. Oxidative stress from advanced glycosylation end products
of blindness worldwide and in adults less than 60 years of age in the and increased formation of polyols contribute to nerve degeneration
United States.82 In comparison to type 1 diabetes, retinopathy seems to and delayed conduction.86 Both somatic and peripheral nerve cells
develop more rapidly in individuals with type 2 diabetes because of the show diffuse or focal damage, resulting in polyneuropathy. Sensory
likelihood of long-standing hyperglycemia before diagnosis. Most indi- deficits (loss of pain, temperature, and vibration sensation) are more
viduals with diabetes will eventually develop retinopathy and they are common than motor involvement and often involve the extremities
also more likely to develop cataracts and glaucoma (see Chapter 13). first in a “stocking and glove” pattern.
Diabetic retinopathy results from relative hypoxemia, damage to Some neuropathies are progressive, but many—such as painful
retinal blood vessels, and RBC aggregation. The three stages of reti- peripheral neuropathy, mononeuropathy (wristdrop, footdrop), dia-
nopathy that lead to loss of vision are nonproliferative (stage I), char- betic amyotrophy, diabetic neuropathic cachexia, and visceral mani-
acterized by an increase in retinal capillary permeability, vein dilation, festations associated with autonomic neuropathy (e.g., delayed gastric
microaneurysm formation, and superficial (flame-shaped) and deep emptying, diabetic diarrhea, altered bladder function, impotence,
(blot) hemorrhages; preproliferative (stage II), a progression of retinal orthostatic hypotension, and heart rate variability)—may spontane-
ischemia with areas of poor perfusion that culminate in infarcts; and ously appear to improve. Neuropathy may occur during periods of
proliferative (stage III), the result of neovascularization (angiogenesis) “good” glucose control and may be the initial clinical manifestation of
and fibrous tissue formation within the retina or optic disc. Traction diabetes. Chronic hyperglycemia also can cause cognitive dysfunction,
of the new vessels on the vitreous humor may cause retinal detachment perhaps by promoting microvascular disease.87
468 CHAPTER 18  Alterations of Hormonal Regulation

Macrovascular Disease
Macrovascular disease (lesions in large- and medium-sized arteries) Hyperglycemia
increases morbidity and mortality and increases risk for accelerated
atherosclerosis and coronary artery disease, stroke, and peripheral vas- Rage, Insulin
cular disease, particularly among individuals with type 2 diabetes mel- PKC activation resistance
litus. Unlike microangiopathy, atherosclerotic disease is unrelated to
the severity of diabetes and is often present in those with insulin resis-
tance and impaired glucose tolerance.88 (Atherosclerosis is discussed Inflammatory Endothelial
LDL
in Chapter 23.) Children with poorly controlled type 2 diabetes have cytokines dysfunction
high risk for macrovascular complications within one to two decades.89
Advanced glycosylated end products attach to proteins in the walls of Oxidative
Reduced NO
blood vessels, promoting oxidative stress and endothelial and vascu- production stress
lar smooth muscle dysfunction (Figure 18-14). The process tends to (vasoconstriction)
be more severe and accelerated in the presence of other risk factors,
including hyperlipidemia, hypertension, and smoking.
Expression of
Coronary artery disease. Cardiovascular disease is the ultimate Platelet adhesion
cause of death in up to 75% of people with diabetes. Coronary artery aggregation/ molecules
disease (CAD) is the most common cause of morbidity and mortality activation,
hypercoagulation
in individuals with diabetes mellitus. Mechanisms of disease include
hyperglycemia and insulin resistance, high levels of low-density lipo- Oxidized LDL
proteins (LDLs) and triglycerides, low levels of high-density lipopro-
teins (HDLs), platelet abnormalities, and endothelial cell dysfunction.90 Adhesion and
Mortality is high for both men and women. In general, the prevalence subendothelial migration
of CAD increases with the duration but not the severity of diabetes. of macrophages
The incidence of congestive heart failure is higher in individuals
with diabetes, even without myocardial infarction. This may be related
to the presence of increased amounts of collagen in the ventricular wall, Smooth muscle Formation of
which reduces the mechanical compliance of the heart during filling. cell migration macrophage
Increased platelet adhesion and decreased fibrinolysis promote throm- and proliferation foam cells
bus formation in persons with diabetes.91 (Heart disease is described
in Chapter 23.) Guidelines have been developed to reduce the risk and
improve treatment of cardiovascular and coronary artery disease in Fibrous
individuals with diabetes.69,92 plaque
Stroke. Stroke is twice as common in those with diabetes (particu-
larly type 2 diabetes) as in the nondiabetic population.93 The survival Complicated
atherosclerotic
rate for individuals with diabetes after a massive stroke is typically lesion
shorter than that for nondiabetic individuals. Hypertension, hyper-
Extracellular
glycemia, hyperlipidemia, and thrombosis are definite risk factors (see matrix production
Chapter 23).
Peripheral vascular disease. The increased incidence of peripheral FIGURE 18-14  Diabetes Mellitus and Atherosclerosis. Diabetes
vascular disease (PVD), with claudication, ulcers, gangrene, and ampu- with its associated hyperglycemia, relative hypoinsulinemia, oxida-
tation, in the individual with diabetes has been well documented.94 Age, tive stress, and proinflammatory state contributes to atherogenesis
duration of diabetes, genetics, and additional risk factors influence the by causing arterial endothelial dysfunction (impaired vasodilation
development and management of PVD. Peripheral vascular disease in and adhesion of inflammatory cells), dyslipidemia, and smooth
those with diabetes is more diffuse and often involves arteries below muscle proliferation. LDL, Low-density lipoprotein; NO, nitric oxide;
PKC, protein kinase C; Rage, receptor advanced glycation end prod-
the knee. Occlusions of the small arteries and arterioles cause most of
uct. (Data from D’Souza A et al: Pathogenesis and pathophysiology
the gangrenous changes of the lower extremities and occur in patchy of accelerated atherosclerosis in the diabetic heart, Mol Cell Bio-
areas of the feet and toes. The lesions begin as ulcers and progress to chem 331[1–2]:89–116, 2009; Stratmann B, Tschoepe D: Athero-
osteomyelitis or gangrene requiring amputation. Loss of sensation and genesis and atherothrombosis—focus on diabetes mellitus, Best
increased risk for infection advance the disease. Significant morbidity Pract Res Clin Endocrinol Metab 23[3]:291–303, 2009.)
and mortality are associated with major amputation.

Infection 3. Pathogens. Some pathogens proliferate rapidly because of increased

The individual with diabetes is at an increased risk for infection glucose in body fluids, which provides an excellent source of
throughout the body for several reasons95: energy.
1. The senses. Impaired vision caused by retinal changes and impaired 4. Blood supply. Decreased blood supply results from vascular changes
touch caused by neuropathy lead to loss of protection with injury and and reduces the supply of white blood cells to the affected area.
repeated trauma, open wounds, and soft tissue or osseous infection. 5. Suppressed immune response. Chronic hyperglycemia impairs both
2. Hypoxia. Once skin integrity is compromised, tissues’ susceptibility to the innate and adaptive immune responses, including abnormal
infection increases as a result of hypoxia. In addition, the glycosylated chemotaxis and vasoactive responses, and defective phagocytosis.
hemoglobin in the RBCs impedes the release of oxygen to tissues. Clinical signs of infection may be absent.
 CHAPTER 18  Alterations of Hormonal Regulation 469

4 QUICK CHECK 18-4

A Cushing-like syndrome may develop as a result of the exogenous
administration of glucocorticoids.96
1. What are the major differences between type 1 and type 2 diabetes in
­relation to insulin?
PATHOPHYSIOLOGY  Whatever the cause, two observations consis-
2. What are three metabolic alterations related to hyperglycemia that contrib-
tently apply to individuals with hypercortisolism: (1) the normal diur-
ute to diabetic complications?
nal or circadian secretion patterns of ACTH and cortisol are lost, and
3. What is the single most important factor in the management of diabetes
(2) there is no increase in ACTH and cortisol secretion in response to a
mellitus?
stressor.97 With ACTH-dependent hypercortisolism, the excess ACTH
stimulates excess production of cortisol and there is loss of feedback
ALTERATIONS OF ADRENAL FUNCTION control of ACTH secretion. In individuals with ACTH-dependent
hypercortisolism, secretion of both cortisol and adrenal androgens
Disorders of the Adrenal Cortex is increased, and cortisol-releasing hormone is inhibited. ACTH-
Disorders of the adrenal cortex are related either to hyperfunction or independent secreting tumors of the adrenal cortex, however, gener-
to hypofunction. Hyperfunction that causes hypercortisolism leads ally secrete only cortisol. When the secretion of cortisol by the tumor
to Cushing disease or Cushing syndrome; that which causes increased exceeds normal cortisol levels, symptoms of hypercortisolism develop.
secretion of adrenal androgens and estrogens leads to virilization or
feminization; and that which causes increased levels of aldosterone CLINICAL MANIFESTATIONS  Weight gain is the most common fea-
leads to hyperaldosteronism, which may be primary or secondary. ture and results from the accumulation of adipose tissue in the trunk,
Hypofunction of the adrenal cortex leads to Addison disease. facial, and cervical areas. These characteristic patterns of fat deposition
have been respectively described as “truncal obesity,” “moon face,”
Hypercortical Function (Cushing Syndrome, Cushing Disease) and “buffalo hump” (Figures 18-15 and 18-16).
Cushing syndrome refers to the clinical manifestations resulting from
chronic exposure to excess cortisol (hypercortisolism). Cushing dis-
ease refers to excess endogenous secretion of ACTH. ACTH-dependent
hypercortisolism results from overproduction of pituitary ACTH by
a pituitary adenoma (which can occur at any age) or by an ectopic
secreting nonpituitary tumor, such as a small cell carcinoma of the
lung (more common in older adults). ACTH-independent hypercorti-
solim is caused by cortisol secretion from a rare benign or malignant
tumor of one or both adrenal glands (more common in children).

Thinning of
scalp hair Acne
Increased
Facial flush
body and
facial hair
Moon face
Supraclavicular
fat pad
Purple striae A
Hyperpigmentation

Trunk obesity
Pendulous
abdomen

Thin
extremities
Easy bruising

B
FIGURE 18-16  Cushing Syndrome. A, Patient before onset of
Cushing syndrome. B, Patient 4 months later. Moon facies is clearly
demonstrated. (From Zitelli BJ, Davis HW: Atlas of pediatric physi-
FIGURE 18-15  Symptoms of Cushing Disease. cal diagnosis, ed 3, London, 1997, Gower.)
470 CHAPTER 18  Alterations of Hormonal Regulation

Glucose intolerance occurs because of cortisol-induced insulin deficiency, which involves both mineralocorticoid and cortisol synthe-
resistance and increased gluconeogenesis and glycogen storage by the sis. Affected female infants are virilized, and infants of both genders
liver. Overt diabetes mellitus develops in approximately 20% of indi- exhibit salt wasting. Disease management requires life-long treatment
viduals with hypercortisolism. Polyuria is a manifestation of hypergly- with glucocorticoids and mineralocorticoids.98a
cemia and resultant glycosuria.
Protein wasting is caused by the catabolic effects of cortisol on Hyperaldosteronism
peripheral tissues. Muscle wasting leads to muscle weakness. In bone, Hyperaldosteronism is characterized by excessive aldosterone secre-
loss of the protein matrix leads to osteoporosis, with pathologic frac- tion by the adrenal glands. Both primary and secondary forms of
tures, vertebral compression fractures, bone and back pain, kyphosis, hyperaldosteronism can occur in individuals.
and reduced height. Cortisol interferes with the action of GH in long Primary hyperaldosteronism (Conn syndrome, primary aldo-
bones; thus children who present with short stature may be experienc- steronism) is caused by excessive secretion of aldosterone from an
ing growth retardation related to Cushing syndrome rather than GH abnormality of the adrenal cortex, usually a single benign aldosterone-
deficiency. Bone disease may contribute to hypercalciuria and resulting producing adrenal adenoma. Bilateral adrenal nodular hyperplasia and
renal stones. adrenal carcinomas account for the remainder of cases. The incidence
In the skin, loss of collagen leads to thin, weakened integumen- is estimated to be about 10% of all hypertensive individuals; however,
tary tissues through which capillaries are more visible and are easily approximately 33% of people with resistant hypertension will have evi-
stretched by adipose deposits. Together, these changes account for the dence of primary hyperaldosteronism.98b
characteristic purple striae seen in the trunk area. Loss of collagenous Secondary hyperaldosteronism results from an extra-adrenal
support around small vessels makes them susceptible to rupture, lead- stimulus of aldosterone secretion, most often angiotensin II through a
ing to easy bruising, even with minor trauma. Thin, atrophied skin is renin-dependent mechanism. This occurs in various situations, includ-
also easily damaged, leading to skin breaks and ulcerations. Bronze or ing decreased circulating blood volume (e.g., in dehydration, shock,
brownish hyperpigmentation of the skin, mucous membranes, and or hypoalbuminemia) and decreased delivery of blood to the kidneys
hair occurs when there are very high levels of ACTH. (e.g., renal artery stenosis, heart failure, or hepatic cirrhosis). Here, the
With elevated cortisol levels, vascular sensitivity to catecholamines activation of the renin-angiotensin system and subsequent aldosterone
increases significantly, leading to vasoconstriction and hypertension. secretion may be seen as compensatory, although in some instances
Mineralocorticoid effects promote sodium and water retention and (e.g., congestive heart failure) the increased circulating volume further
hypokalemia with transient weight gain. Suppression of the immune sys- worsens the condition. Other causes of secondary hyperaldosteronism
tem and increased susceptibility to infections also occur. Approximately are Bartter syndrome, in which the underlying disorder is a renal tubu-
50% of individuals with Cushing syndrome experience alterations in lar defect leading to hypokalemia, and renin-secreting tumors of the
their mental status that range from irritability and depression to severe kidney.
psychiatric disturbances, such as schizophrenia.97 Females with ACTH-
dependent hypercortisolism may experience symptoms of increased PATHOPHYSIOLOGY  In primary hyperaldosteronism, pathophysi-
adrenal androgen levels, increased hair growth (especially facial hair), ologic alterations are caused by excessive aldosterone secretion and
acne, and oligomenorrhea. Rarely, unless an adrenal carcinoma is the fluid and electrolyte imbalances that ensue. Hyperaldosteronism
involved, do androgen levels become high enough to cause changes of promotes (1) increased renal sodium and water reabsorption with cor-
the voice, recession of the hairline, and hypertrophy of the clitoris. responding hypervolemia (see Chapter 4) and hypertension and (2)
renal excretion of potassium. The extracellular fluid volume overload,
EVALUATION AND TREATMENT  Routine laboratory examinations hypertension, and suppression of renin secretion are characteristic of
may reveal hyperglycemia, glycosuria, hypokalemia, and metabolic primary disorders. Edema usually does not occur with primary aldo-
alkalosis. A variety of laboratory tests are used to confirm the diagnosis steronism because hypervolemia-induced atrial natriuretic factor
of hypercortisolism and to determine the underlying disorder. These release results in loss of sodium and water.99
include urinary free cortisol level higher than 50 mcg in 24 hours, In secondary hyperaldosteronism, the effect of increased extracel-
abnormal dexamethasone suppressibility of either urinary or serum lular volume on renin secretion may vary. If renin secretion is being
cortisol, and simultaneous measurement of ACTH and cortisol levels. stimulated by variables other than pressure-initiated cellular changes
Late evening salivary cortisol levels are used as a screening test and to at the juxtaglomerular apparatus (see Chapter 28), increased circulat-
document alterations in the diurnal variation of cortisol level. Tumors ing blood volume may not decrease renin secretion through feedback
are diagnosed using imaging procedures.98 mechanisms. This process occurs, for instance, in states of increased
Treatment is specific for the cause of hypercorticoadrenalism and estrogen levels.
includes medication, radiation, and surgery. Differentiation between Potassium secretion is promoted by aldosterone; therefore with
pituitary ectopic and adrenal causes is essential for effective treatment. excessive aldosterone, hypokalemia occurs (see Chapter 4). Hypoka-
Without treatment, approximately 50% of individuals with Cush- lemic alkalosis, changes in myocardial conduction, and skeletal muscle
ing syndrome die within 5 years of onset as a result of overwhelming alterations may be seen, particularly with severe potassium depletion.
infection, suicide, complications from generalized arteriosclerosis, and The renal tubules may become insensitive to ADH, thus promoting
hypertensive disease. excessive loss of free water. In this situation, hypernatremia also may
occur because water is not able to follow the sodium that is reabsorbed.
Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia results from the deficiency of an CLINICAL MANIFESTATIONS  Hypertension and hypokalemia
enzyme that is critical in cortisol biosynthesis. Because cortisol produc- are the hallmarks of primary hyperaldosteronism. With sustained
tion is low, the concentration of ACTH increases and causes adrenal hypertension, the chronic effects of elevated arterial pressure become
hyperplasia, which results in the overproduction of either mineralo- evident, for example, left ventricular dilation and hypertrophy and
corticoids or androgens. The most common form is a 21-hydroxylase progressive arteriosclerosis.100 Aldosterone-stimulated potassium loss
 CHAPTER 18  Alterations of Hormonal Regulation 471

can be substantial, resulting in typical manifestations of hypokalemia.

Hypokalemic alkalosis may develop (see Chapter 4).

EVALUATION AND TREATMENT  Various clinical and labora-

tory measurements are useful in assessing hyperaldosteronism. Tests
include the following:
1. Blood pressure is elevated.
2. Serum and urinary electrolyte levels: serum sodium level is nor-
mal or elevated and serum potassium level is depressed, but urinary
potassium level is elevated.
3. Serum and urinary levels of aldosterone increase.
4. Aldosterone suppression testing: fludrocortisone acetate (Florinef)
is used.
5. Plasma renin activity is suppressed.
6. Imaging techniques may be used to localize an aldosterone-­
secreting adenoma.
Treatment includes management of hypertension and hypokalemia,
as well as correction of any underlying causal abnormalities. If an aldo-
sterone-secreting adenoma is present, it must be surgically removed.101

Hypersecretion of Adrenal Androgens and Estrogens

Hypersecretion of adrenal androgens and estrogens may be caused by
adrenal tumors, either adenomas or carcinomas, Cushing syndrome,
or defects in steroid synthesis. The clinical syndrome that results
depends on the hormone secreted, the gender of the individual, and
the age at which the hypersecretion is initiated. Hypersecretion of
estrogens causes feminization, the development of female secondary
sex characteristics. Hypersecretion of androgens causes virilization,
the development of male secondary sex characteristics (Figure 18-17).
The effects of an estrogen-secreting tumor are most evident in
males and result in gynecomastia (98% of cases), testicular atro- FIGURE 18-17  Virilization. Virilization of a young girl by an andro-
phy, and decreased libido. In female children, such tumors may lead gen-secreting tumor of the adrenal cortex. Masculine features
to early development of secondary sex characteristics. The changes include lack of breast development, increased muscle bulk, and hir-
caused by an androgen-secreting tumor are more easily observed in sutism (excessive hair). (From Thibodeau GA, Patton KT: Anatomy &
females and include excessive face and body hair growth (hirsutism), physiology, St Louis, 1987, Mosby.)
clitoral enlargement, deepening of the voice, amenorrhea, acne, and
breast atrophy. In children, virilizing tumors promote precocious
sexual development and bone aging. Treatment of androgen-secreting Idiopathic Addison disease (organ-specific autoimmune adrenal-
tumors usually involves surgical excision. itis) causes adrenal atrophy and hypofunction and is an organ-specific
autoimmune disease. It may occur in childhood (type 1) or adulthood
Adrenocortical Hypofunction (type 2). 21-Hydroxylase autoantibodies and autoreactive T cells specific
Hypocortisolism (low levels of cortisol secretion) develops because to adrenal cortical cells are present in 50% to 70% of individuals with
of either inadequate stimulation of the adrenal glands by ACTH or a idiopathic Addison disease, and this percentage increases in younger
primary inability of the adrenals to produce and secrete the adreno- persons and in those with other autoimmune diseases. This deficiency
cortical hormones. Sometimes there is partial dysfunction of the adre- allows the proliferation of immunocytes directed against specific anti-
nal cortex, so only synthesis of cortisol and aldosterone or the adrenal gens within the adrenocortical cells.102 The adrenal glands in idiopathic
androgens is affected. Hypofunction of the adrenal cortex may affect Addison disease are smaller than normal and may be misshapen.
glucocorticoid or mineralocorticoid secretion, or both. Idiopathic Addison disease is often associated with other autoim-
Addison disease. Primary adrenal insufficiency is termed Addi- mune diseases, especially Hashimoto thyroiditis, pernicious anemia,
son disease. It is relatively rare, occurring most often in adults ages and idiopathic hypoparathyroidism. In these cases, Addison disease
30 to 60 years, although it may appear at any time. Addison disease is may be inherited as an autosomal recessive trait. (Mechanisms of
caused by autoimmune mechanisms that destroy adrenal cortical cells inheritance are described in Chapter 2.)
and is more common in women. Chronic infections, such as tubercu-
losis, account for the majority of cases of primary adrenal insufficiency CLINICAL MANIFESTATIONS  The symptoms of Addison disease
in underdeveloped countries. are primarily a result of hypocortisolism and hypoaldosteronism.
With mild to moderate hypocortisolism, symptoms usually begin with
PATHOPHYSIOLOGY  Addison disease is characterized by inad- weakness and easy fatigability. Skin changes, including hyperpigmen-
equate corticosteroid and mineralocorticoid synthesis and elevated tation and vitiligo, may occur. As the condition progresses, anorexia,
levels of serum ACTH (loss of negative feedback). Before clinical mani- nausea, vomiting, and diarrhea may develop. Of greatest concern is the
festations of hypocortisolism are evident, more than 90% of total adre- development of hypotension that can progress to complete vascular
nocortical tissue must be destroyed. collapse and shock.
472 CHAPTER 18  Alterations of Hormonal Regulation

EVALUATION AND TREATMENT  Serum and urine levels of corti- with these tumors have no symptoms, apparently because the tumor
sol are depressed with primary hypocortisolism and ACTH levels are is nonfunctioning. Such tumors can, however, release catecholamines,
increased. Because of dehydration, blood urea nitrogen levels may especially in response to a stressor, such as surgery.
increase. Serum glucose level is low. Eosinophil and lymphocyte counts
often are elevated. Hyperkalemia is seen in Addison disease and may CLINICAL MANIFESTATIONS  The clinical manifestations of a pheo-
cause mild alkalosis (see Chapter 4). The ACTH stimulation test may chromocytoma and sympathetic paragangliomas are related to the chronic
be used to evaluate serum cortisol levels. effects of catecholamine secretion and include persistent hypertension,
The treatment of Addison disease involves lifetime glucocorticoid headache, pallor, diaphoresis, tachycardia, and palpitations. Hypertension
and possibly mineralocorticoid replacement therapy, together with results from increased peripheral vascular resistance and may be sustained
dietary modifications and correction of any underlying disorders.103 or paroxysmal. An acute episode of hypertension related to hypersecre-
With acute stressors, additional cortisol must be administered to tion of catecholamines may follow specific events, such as exercise, exces-
approximate the amount of cortisol that might be expected if normal sive ingestion of tyrosine-containing foods (aged cheese, red wine, beer,
adrenal function were present (approximately 100 to 300 mg/day). The yogurt), ingestion of caffeine-containing foods, external pressure on the
individual’s diet should include at least 150 mEq of sodium per day, tumor, and induction of anesthesia. Headaches appear because of sud-
and sodium intake should be increased if the individual experiences den changes in catecholamine levels in the blood, affecting cerebral blood
excessive sweating or diarrhea. flow. Hypermetabolism and sweating are related to chronic activation of
Secondary hypocortisolism. Secondary hypocortisolism com- sympathetic receptors in adipocytes, hepatocytes, and other tissues. Glu-
monly results from prolonged administration of exogenous gluco- cose intolerance may occur because of catecholamine-induced inhibition
corticoids; they suppress ACTH secretion and cause adrenal atrophy, of insulin release by the pancreas. These tumors tend to be extremely vas-
resulting in inadequate corticosteroidogenesis once the exogenous glu- cular and can rupture, causing massive and potentially fatal hemorrhage.
cocorticoids are withdrawn. Decreased ACTH secretion also can result
from pituitary infarction, pituitary tumors that compress ACTH- EVALUATION AND TREATMENT  A diagnosis of pheochromocy-
secreting cells, or hypophysectomy. In all instances of low ACTH lev- toma is made when increased catecholamine production is demon-
els, adrenal atrophy occurs and endogenous adrenal steroidogenesis is strated in the blood or urine. The site of the tumor is then determined
depressed. Clinical manifestations of secondary hypocortisolism are using abdominal imaging techniques. Because of the possibility of
similar to those of Addison disease, although hyperpigmentation usu- metastasis, whole-body scanning may be done.
ally does not occur. The renin-angiotensin system usually is normal, so Management of catecholamine excess is essential to prevent hyper-
aldosterone and potassium levels also tend to be normal. tensive emergencies and requires the use of α- and β-adrenergic block-
ers. The usual treatment of pheochromocytoma is laparoscopic surgical
Disorders of the Adrenal Medulla excision of the tumor, although open resection is still completed for
Tumor of the Adrenal Medulla large tumors or when metastasis is suspected. Medical therapy is con-
Adrenomedullary hyperfunction is caused by pheochromocytomas tinued to stabilize blood pressure before, during, or after surgery.104
(chromaffin cell tumors) or sympathetic paragangliomas of the adrenal Malignant pheochromocytoma is rarely curable and is usually man-
medulla that secrete catecholamines on a continual basis. They are rare, aged by a combination of surgical debulking of the tumor combined
and about 10% are malignant. Those that are malignant metastasize to with chemotherapy.105
the lungs, liver, bones, or para-aortic lymph nodes. These tumors are rare
and usually sporadic although up to 30% of them can be inherited.103a 4 QUICK CHECK 18-5
1. What are the symptoms of hyperaldosteronism?
PATHOPHYSIOLOGY  Pheochromocytomas and sympathetic para- 2. What major diseases are classified as hypocortisolism?
gangliomas cause excessive production of catecholamines because 3. What are pheochromocytomas?
of autonomous secretion of the tumor. Approximately 5% of people

DID YOU UNDERSTAND?

Mechanisms of Hormonal Alterations 3. In SIADH, high ADH levels interfere with renal free water clearance, lead-
1. Abnormalities in endocrine function may be caused by elevated or ing to hyponatremia and hypoosmolality, and are associated with brain
depressed hormone levels that result from (a) faulty feedback systems, (b) injury and with certain forms of cancer, apparently because of ectopic
dysfunction of the gland, (c) altered metabolism of hormones, or (d) produc- secretion of ADH by tumor cells.
tion of hormones from nonendocrine tissues. 4. Diabetes insipidus may be neurogenic (caused by insufficient amounts of
2. Target cells may fail to respond to hormones because of (a) cell surface recep- ADH) or nephrogenic (caused by an inadequate response to ADH). Its prin-
tor–associated disorders, (b) intracellular disorders, or (c) circulating inhibitors. cipal clinical features are polyuria and polydipsia.
5. Hypopituitarism can be primary (dysfunction of the pituitary) or secondary
Alterations of the Hypothalamic-Pituitary System (dysfunction of the hypothalamus). Primary hypopituitarism can result from
1. Dysfunction in the action of hypothalamic hormones is most commonly a pituitary tumor, trauma, infections, stroke, or surgical removal.
related to interruption of the connection between the hypothalamus and 6. Hypopituitarism can affect any or all of the pituitary hormones and symp-
pituitary—the pituitary stalk. toms may range from mild to life-threatening.
2. Disorders of the posterior pituitary include syndrome of inappropriate ADH 7. Hyperpituitarism is caused by pituitary adenomas. These are usually
secretion (SIADH) and diabetes insipidus. SIADH secretion is characterized benign, slow-growing tumors that arise from cells of the anterior pituitary.
by abnormally high ADH secretion; diabetes insipidus is characterized by
abnormally low ADH secretion.
 CHAPTER 18  Alterations of Hormonal Regulation 473

DID YOU UNDERSTAND?—cont’d

8. E xpansion of a pituitary adenoma causes both neurologic and secretory Alterations of Parathyroid Function
effects. Pressure from the expanding tumor causes hyposecretion of cells, 1. Hyperparathyroidism, which may be primary or secondary, is characterized
dysfunction of the optic chiasma (leading to visual disturbances), and dys- by greater than normal secretion of parathyroid hormone (PTH).
function of the hypothalamus and some cranial nerves. 2. Primary hyperparathyroidism is caused by an interruption of the normal
9. Hypersecretion of growth hormone (GH) in adults causes acromegaly, in mechanisms that regulate calcium and PTH levels. Manifestations include
which GH secretion becomes high and unpredictable. Pituitary adenoma is chronic hypercalcemia, increased bone resorption, and hypercalciuria.
the most common cause of acromegaly. 3. Secondary hyperparathyroidism is a compensatory response to hypocalce-
10. Prolonged, abnormally high levels of GH lead to proliferation of body and mia and often occurs with chronic renal failure and vitamin D deficiency.
connective tissue and slowly developing renal, thyroid, and reproductive 4. Hypoparathyroidism, defined by abnormally low PTH levels, is caused by
dysfunction. thyroid surgery, autoimmunity, or genetic mechanisms.
11. Prolactinomas result in galactorrhea, hirsutism, amenorrhea, hypogonad- 5. The lack of circulating PTH in hypoparathyroidism causes depressed serum
ism, and osteopenia. calcium levels, increased serum phosphate levels, decreased bone resorp-
tion, and hypocalciuria.
Alterations of Thyroid Function
1. Thyrotoxicosis is a general condition in which elevated thyroid hormone Dysfunction of the Endocrine Pancreas: Diabetes Mellitus
(TH) levels cause greater than normal physiologic responses. The condition 1. Diabetes mellitus is a group of disorders characterized by glucose intoler-
can be caused by a variety of specific diseases, each of which has its own ance, chronic hyperglycemia, and disturbances of carbohydrate, protein,
pathophysiology and course of treatment. and fat metabolism.
2. In general, hyperthyroidism has a range of endocrine, reproductive, gas- 2. A diagnosis of diabetes mellitus is based on elevated plasma glucose con-
trointestinal, integumentary, and ocular manifestations. These are caused centrations and measurement of glycosylated hemoglobin. Classic signs
by increased circulating levels of TH and by stimulation of the sympathetic and symptoms are often present as well.
division of the autonomic nervous system. 3. The two most common types of diabetes mellitus are type 1 and type 2.
3. Graves disease, the most common form of hyperthyroidism, is caused by an 4. Type 1 diabetes mellitus is characterized by loss of beta cells, presence of
autoimmune mechanism that overrides normal mechanisms for control of islet cell antibody, lack of insulin, and excess of glucagon, which causes
TH secretion and is characterized by thyrotoxicosis, ophthalmopathy, and improper metabolism of fat, protein, and carbohydrates.
circulating thyroid-stimulating immunoglobulins. 5. Type 1 diabetes mellitus seems to be caused by a gradual process of auto-
4. Toxic nodular goiter and toxic multinodular goiter occur when TH-regulating immune destruction of beta cells in genetically susceptible individuals.
mechanisms and abnormal hypertrophy of the thyroid gland cause hyper- 6. In type 1 diabetes mellitus, hyperglycemia causes polyuria and polydipsia
thyroidism. Toxic multinodular goiter is caused by independently function- resulting from osmotic diuresis.
ing follicular cell adenomas. 7. Ketoacidosis is caused by increased levels of circulating ketones without the
5. Thyrotoxic crisis is a severe form of hyperthyroidism that is often asso- inhibiting effects of insulin. Increased levels of circulating fatty acids and
ciated with physiologic or psychologic stress. Without treatment, death weight loss are both manifestations of type 1 uncontrolled diabetes mellitus.
occurs quickly. 8. Type 2 diabetes mellitus is caused by genetic susceptibility that is triggered by
6. Primary hypothyroidism is caused by deficient production of TH by the environmental factors. The most compelling environmental risk factor is obesity.
thyroid gland. Secondary hypothyroidism is caused by hypothalamic or 9. In the obese, many factors, such as altered adipokines, increased fatty
pituitary dysfunction. Symptoms depend on the degree of TH deficiency. acids, inflammation, and hyperinsulinemia, contribute to the development
Common manifestations include decreased energy metabolism, decreased of insulin resistance.
heat production, and myxedema. 10. Some insulin production continues in type 2 diabetes mellitus, but the
7. Primary hypothyroidism is characterized by an increased level of TSH, weight and number of beta cells decrease. There are dysfunctional levels
which stimulates goiter formation. of both insulin and glucagon.
8. Autoimmune thyroiditis (Hashimoto disease) is associated with humoral 11. Other specific types of diabetes mellitus include monogenetic forms of dia-
(antibodies) and cellular autoimmune destruction of the thyroid and gradual betes called maturity-onset diabetes mellitus (MODY).
loss of thyroid function. Autoimmune thyroiditis occurs in those individu- 12. Gestational diabetes is glucose intolerance during pregnancy.
als with genetic susceptibility to an autoimmune mechanism that causes 13. Acute complications of diabetes mellitus include hypoglycemia, diabetic
thyroid damage and eventual hypothyroidism. ketoacidosis, and hyperosmolar hyperglycemic nonketotic syndrome.
9. Subacute thyroiditis is a self-limiting nonbacterial inflammation of the 14. Hypoglycemia in diabetes is a complication related to insulin treatment.
thyroid gland. The inflammatory process damages follicular cells, causing 15. Diabetic ketoacidosis develops when there is an absolute or relative defi-
leakage of T3 and T4. Hyperthyroidism then is followed by transient hypo- ciency of insulin and an increase in the insulin counterregulatory hormones
thyroidism, which is corrected by cellular repair and a return to normal of catecholamines—cortisol, glucagon, and growth hormone.
levels in the thyroid. 16. Hyperosmolar hyperglycemic nonketotic syndrome is pathophysiologically
10. Myxedema is a sign of hypothyroidism caused by alterations in connec- similar to diabetic ketoacidosis, although levels of free fatty acids are
tive tissue with water-binding proteins that lead to edema and thickened lower in hyperosmolar nonacidotic diabetes and lack of ketosis indicates
mucous membranes. that some level of insulin is present.
11. Myxedema coma is a severe form of hypothyroidism that may be life- 17. The Somogyi effect is a combination of hypoglycemia with rebound
threatening without emergency medical treatment. hyperglycemia.
12. Congenital hypothyroidism is the absence of thyroid tissue during fetal 18. The dawn phenomenon is an early morning rise in glucose levels caused by
development or defects in hormone synthesis. nocturnal elevations in growth hormone.
13. Thyroid carcinoma is a relatively rare cancer. The most consistent causal 19. Chronic complications of diabetes mellitus include microvascular disease
risk factor associated with thyroid carcinoma is exposure to ionizing radia- (e.g., neuropathy, retinopathy, nephropathy), macrovascular disease (e.g.,
tion, especially in childhood. coronary artery disease, stroke, peripheral vascular disease), and infection.

Continued
474 CHAPTER 18  Alterations of Hormonal Regulation

DID YOU UNDERSTAND?—cont’d

20. M icrovascular disease is characterized by thickening of the capillary base- 5. H yperaldosteronism promotes increased sodium reabsorption, correspond-
ment membrane and eventual decreased tissue perfusion affecting the ing hypervolemia, increased extracellular volume (which is variable),
microcirculation. hypokalemia related to renal reabsorption of sodium, and excretion of
21. Macrovascular disease associated with diabetes mellitus is most often potassium.
related to the proliferation of atherosclerotic plaques in the arterial wall. 6. Hypersecretion of adrenal androgens and estrogens can be a result of adre-
22. The incidence of coronary heart disease, peripheral vascular disease, and nal tumors, either adenomas or carcinomas. Hypersecretion of estrogens
stroke is greater in those with diabetes than in nondiabetic individuals. causes feminization, the development of female secondary sexual charac-
23. Individuals with diabetes are at risk for a variety of infections. Infection may teristics. Hypersecretion of androgens causes virilization, the development
be related to sensory impairment and resulting injury, hypoxia, increased pro- of male secondary sexual characteristics.
liferation of pathogens in elevated concentrations of glucose, decreased blood 7. Hypofunction of the adrenal cortex can affect glucocorticoid or mineralo-
supply associated with vascular damage, and impaired white cell function. corticoid secretion, or both. Hypofunction can be caused by a deficiency of
ACTH or by a primary deficiency in the gland itself.
Alterations of Adrenal Function 8. Hypocortisolism, or low levels of cortisol, is caused by inadequate adrenal
1. Disorders of the adrenal cortex are related to hyperfunction or hypofunc- stimulation by ACTH or by primary cortisol hyposecretion. Primary adrenal
tion. No known disorders are associated with hypofunction of the adrenal insufficiency is termed Addison disease.
medulla, but medullary hyperfunction causes clinically defined syndromes. 9. Addison disease is characterized by elevated ACTH levels with inadequate
2. Cortical hyperfunction, or hypercortisolism, causes Cushing syndrome, corticosteroid synthesis and output.
which does not involve the pituitary gland, and Cushing disease, which is 10. Manifestations of Addison disease are related to hypocortisolism and
hypercortisolism with pituitary involvement. hypoaldosteronism. Symptoms include weakness, fatigability, hypogly-
3. Hypercortisolism is usually caused by Cushing disease (pituitary-depen- cemia and related metabolic problems, lowered response to stressors,
dent) and very rarely can be caused by ectopic production of ACTH. Com- hyperpigmentation, vitiligo, and manifestations of hypovolemia and
plications include obesity, diabetes, protein wasting, immune suppression, hyperkalemia.
and mental status changes. 11. Hyperfunction of the adrenal medulla is usually caused by a pheochromo-
4. Excessive aldosterone secretion causes hyperaldosteronism, which may be cytoma, a catecholamine-producing tumor. Symptoms of catecholamine
primary or secondary. Primary hyperaldosteronism is caused by an abnor- excess are related to their sympathetic nervous system effects and include
mality of the adrenal cortex. Secondary hyperaldosteronism involves an hypertension, palpitations, tachycardia, glucose intolerance, excessive
extra-adrenal stimulus, often angiotensin. sweating, and constipation.

 KEY TERMS
• A cromegaly  451 •  lycosylated hemoglobin  459
G • P ostpartum thyroiditis  457
• Addison disease (primary adrenal • Graves disease  454 • Pretibial myxedema (Graves
insufficiency)  471 • Hyperaldosteronism  470 dermopathy)  455
• Advanced glycation end product • Hypercortisolism  469 • Primary hyperaldosteronism (Conn
(AGE)  467 • Hyperosmolar hyperglycemic nonketotic ­syndrome, primary aldosteronism)  470
• Aldose reductase  466 syndrome (HHNKS)  465 • Primary hyperparathyroidism  457
• Amylin  461 • Hyperparathyroidism  457 • Primary hyperthyroidism  453
• Autoimmune thyroiditis (Hashimoto dis- • Hypocortisolism  471 • Primary hypothyroidism  456
ease, chronic lymphocyte thyroiditis)  456 • Hypoglycemia  465 • Primary thyroid disorder  453
• Beta-cell dysfunction  463 • Hypoparathyroidism  458 • Prolactinoma  453
• Central (secondary) hyperthyroidism  454 • Hypopituitarism  450 • Protein kinase C (PKC)  466
• Central (secondary) hypothyroidism  456 • Hypothyroidism  456 • Secondary hyperaldosteronism  470
• Central (secondary) thyroid disorders  453 • Idiopathic Addison disease (organ-specific • Secondary hyperparathyroidism  457
• Congenital adrenal hyperplasia  470 autoimmune adrenalitis)  471 • Secondary hypocortisolism  472
• Cushing disease  469 • Incretin  463 • Somogyi effect  465
• Cushing-like syndrome  469 • Insulin resistance  462 • Subacute thyroiditis  457
• Cushing syndrome  469 • Macular edema  467 • Subclinical thyroid disease  453
• Dawn phenomenon  465 • Maturity-onset diabetes of youth • Syndrome of inappropriate ADH secretion
• Diabetes insipidus (DI)  449 (MODY)  463 (SIADH)  449
• Diabetes mellitus  458 • Myxedema  456 • Thyrotoxic crisis (thyroid storm)  455
• Diabetic ketoacidosis (DKA)  465 • Myxedema coma  456 • Thyrotoxicosis  453
• Diabetic neuropathy  467 • Nonenzymatic glycation  467 • Toxic adenoma  455
• Diabetic retinopathy  467 • Painless thyroiditis  457 • Toxic multinodular goiter  455
• Feminization  471 • Panhypopituitarism  450 • Type 1 diabetes mellitus  459
• Gestational diabetes mellitus (GDM)  464 • Pheochromocytoma (chromaffin cell • Type 2 diabetes mellitus (non–insulin-
• Ghrelin  463 tumor)  472 dependent diabetes mellitus)  462
• Giantism  452 • Pituitary adenoma  451 • Vasopressin dysregulation  449
• Glucagon  461 • Polyol pathway  466 • Virilization  471
 CHAPTER 18  Alterations of Hormonal Regulation 475

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476 CHAPTER 18  Alterations of Hormonal Regulation

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 CHAPTER

19
Structure and Function of the
Hematologic System
Neal S. Rote and Kathryn L. McCance*

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Components of the Hematologic System, 477 Mechanisms of Hemostasis, 489
Composition of Blood, 477 Function of Platelets and Blood Vessels, 490
Lymphoid Organs, 482 Function of Clotting Factors, 491
The Mononuclear Phagocyte System, 483 Retraction and Lysis of Blood Clots, 493
Development of Blood Cells, 483 Pediatrics & Hematologic Value Changes, 496
Hematopoiesis, 483 Aging & Hematologic Value Changes, 496
Development of Erythrocytes, 485
Development of Leukocytes, 489
Development of Platelets, 489

All the body’s tissues and organs require oxygen and nutrients to of the body to carry out their chief functions: (1) delivery of substances
survive. These essential needs are provided by the blood that flows needed for cellular metabolism in the tissues, (2) removal of the wastes
through miles of vessels throughout the human body. The red blood of cellular metabolism, (3) defense against invading microorganisms
cells provide the oxygen, and the fluid portion of the blood carries the and injury, and (4) maintenance of acid-base balance.
nutrients. The blood also cleans discarded waste from the tissues and
transports cells (white blood cells) and other ingredients that are nec- Plasma and Plasma Proteins
essary for protecting the entire body from injury and infection. In adults, plasma accounts for 50% to 55% of blood volume ­(Figure
19-1). Plasma is a complex aqueous liquid containing a variety of
COMPONENTS OF THE HEMATOLOGIC SYSTEM organic and inorganic elements (Table 19-1). The concentration of
these elements varies depending on diet, metabolic demand, hor-
Composition of Blood mones, and vitamins. Plasma differs from serum in that serum is
Blood consists of various cells that circulate suspended in a solution plasma that has been allowed to clot in the laboratory in order to
of protein and inorganic materials (plasma), which is approximately remove fibrinogen and other clotting factors that may interfere with
92% water and 8% dissolved substances (solutes). The blood volume some diagnostic tests.
amounts to about 6 quarts (5.5 L) in adults. The continuous movement The plasma contains a large number of proteins (plasma proteins).
of blood guarantees that critical components are available to all parts These vary in structure and function and can be classified into two major
groups, albumin and globulins. Most plasma proteins are produced by
the liver. The major exception is antibody, which is produced by plasma
*Thom J. Mansen, RN, PhD, contributed to this chapter in the previous edition. cells in the lymph nodes and other lymphoid tissues (see Chapter 6).

477
478 CHAPTER 19  Structure and Function of the Hematologic System

TABLE 19-1 ORGANIC AND INORGANIC COMPONENTS OF ARTERIAL PLASMA

CONSTITUENT AMOUNT/CONCENTRATION MAJOR FUNCTIONS
Water 92% of plasma weight Medium for carrying all other constituents
Electrolytes Total >1% of plasma Maintain H2O in extracellular compartment; act as buffers; function in mem-
brane excitability
Na+ 142 mEq/L (142 mM)
K+ 4 mEq/L (4 mM)
Ca++ 5 mEq/L (2.5 mM)
Mg++ 3 mEq/L (1.5 mM)
Cl− 103 mEq/L (103 mM)
HCO− 3 27 mEq/L (27 mM)
Phosphate (mostly HPO4−) 2 mEq/L (1 mM)
S4− − 1 mEq/L (0.5 mM)
Proteins 7.3 g/dl (2.5 mM) Provide colloid osmotic pressure of plasma; act as buffers; see text for other
functions
Albumins 4.5 g/dl
Globulins 2.5 g/dl
Fibrinogen 0.3 g/dl
Transferrin 250 mg/dl
Ferritin 15-300 mg/L

Gases
CO2 content 22-20 mmol/L plasma By-product of oxygenation, most CO2 content is from HCO−
3 and acts as buffer
O2 Pao2 80 torr or greater (arterial); Oxygenation
Pvo2 30-40 torr (venous)
N2 0.9 ml/dl By-product of protein catabolism

Nutrients Provide nutrition and substances for tissue repair

Glucose and other carbohydrates 100 mg/dl (5.6 mM)
Total amino acids 40 mg/dl (2 mM)
Total lipids 500 mg/dl (7.5 mM)
Cholesterol 150-250 mg/dl (4-7 mM)
Individual vitamins 0.0001-2.5 mg/dl
Individual trace elements 0.001-0.3 mg/dl
Iron 50-150 mg/dl

Waste Products
Urea (BUN) 7-18 mg/dl (5.7 mM) End product of protein catabolism
Creatinine (from creatine) 1 mg/dl (0.09 mM) End product from energy metabolism
Uric acid (from nucleic acids) 5 mg/dl (0.3 mM) End product from protein metabolism
Bilirubin (from heme) 0.2-1.2 mg/dl (0.003-0.018 mM) End product of red blood cell destruction
Individual hormones 0.000001-0.5 mg/dl Functions specific to target tissue

Data from Vander AJ, Sherman JH, Luchiano DS: Human physiology: the mechanisms of body function, New York, 2001, McGraw-Hill.

Albumin (about 60% of total plasma protein) serves as a carrier mol- case of decreased production (e.g., cirrhosis, other diffuse liver diseases,
ecule for both normal components of blood and drugs. Its most essential protein malnutrition) or excessive loss of albumin (e.g., certain kidney
role is regulation of the passage of water and solutes through the capil- diseases), the reduced oncotic pressure leads to excessive movement of
laries. Albumin molecules are large and do not diffuse freely through fluid and solutes into the tissue and decreased blood volume.1
the vascular endothelium, and thus they maintain the critical colloidal The remaining plasma proteins, or globulins, are often classified
osmotic pressure (or oncotic pressure) that regulates the passage of by their properties in an electric field (serum electrophoresis). Under
water and solutes into the surrounding tissues (see Chapters 1 and 3). the normal conditions used to perform serum electrophoresis, albu-
Water and solute particles tend to diffuse out of the arterial portions of min is the most rapidly moving protein. The globulins are classified
the capillaries because blood pressure is greater in arterial than in venous by their movement relative to albumin: alpha globulins (those moving
blood vessels. Water and solutes move from tissues into the venous por- most closely to albumin), beta globulins, and gamma globulins (those
tions of the capillaries where the pressures are reversed, oncotic pressure with the least movement). The alpha and beta globulins may be subdi-
being greater than intravascular pressure or hydrostatic pressure. In the vided into subregions (alpha-1, alpha-2, beta-1, or beta-2 globulins).
 CHAPTER 19  Structure and Function of the Hematologic System 479

PLASMA PROTEINS
(percentage by weight)
WHOLE BLOOD Albumins 57%–60%
(percentage Proteins
by volume) 7% Globulins 38%
Fibrinogen 4%
Prothrombin 1%
Blood 8%
Water OTHER SOLUTES
92%
Ions
Nutrients
PLASMA
55% Waste products
Other solutes
1% Gases
Other fluids and tissues 92%
Regulatory substances
Buffy coat Platelets
140,000–340,000
LEUKOCYTES
FORMED
ELEMENTS Leukocytes
Neutrophils 40%–60%
45% 5000–10,000

Erythrocytes Lymphocytes 20%–40%

4.2–6.2 million
TOTAL BODY WEIGHT CENTRIFUGED Monocytes 2%–8%
SAMPLE
OF BLOOD
Eosinophils 2%–4%

Basophils 0.5%–1%
FORMED ELEMENTS
(number per cubic mm)
FIGURE 19-1  Composition of Whole Blood. Approximate values for the components of blood in a
normal adult. (From Patton KT, Thibodeau GA: Anatomy & Physiology, ed 7, St Louis, 2010, Mosby.)

TABLE 19-2 CELLULAR COMPONENTS OF THE BLOOD

STRUCTURAL NORMAL AMOUNTS OF
CELL CHARACTERISTICS CIRCULATING BLOOD FUNCTION LIFE SPAN
Erythrocyte (red blood cell) Nonnucleated cytoplasmic disk 4.2-6.2 million/mm3 Gas transport to and from tissue cells 80-120 days
containing hemoglobin and lungs
Reticulocyte 60,000/mm3 Immature erythrocyte
Absolute reticulocyte count 0.5-2.0% of erythrocytes
Leukocyte (white blood cell) Nucleated cell 5000-10,000/mm3 Body defense mechanisms See below
Lymphocyte Mononuclear immunocyte 25-36% of leukocyte count Humoral and cell-mediated immunity Days or years
(­leukocyte differential) (see Chapter 6) ­depending on type
Natural killer cell Large granular lymphocyte 5-10% circulatory pool Defense against some tumors and Unknown
(some in spleen) viruses (see Chapters 5 and 6)
Monocyte and macrophage Large mononuclear phagocyte 3-8% of leukocyte differential Phagocytosis; mononuclear ­phagocyte Months or years
system
Eosinophil Segmented polymorphonuclear 2-4% of leukocyte differential Control of inflammation, ­phagocytosis, Unknown
granulocyte defense against parasites, allergic
reactions
Neutrophil Segmented polymorphonuclear 40-60% of leukocyte differential Phagocytosis, particularly during 4 days
granulocyte early phase of inflammation
Basophil Segmented polymorphonuclear 0.5-1% of leukocyte differential Mast cell–like functions, ­associated Unknown
granulocyte with allergic reactions and
­mechanical irritation
Platelet Irregularly shaped cytoplasmic 150,000-400,000/mm3 Hemostasis after vascular ­injury; 8-11 days
­fragment (not a cell) ­normal coagulation and clot
­formation/retraction
480 CHAPTER 19  Structure and Function of the Hematologic System

Fibrinogen is a major plasma protein (about 4% of total plasma pro-

tein) that would move between the beta and gamma regions but is
removed during the formation of serum. The gamma-globulin region
consists primarily of antibodies (see Chapter 6).
Plasma proteins can also be classified by function: clotting, defense,
transport, or regulation. The clotting factors promote coagulation and
stop bleeding from damaged blood vessels. Fibrinogen is the most plen-
tiful of the clotting factors and is the precursor of the fibrin clot (see
Figure 19-7). Proteins involved in defense, or protection, against infec-
tion include antibodies and complement proteins (see Chapters 5 and
6). Transport proteins specifically bind and carry a variety of inorganic
and organic molecules, including iron (transferrin), copper (ceruloplas-
min), lipids and steroid hormones (lipoproteins) (see Chapters 1 and
22), and vitamins (e.g., retinol-binding protein). Regulatory proteins
include a variety of enzymatic inhibitors (e.g., alpha-1 antitrypsin) that
protect the tissues from damage, precursor molecules (e.g., kininogen)
that are converted into active biologic molecules when needed, and
protein hormones (e.g., cytokines) that communicate between cells.
Plasma also contains several inorganic ions that regulate cell func- FIGURE 19-2  Blood Cells. Leukocytes are spherical and have
tion, osmotic pressure, and blood pH. These include electrolytes, irregular surfaces with numerous extending pili. Leukocytes are
sodium, potassium, calcium, chloride, and phosphate. (Electrolytes the cotton candy–like cells in yellow. Erythrocytes are flattened
are described in Chapters 1 and 3.) spheres with a depressed center (red). (Copyright Dennis Kunkel
Microscopy, Inc.)
Cellular Components of the Blood
The cellular elements of the blood are broadly classified as red blood of killing microorganisms and catabolizing debris ingested during
cells (i.e., erythrocytes), white blood cells (i.e., leukocytes), and plate- phagocytosis. The granules also contain powerful biochemical media-
lets. The components of the blood are listed in Table 19-2. tors with inflammatory and immune functions. These mediators, along
Erythrocytes. Erythrocytes (red blood cells) are the most abundant with the digestive enzymes, are released from granulocytes in response
cells of the blood, occupying approximately 48% of the blood volume to specific stimuli and affect other cells in the circulation. Granulocytes
in men and about 42% in women. Erythrocytes are primarily respon- are capable of ameboid movement, by which they migrate through ves-
sible for tissue oxygenation. Hemoglobin (Hb) carries the gases, and sel walls (diapedesis) and then to sites where their action is needed.
electrolytes regulate gas diffusion through the cell’s plasma membrane. The neutrophil (polymorphonuclear neutrophil [PMN]) is the
The mature erythrocyte lacks a nucleus and cytoplasmic organelles most numerous and best understood of the granulocytes (Figure
(e.g., mitochondria), so it cannot synthesize protein or carry out oxi- 19-3).3 Neutrophils constitute about 55% of the total leukocyte count
dative reactions. Because it cannot undergo mitotic division, the eryth- in adults.
rocyte has a limited life span (approximately 120 days). Neutrophils are the chief phagocytes of early inflammation. Soon
The erythrocyte’s size and shape are ideally suited to its function as after bacterial invasion or tissue injury, neutrophils migrate out of the
a gas carrier. It is a small disk with two unique properties: (1) a bicon- capillaries and into the damaged tissue, where they ingest and destroy
cave shape and (2) the capacity to be reversibly deformed. The flattened, contaminating microorganisms and debris. Neutrophils are sensitive
biconcave shape provides a surface area/volume ratio that is optimal to the environment in damaged tissue (e.g., low pH, enzymes released
for gas diffusion into and out of the cell. During its life span, the eryth- from damaged cells) and die in 1 or 2 days. The breakdown of dead
rocyte, which is 6 to 8 μm in diameter, repeatedly circulates through neutrophils releases digestive enzymes from their cytoplasmic granules.
splenic sinusoids (see Figure 19-5) and capillaries that are only 2 μm These enzymes dissolve cellular debris and prepare the site for healing.
in diameter. Reversible deformity enables the erythrocyte to assume a Eosinophils, which have large, coarse granules, constitute only
more compact torpedo-like shape, squeeze through the microcircula- 2% to 4% of the normal leukocyte count in adults.4 Like neutrophils,
tion, and return to normal.2 eosinophils are capable of ameboid movement and phagocytosis.
Leukocytes. Leukocytes (white blood cells) defend the body Unlike neutrophils, eosinophils ingest antigen-antibody complexes
against organisms that cause infection and also remove debris, includ- and are induced by immunoglobulin E (IgE)-mediated hypersensitiv-
ing dead or injured host cells of all kinds (Figure 19-2). The leukocytes ity reactions to attack parasites (see Chapters 5 and 6). The eosinophil
act primarily in the tissues but are transported in the circulation. The granules contain a variety of enzymes (e.g., histaminase) that help to
average adult has approximately 5000 to 10,000 leukocytes/mm3 of control inflammatory processes. During type I hypersensitivity, aller-
blood. gic reactions and asthma are characterized by high eosinophil counts,
Leukocytes are classified according to structure as either granu- which may be involved in limiting the inflammatory response but may
locytes or agranulocytes and according to function as either phago- also contribute to the destructive inflammatory processes observed in
cytes or immunocytes. The granulocytes, which include neutrophils, the lungs of asthmatics.
basophils, and eosinophils, are all phagocytes. (Phagocytic action is Basophils, which make up less than 1% of the leukocytes, are
described in Chapter 5.) Of the agranulocytes, the monocytes and structurally similar to the mast cells found throughout extravascular
macrophages are phagocytes, whereas the lymphocytes are immuno- tissue (see Figure 19-3).5 Like the mast cells, basophils have cytoplas-
cytes (cells that create immunity; see Chapter 6). mic granules that contain vasoactive amines (e.g., histamine) and an
Granulocytes. The granulocytes have many membrane-bound anticoagulant (heparin). Their function is similar to that of tissue mast
granules in their cytoplasm. These granules contain enzymes capable cells (see Chapter 5).
 CHAPTER 19  Structure and Function of the Hematologic System 481

A B C

D E
FIGURE 19-3  Leukocytes. An example of leukocytes in human blood smear. A, Neutrophil. B, Eosino-
phil. C, Basophil with obscured nucleus. D, Typical monocyte showing vacuolated cytoplasm and cere-
briform nucleus. E, Lymphocyte. (A, C, D, and E from Rodak BF: Hematology: clinical principles and
applications, ed 2, Philadelphia, 2002, Saunders; B from Carr JC, Rodak BF: Clinical hematology atlas,
Philadelphia, 1999, Saunders.)

Agranulocytes. The agranulocytes—monocytes, macrophages,

and lymphocytes—contain relatively fewer granules than granulocytes.
Monocytes and macrophages make up the mononuclear phagocyte
system (or MPS, described on p. 483). Both monocytes and macro-
phages participate in the immune and inflammatory response, being
powerful phagocytes. They also ingest dead or defective host cells, par-
ticularly blood cells.
Monocytes are immature macrophages (see Figure 19-3). Mono-
cytes are formed and released by the bone marrow into the blood-
stream. As they mature, monocytes migrate into a variety of tissues
(e.g., liver, spleen, lymph nodes, peritoneum, gastrointestinal tract)
and fully mature into tissue macrophages. Other monocytes may
mature into macrophages and migrate out of the vessels in response to
infection or inflammation.
Lymphocytes constitute approximately 20-40% of the total leu-
kocyte count and are the primary cells of the immune response (see
Figure 19-3) (see Chapter 6). Most lymphocytes transiently circulate in FIGURE 19-4  Colored Micrograph of Platelets. The platelet on
the blood and eventually reside in lymphoid tissues as mature T cells, the left is moderately activated, with a generally round shape and
the beginning of formation of pseudopodia (foot-like extensions
B cells, or plasma cells. (Lymphocyte function and dysfunction are
from the membrane). The platelet on the right is fully activated, with
described in detail in Unit 2.) extensive pseudopodia. (Copyright Dennis Kunkle Microscopy, Inc.)
Natural killer (NK) cells, which resemble lymphocytes, kill some
types of tumor cells (in  vitro) and some virus-infected cells without
prior exposure (see Chapter 6). They develop in the bone marrow and a hormone growth factor, is the main regulator of the circulating plate-
circulate in the blood. let mass. TPO is primarily produced by the liver and induces platelet
Platelets. Platelets (thrombocytes) are not true cells but disk- production in the bone marrow.6 Platelets express receptors for TPO,
shaped cytoplasmic fragments that are essential for blood coagulation and when circulating platelet levels are normal, TPO is adsorbed onto
and control of bleeding. They lack a nucleus, have no deoxyribonucleic the platelet surface and prevented from accessing the bone marrow
acid (DNA), and are incapable of mitotic division. They do, however, and initiating further platelet production. When platelet levels are low,
contain cytoplasmic granules capable of releasing proinflammatory however, the amount of TPO exceeds the number of available platelet
biochemical mediators when stimulated by injury to a blood vessel TPO receptors, and free TPO can enter the bone marrow.
(Figure 19-4) (see Chapter 5).
The normal platelet concentration is 150,000 to 400,000 plate-
lets/mm3 of circulating blood, although the normal ranges may vary
4 QUICK CHECK 19-1
. Why are plasma proteins important to blood volume?
1
slightly from laboratory to laboratory. An additional one third of the 2. Which leukocytes are granulocytes?
body’s available platelets are in a reserve pool in the spleen. A platelet 3. Compare and contrast granulocytes, agranulocytes, phagocytes, and
circulates for approximately 10 days, ages, and is removed by mac- immunocytes.
rophages of the MPS, mostly in the spleen. Thrombopoietin (TPO),
482 CHAPTER 19  Structure and Function of the Hematologic System

debris. Hemoglobin from phagocytosed erythrocytes is catabolized,

Lymphoid Organs and heme (iron) is stored in the cytoplasm of the macrophages or
The lymphoid system is closely integrated with the circulatory system. released back into the blood plasma (see Figure 19-13). Blood that fil-
The role of lymphoid organs in the immune response was discussed in ters through the red pulp then moves through the venous sinuses and
Chapter 6. Lymphoid organs are sites of residence, proliferation, dif- into the portal circulation.
ferentiation, and function of lymphocytes and mononuclear phagocytes The venous sinuses (and the red pulp) can store more than 300 ml
(monocytes, macrophages). (The liver, which also has hematologic of blood. Sudden reductions in blood pressure cause the sympathetic
functions, is primarily a digestive organ and is described in Chapter 33.) nervous system to stimulate constriction of the sinuses and expel as
much as 200 ml of blood into the venous circulation, helping to restore
Spleen blood volume or pressure in the circulation and increasing the hema-
The spleen is the largest of the lymphoid organs. It is a site of fetal tocrit by as much as 4%.
hematopoiesis, its mononuclear phagocytes filter and cleanse the The spleen is not necessary for life or for adequate hematologic func-
blood, its lymphocytes mount immune responses to blood-borne tion. Its absence, however, has several effects that indicate its function.
microorganisms, and it serves as a blood reservoir. For example, leukocytosis (high levels of circulating leukocytes) often
The spleen is a concave, encapsulated organ that weighs about 150 g occurs after splenectomy, so the spleen must exert some control over
and is about the size of a fist (see Figure 6-2). It is located in the left upper the rate of proliferation of leukocytes. After splenectomy iron levels in
abdominal cavity, curved around a portion of the stomach. Strands of the circulation are decreased, immune function is diminished, and the
connective tissue (trabeculae) extend throughout the spleen from the blood contains more structurally defective blood cells than normal.
splenic capsule, dividing it into compartments that contain masses of
lymphoid tissue called splenic pulp. The spleen is interlaced with many Lymph Nodes
blood vessels, some of which can distend to store blood. Structurally, lymph nodes are part of the lymphatic system. Thousands
Blood that circulates through the spleen first encounters the white are clustered around the lymphatic veins, which collect interstitial fluid
splenic pulp, which consists of masses of lymphoid tissue containing from the tissues and transport it, as lymph, back into the circulatory
lymphocytes and macrophages. The white pulp forms clumps around system near the heart. Functionally, however, lymph nodes are part of
the splenic arterioles and is the chief site of immune and phagocytic the hematologic and immune systems because large numbers of lym-
function within the spleen. Here blood-borne antigens encounter lym- phocytes, monocytes, and macrophages develop or function within the
phocytes, initiating the immune response (see Chapter 6).7 lymph nodes.8 As the lymph filters through the bean-shaped lymph
Some of the blood continues through the microcirculation and nodes clustered in the inguinal, axillary, and cervical regions of the
enters highly distensible storage areas called venous sinuses. Most of the body, it is cleansed of foreign particles and microorganisms by the
blood, however, oozes through the capillary walls into the principal monocytes and macrophages. The microorganisms in lymph stimulate
site of splenic filtration, the red pulp (Figure 19-5). Here the resident the resident lymphocytes to develop into antibody-producing plasma
macrophages of the MPS phagocytose damaged or old blood cells of cells. During an infection, the rate of proliferation of lymphocytes
all kinds (but chiefly erythrocytes), microorganisms, and particles of within the nodes is so great that the nodes enlarge and become tender.9
Each lymph node is enclosed in a fibrous capsule (Figure 19-6),
with strands of connective tissue (trabeculae) extending inward,

Afferent Lymph
lymph
vessels
Capsule

Sinuses

Germinal
center
Cortical
nodules
Medullary
cords Trabeculae
Medullary
sinus

FIGURE 19-5  Red Cells in the Spleen. Scanning electron micro-

graph of spleen, demonstrating erythrocytes (numbered 1 through Hilus Efferent lymph vessel
6) squeezing through the fenestrated wall in transit from the splenic FIGURE 19-6  Cross Section of Lymph Node. Several afferent
cord to the sinus. The view shows the endothelial lining of the sinus valved lymphatics bring lymph to node. A single efferent lymphatic
wall, to which platelets (P) adhere, along with “hairy” white cells, leaves the node at the hilus. Note that the artery and vein also enter
probably macrophages. The arrow shows a protrusion on a red and leave at the hilus. Arrows show direction of lymph flow. (From
blood cell (×5000). (From Weiss L: A scanning electron microscope Thibodeau GA, Patton KT: Anatomy & physiology, ed 6, St Louis,
study of the spleen, Blood 43:665, 1974; reprinted with permission.) 2007, Mosby.)
 CHAPTER 19  Structure and Function of the Hematologic System 483

dividing the node into several compartments. Reticular fibers divide DEVELOPMENT OF BLOOD CELLS
the compartments into smaller sections and trap and store large num-
bers of lymphocytes, monocytes, and macrophages. The node has an Hematopoiesis
outer cortex area and an inner medullary area. Within the cortex are The typical human requires about 100 billion new blood cells per day.
germinal centers, or separate masses of lymphoid tissue (see Figure Blood cell production, termed hematopoiesis, is constantly ongoing,
19-6). Lymph enters the node, slowly filters through its sinuses, and occurring in the liver and spleen of the fetus and only in bone mar-
leaves through efferent lymphatic vessels.10 row after birth, and is known as medullary hematopoiesis. This pro-
cess involves the biochemical stimulation of populations of relatively
The Mononuclear Phagocyte System undifferentiated cells to undergo mitotic division (i.e., proliferation)
The mononuclear phagocyte system (MPS) consists of cells that origi- and maturation (i.e., differentiation) into mature hematologic cells.
nate in the bone marrow, are transported by the bloodstream, and, Certain blood cells proliferate and differentiate simultaneously. Pro-
after differentiation to blood monocytes, finally settle in the tissues as liferation usually ceases after a number of doubling divisions, but
mature macrophages. Table 19-3 lists the various names given to mac- differentiation continues. Erythrocytes and neutrophils generally dif-
rophages localized in specific tissues. ferentiate fully before entering the blood, but monocytes and lympho-
The cells of the MPS ingest and destroy (by phagocytosis) unwanted cytes do not.
materials, such as foreign protein particles, microorganisms, debris from Hematopoiesis continues throughout life, increasing in response to
dead or injured cells, defective or injured erythrocytes, and dead neutro- proliferative disease, hemorrhage, hemolytic anemia (in which eryth-
phils (see Figure 5-10). The MPS (mostly in the liver and spleen) is also rocytes are destroyed), chronic infection, thrombocytopenic purpura
the main line of defense against bacteria in the bloodstream. In addition, (bleeding caused by platelet insufficiency; see Chapter 20), and other
the MPS cleanses the blood of old, injured, or dead erythrocytes, leuko- disorders that deplete blood cells. In general, long-term stimuli, such
cytes, platelets, coagulation products, antigen-antibody complexes, and as chronic diseases, cause a greater increase in hematopoiesis than
macromolecules. Recently, the osteoclast was classified as a true member acute conditions, such as hemorrhage. Abnormal proliferation of
of the MPS. Osteoclasts are multinucleated cells specialized for the func- erythrocytes occurs in polycythemia vera, a myeloproliferative disease
tion of lacunar bone resorption; however, they are also known to have (discussed in Chapter 20). In adults, extramedullary hematopoiesis—
phagocytic abilities. The osteoclast originates from the monocyte cell blood cell production in tissues other than bone marrow—is usually
lineage (Figure 19-7). Macrophages also play a role in blood coagulation, a sign of disease, occurring in pernicious anemia, sickle cell anemia,
wound healing, tissue remodeling, and the control of blood production. thalassemia, hemolytic disease of the newborn (erythroblastosis
The origin and turnover time of all the tissue macrophages named fetal­is), hereditary spherocytosis, and certain leukemias. Extramedul-
in Table 19-3 are not precisely known. Once monocytes leave the cir- lary hematopoiesis of apparently normal blood cells has been reported
culation, they do not return. In the tissues, monocytes differentiate in the spleen, liver, and, less frequently, lymph nodes, adrenal glands,
into macrophages without dividing and can survive for many months cartilage, adipose tissue, intrathoracic areas, and kidneys.
or perhaps even years.
Bone Marrow

4 QUICK CHECK 19-2

Bone marrow is confined to the cavities of bone. It consists of blood
vessels, nerves, mononuclear phagocytes, stromal cells, blood cells in
1. Why is the spleen considered a hematologic organ? Why can humans live various stages of differentiation, and fatty tissue. Adults have two kinds
without it? of bone marrow: red, or active (hematopoietic), marrow (also called
2. Why are lymph nodes considered part of the hematologic system? myeloid tissue); and yellow, or inactive, marrow. The large quantities
3. What is the MPS? of fat in inactive marrow make it yellow. Not all bones contain active
marrow. In adults, active marrow is found primarily in the flat bones
of the pelvis (34%), vertebrae (28%), cranium and mandible (13%),
sternum and ribs (10%), and in the extreme proximal portions of the
TABLE 19-3 MONONUCLEAR PHAGOCYTE
humerus and femur (4% to 8%). Inactive marrow predominates in
SYSTEM (FORMERLY CALLED cavities of other bones. (Bones are discussed further in Chapter 36.)
THE RETICULOENDOTHELIAL Hematopoietic marrow receives oxygen and nutrients needed for
SYSTEM) cellular differentiation from the primary arteries of the bones. Branches
NAME OF CELL LOCATION of these arteries terminate in a capillary network that coalesces into
Monocytes/macrophages Bone marrow and peripheral blood
large venous sinuses, which eventually drain into a central vein. Hema-
Kupffer cells (inflammatory Liver
topoietic marrow and fat fill the spaces surrounding the network of
­macrophages)
venous sinuses. Newly produced blood cells traverse narrow openings
Alveolar macrophages Lung
in the venous sinus walls and thus enter the circulation. Normally, cells
Histiocytes Connective tissue
do not enter the circulation until they have differentiated to a certain
Macrophages Bone marrow
extent, but premature release occurs in certain diseases.
Fixed and free macrophages Spleen and lymph nodes
Cellular Differentiation
Pleural and peritoneal macrophages Serous cavities
Microglial cells Nervous system The hematologic system arises from the proliferation and differentia-
Mesangial cells Kidney tion of hematopoietic stem cells. All humans originate from a single
Osteoclasts Bone cell (the fertilized egg) that has the capacity to proliferate and eventu-
Langerhans cells Skin ally differentiate into the huge diversity of cells of the human body.
Dendritic cells Lymphoid tissue After fertilization, the egg divides over a 5-day period to form a hollow
ball (blastocyst) that implants on the uterus. Until about 3 days after
484 CHAPTER 19  Structure and Function of the Hematologic System

fertilization, each cell (blastomere) is undifferentiated and retains the so that a relatively constant population of stem cells is available. Some
capacity to differentiate into any cell type. In the 5-day blastocyst, the hematopoietic stem cells will continue differentiation into hematopoi-
outer layer of cells has undergone differentiation and commitment to etic progenitor cells. Progenitor cells retain proliferative capacity but
become the placenta. Cells of the inner cell mass, however, continue are committed to possible further differentiation into particular types
to have unlimited differentiation potential (currently referred to as of hematologic cells: lymphoid (lymphocytes, NK cells), granulocyte/
being pluripotent) and can grow into different kinds of tissue—blood, monocyte (granulocytes, monocytes, macrophages), and megakaryo-
nerves, heart, bone, and so forth. After implantation, cells of the inner cyte/erythroid (platelets, erythrocytes) progenitor cells.
cell mass begin differentiation into other cell types. Differentiation is a As with all other forms of cellular differentiation, successful hema-
multistep process and results in intermediate groups of stem cells with topoiesis requires that progenitor cells interact with neighboring cells
more limited, but still impressive, abilities to differentiate into many (stromal cells of the bone marrow) through a variety of adhesion
different types of cells.11 molecules and are exposed to particular signaling molecules (cyto-
The bone marrow contains a population of hematopoietic stem kines).13 Populations of stromal stem cells differentiate into many
cells that have partially differentiated (see Figure 19-7).12 They have the different bone marrow cell types, including bone cells (chondrocytes
capacity to differentiate into any of the hematologic cell populations that produce cartilage and osteoblasts that produce bone), fat cells
but can no longer differentiate into other cell types, like nerve or muscle (adipocytes), muscle (myocytes), and fibroblasts. Interactions between
cells. As with all stem cells, the hematopoietic stem cells are self-renew- osteoclasts and hematopoietic stem cells appear to be the most impor-
ing (they have the ability to proliferate without further differentiation) tant for hematopoiesis.

B lymphocyte Plasma cell

Common
lymphoid NK cell
progenitor

T lymphocyte

Hematopoietic Flt3+ DC
stem cell precursor
Dendritic cell

CFU-GM Monocyte
Macrophage
Neutrophil

Eosinophil
CFU-Eo

Basophil

CFU-Baso
Myeloid Mast cell
stem cell
CFU-MC

Megakaryocyte

CFU-Meg

Erythrocyte

CFU-E
FIGURE 19-7  Differentiation of Hematopoietic Cells. Curved arrows indicate proliferation and expan-
sion of pre-hematopoietic stem cell populations. EPO, Erythropoietin; G-CSF, granulocyte colony-
stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; M-CSF,
macrophage colony-stimulating factor; NK, natural killer; SCF, stem cell factor; TPO, thrombopoietin.
(Mast cells are discussed in Chapter 5.)
 CHAPTER 19  Structure and Function of the Hematologic System 485

Several cytokines participate in hematopoiesis, particularly colony- Under certain conditions, the levels of circulating hematologic cells
stimulating factors (CSFs or hematopoietic growth factors), which need to be rapidly replenished. Medullary hematopoiesis can be accel-
stimulate the proliferation of progenitor cells and their progeny and erated by any or all of three mechanisms: (1) conversion of yellow bone
initiate the maturation events necessary to produce fully mature cells. marrow, which does not produce blood cells, to red marrow, which
Multiple cell types, including endothelial cells, fibroblasts, and lym- does, by the actions of erythropoietin (a hormone that stimulates
phocytes, produce CSFs. erythrocyte production); (2) faster differentiation of daughter cells;
Hematopoiesis in the bone marrow occurs in two separate pools, and presumably (3) faster proliferation of stem cells.
the stem cell pool and the bone marrow pool, with eventual release of
mature cells into the peripheral circulation (Figure 19-8). The stem cell
pool contains pluripotent stem cells and partially committed progeni- 4 QUICK CHECK 19-3
tor cells. In addition, there is a bone marrow pool that contains cells 1. Why is the stem cell system important to hematopoiesis?
that are proliferating and maturing and cells that are stored for later 2. Why are some stem cells called pluripotent?
release into the peripheral blood. In the peripheral blood, two pools of 3. What role do stromal cells play in hematopoiesis?
cells are also categorized: those circulating and those stored around the
walls of the blood vessels (often called the marginating storage pool).
The marginating storage pool primarily consists of neutrophils that Development of Erythrocytes
adhere to the endothelium in vessels where the blood flow is relatively For almost 100 years it was believed that erythrocytes developed in the
slow. These cells can rapidly move into tissues and mucous membranes spleen. It was not until the 1950s that the bone marrow was identi-
when needed. Cells from the circulating pool join the marginating pool fied as the site of erythropoiesis, or development of red blood cells
to replace the cells that have migrated out of the capillaries. (Figure 19-9).

Stem cell pool Bone marrow pool Peripheral blood

Unipotential Proliferating
committed and maturing Storage Storage Functional

Bone
Multipotential Marrow 50% 50% Granulocyte
(totipotential)

70%

Thrombocyte
30%

100%

0% Erythrocyte

FIGURE 19-8  Hematopoiesis. Hematopoiesis from the stem cell pool; activity mainly in the bone mar-
row and in the peripheral blood.

Uncommitted Committed Normoblast Reticulocyte Erythrocyte

pluripotential proerythroblast (nucleus shrinks (cell leaves marrow (cell achieves final
stem cell and is reabsorbed) and enters blood- size and shape:
stream) hemoglobin
Erythropoietin synthesis ceases)
FIGURE 19-9  Erythrocyte Differentiation. Erythrocyte differentiation from large, nucleated stem cell
to small, nonnucleated erythrocyte.
486 CHAPTER 19  Structure and Function of the Hematologic System

1
Decreased RBCs
Decreased hemoglobin synthesis
Decreased blood flow
5 Hemorrhage
Bone EPO
2 Increased O2 consumption by tissues
marrow O2
4 3

6 9
Erythrocytes
EPO
8
O2

FIGURE 19-10  Role of Erythropoietin in Regulation of Erythropoiesis. (1) Decreased arterial oxy-
gen levels result in (2) decreased tissue oxygen (hypoxia) that (3) stimulates the kidney to increase
(4) production of erythropoietin. Erythropoietin is carried to the bone marrow (5) and binds to eryth-
ropoietin receptors on proerythroblasts, resulting in increased red cell production and maturation and
expansion of the erythron (6). The increased release of red cells into the circulation frequently cor-
rects the hypoxia in the tissues (7). (8) Perception of normal oxygen levels by the kidney causes
(9) diminished production of erythropoietin (negative feedback) and return to normal levels of erythro-
cyte production. EPO, Erythropoietin; O2, oxygen in the blood and tissue; RBCs, red blood cells.

Erythropoiesis
In the confines of the bone marrow erythroid progenitor cells prolifer-
ate and differentiate into large, nucleated proerythroblasts, which are
committed into producing cells of the erythroid series. The proerythro- α2 β1
blast differentiates through several intermediate forms of erythroblast
(sometimes called normoblast) while progressively eliminating most
intracellular structures, including the nucleus, synthesizing hemoglo- Heme
bin, and becoming more compact, eventually taking on the shape and
characteristics of an erythrocyte.
The last immature form is the reticulocyte, which contains a Heme
mesh-like (reticular) network of ribosomal RNA that is visible micro-
scopically after staining with certain dyes. Reticulocytes remain in the
marrow approximately 1 day and are released into the venous sinuses.
They continue to mature in the bloodstream and may travel to the α1
spleen for several days of additional maturation. The normal reticulo- β2
cyte count is 1% of the total red blood cell count. Approximately 1%
of the body’s circulating erythrocyte mass normally is generated every β-polypeptide α-polypeptide
24 hours. Therefore, the reticulocyte count is a useful clinical index of (globin) chain (globin) chain
erythropoietic activity and indicates whether new red cells are being
produced.
Most steps of this process are primarily under the control of eryth- FIGURE 19-11  Molecular Structure of Hemoglobin. Molecule
is a spherical tetramer weighing approximately 64,500 daltons. It
ropoietin.14 In healthy humans, the total volume of circulating eryth-
contains a pair of α-polypeptide chains and a pair of β-polypeptide
rocytes remains surprisingly constant. In conditions of tissue hypoxia, chains and several heme groups.
erythropoietin is secreted by the kidney (Figure 19-10). It causes a
compensatory increase in erythrocyte production if the oxygen content
of blood decreases because of anemia, high altitude, or pulmonary dis-
ease. The normal steady-state rate of production (2.5 million erythro- carbon dioxide in the tissues. A single erythrocyte can contain as many
cytes per second) can increase (to 17 million per second) under anemic as 300 hemoglobin molecules. Hemoglobin increases the oxygen-
or low-oxygen states. Thus, the body responds to reduced oxygenation carrying capacity of blood by 100-fold. Each hemoglobin molecule is
of blood in two ways: (1) by increasing the intake of oxygen through composed of two pairs of polypeptide chains (the globins) and four
increased respiration and (2) by increasing the oxygen-­carrying capac- colorful complexes of iron plus protoporphyrin (the hemes) (Figure
ity of the blood through increased erythropoiesis. 19-11). Hemoglobin is responsible for blood’s ruby-red color.15
Several variants of hemoglobin exist, but they differ only slightly
Hemoglobin Synthesis in primary structure based on the use of different polypeptide chains:
Hemoglobin (Hb), the oxygen-carrying protein of the erythrocyte, alpha, beta, gamma, delta, epsilon, or zeta (α, β, γ, δ, ε, or ζ). Hemo-
constitutes approximately 90% of the cell’s dry weight. Hemoglobin- globin A, the most common type in adults, is composed of two α- and
packed blood cells take up oxygen in the lungs and exchange it for two β-polypeptide chains.
 CHAPTER 19  Structure and Function of the Hematologic System 487

Heme is a large, flat, iron-protoporphyrin disk that can carry oxidizes Fe2+ to Fe3+ (oxyhemoglobin), but after the release of oxy-
one molecule of oxygen (O2). Thus, an individual hemoglobin mol- gen the body reduces the iron to Fe2+ and reactivates the hemoglobin
ecule with its four hemes can carry four oxygen molecules.16 If all (deoxyhemoglobin [reduced hemoglobin]). Without reactivation, the
four oxygen-binding sites are occupied by oxygen, the molecule is Fe3+-containing hemoglobin (methemoglobin) cannot bind oxygen.
said to be saturated. Through a series of complex biochemical reac- An excess of ferric iron occurs with certain drugs and chemicals, such
tions, protoporphyrin, a complex four-ringed molecule, is produced as nitrates and sulfonamides.
and bound with ferrous iron. It is crucial that the iron be correctly Several other molecules can competitively bind to deoxyhemo-
charged; reduced ferrous iron (Fe2+) can bind oxygen, whereas fer- globin. Carbon monoxide (CO) directly competes with oxygen for
ric iron (Fe3+) cannot. Binding of oxygen to ferrous iron temporarily binding to ferrous ion with an affinity that is about 200-fold greater
than that of oxygen. Thus, even a small amount of CO can dramati-
cally decrease the ability of hemoglobin to bind and transport oxygen.
O2 Hemoglobin also binds carbon dioxide (CO2), but at a binding site
SNO separate from where oxygen binds. In the lungs, CO2 is released allow-
O2 Fe
ing hemoglobin to bind oxygen.
Erythrocytes may play a role in the maintenance of vascular relax-
HbO2 ation. Nitric oxide (NO) produced by blood vessels is a major mediator
CO2 NO Fe of relaxation and dilation of the vessel walls.16 In the lungs, hemoglobin
CO2
can concurrently bind oxygen to the ferrous ion and NO to cysteine res-
NO
idues in the globins (Figure 19-12). As hemoglobin transfers its oxygen
Lung blood vessel to tissue, it may also shed small amounts of nitric oxide contributing
to dilation of the blood vessels and helping get the oxygen into tissues.
O2 Nutritional Requirements for Erythropoiesis
S SNO Normal development of erythrocytes and synthesis of hemoglobin
Fe depend on an optimal biochemical state and adequate supplies of the
Hb necessary building blocks, including protein, vitamins, and minerals
(Table 19-4). If these components are lacking for a prolonged time,
NO Fe
N erythrocyte production slows and anemia (insufficient numbers of
CO2
functional erythrocytes) may result (see Chapter 20).
Tissue blood vessel Iron cycle. Approximately 67% of total body iron is bound to heme
FIGURE 19-12  Hemoglobin (Hb) Binding to Nitric Oxide. In the in erythrocytes (hemoglobin) and muscle cells (myoglobin), and
lungs, hemoglobin (Hb) binds to nitric oxide (NO) as S-nitrosothiol approximately 30% is stored in mononuclear phagocytes (i.e., mac-
(SNO). In tissue, this SNO is released, and free, circulating NO is rophages) and hepatic parenchymal cells as either ferritin or hemosid-
bound to a different site for exhalation. Fe, Iron; N, nitrogen. erin. The remaining 3% (less than 1 mg) is lost daily in urine, sweat,

TABLE 19-4 NUTRITIONAL REQUIREMENTS FOR ERYTHROPOIESIS

CONSEQUENCE OF DEFICIENCY
NUTRIENT ROLE IN ERYTHROPOIESIS (See Chapter 20)
Protein (amino acids) Structural component of plasma membrane Decreased strength, elasticity, and flexibility
of membrane; hemolytic anemia
Synthesis of hemoglobin Decreased erythropoiesis and life span of erythrocytes
Intrinsic factor Gastrointestinal absorption of vitamin B12 Pernicious anemia
Cobalamin (vitamin B12) Synthesis of DNA, maturation of erythrocytes, facilitator of folate metabolism Macrocytic (megaloblastic) anemia
Folate (folic acid) Synthesis of DNA and RNA, maturation of erythrocytes Macrocytic (megaloblastic) anemia
Vitamin B6 (pyridoxine) Heme synthesis, possibly increases folate metabolism Hypochromic-microcytic anemia
Vitamin B2 (riboflavin) Oxidative reactions Normochromic-normocytic anemia
Vitamin C (ascorbic acid) Iron metabolism, acts as reducing agent to maintain iron in its ferrous (Fe++) form Normochromic-normocytic anemia
Pantothenic acid Heme synthesis Unknown in humans*
Niacin None, but needed for respiration in mature erythrocytes Unknown in humans
Vitamin E Synthesis of heme; possible protection against oxidative damage in mature Hemolytic anemia with increased cell
­erythrocytes membrane fragility; shortens life span of
erythrocytes in individual with cystic fibrosis
Iron Hemoglobin synthesis Iron deficiency anemia
Copper Structural component of plasma membrane Hypochromic-microcytic anemia

Data from Lee GR et al: Wintrobe’s clinical hematology, ed 9, Philadelphia, 1993, Lee & Febiger; Harmening DM: Clinical hematology and funda-
mentals of hemostasis, ed 3, Philadelphia, 1997, FA Davis.
DNA, Deoxyribonucleic acid; RNA, ribonucleic acid.
*Although pantothenic acid is important for optimal synthesis of heme, experimentally induced deficiency failed to produce anemia or other hema-
topoietic disturbances.
488 CHAPTER 19  Structure and Function of the Hematologic System

Iron reused in the

synthesis of new
hemoglobin Direct release

Release Storage
Bone in spleen
marrow Release

Iron plus
transferrin
Storage in
Erythrocytes liver

Bilirubin Iron
Heme
Secreted Hemoglobin
with bile
Bloodstream Globin

Macrophages (of MPS) in

spleen, liver, and bone marrow

Aged, abnormal, or
damaged erythrocytes
FIGURE 19-13  Iron Cycle. Iron (Fe) released from gastrointestinal epithelial cells circulates in the
bloodstream associated with its plasma carrier, transferrin. It is delivered to erythroblasts in bone mar-
row, where most of it is incorporated into hemoglobin. Mature erythrocytes circulate for approximately
120 days, after which they become senescent and are removed by the mononuclear phagocyte system
(MPS). Macrophages of MPS (mostly in spleen) break down ingested erythrocytes and return iron to
the bloodstream directly or after storing it as ferritin or hemosiderin.

bile, and epithelial cells shed from the gut. Iron is transported in the of adenosine triphosphate (ATP). ATP provides the energy needed
blood bound to transferrin, a glycoprotein synthesized primarily by to maintain cell function and its plasma membrane pliable (see Fig-
the liver but also by tissue macrophages, submaxillary and mammary ure 1-1). Metabolic processes diminish as the erythrocyte ages, so less
glands, and ovaries or testes (Figure 19-13). ATP is available to maintain plasma membrane function. The aged or
Iron for hemoglobin production is carried by transferrin to eryth- senescent red cell becomes increasingly fragile and loses its reversible
roblasts in the bone marrow, where it binds to transferrin receptors deformability, becoming susceptible to rupture while passing through
on erythroblasts. The iron is transported to the erythroblast’s mito- narrowed regions of the microcirculation.19
chondria (the site of hemoglobin production) and incorporated into Additionally, the plasma membrane of senescent red cells under-
protoporphyrin by the action of the enzyme heme synthetase. goes phospholipid rearrangement that is recognized by receptors
Aged or damaged erythrocytes are removed from the bloodstream on macrophages (primarily in the spleen), which selectively remove
by macrophages of the MPS—chiefly in the spleen. Within the pha- and sequester the red cells. If the spleen is dysfunctional or absent,
golysosomes (digestive vacuoles) of the macrophage, the erythrocyte macrophages in the liver (Kupffer cells) take over. During digestion
is broken down, the hemoglobin molecule catabolized, and the iron of hemoglobin in the macrophage, porphyrin reduces to bilirubin,
stored as ferritin or hemosiderin. The stored iron is released into the which is transported to the liver, conjugated, and finally excreted
bloodstream, where it binds to transferrin (see Figure 19-13).17 in the bile as glucuronide (Figure 19-14). Bacteria in the intestinal
Iron balance is maintained through controlled absorption rather lumen transform conjugated bilirubin into urobilinogen. Although
than excretion. Regulation of iron transport across the plasma mem- a small portion is reabsorbed, most urobilinogen is excreted in
brane of gastrointestinal epithelial cells is related to the cell’s iron con- feces.
tent and the overall rate of erythropoiesis.18 If the body’s iron stores Conditions causing accelerated erythrocyte destruction increase
are low or the demand for erythropoiesis increases, iron is transported the load of bilirubin for hepatic clearance, leading to increased serum
rapidly through the epithelial cell and into the plasma. If body stores levels of unconjugated bilirubin and increased urinary excretion of
are high and erythropoiesis is not increased, iron crosses the epithelial urobilinogen. Gallstones (cholelithiasis) can result from a chronically
cell’s plasma membrane passively and is stored as ferritin. Excretion of elevated rate of bilirubin excretion.
iron occurs when the epithelial cells of the intestinal mucosa slough off.

Normal Destruction of Senescent Erythrocytes

4 QUICK CHECK 19-4
1. Why is the reticulocyte count important?
Although mature erythrocytes lack nuclei, mitochondria, and endo- 2. Why is iron important to erythropoiesis?
plasmic reticula, they do have cytoplasmic enzymes capable of glycoly- 3. What happens to aging erythrocytes?
sis (anaerobic glucose metabolism) and production of small quantities
 CHAPTER 19  Structure and Function of the Hematologic System 489

Conjunction by
glucuronyl transferase
2
1 Uptake of complex
Liver

Enterohepatic Free bilirubin-

circulation of albumin complex
3
Bone Excretion urobilinogen
marrow Bacterial
conversion Free bilirubin 250 mg/day
(unconjugated; water soluble)

Kidney Gut
Erythrocytes
Catabolism
Renal excretion
of urobilinogen Heme
(4 mg/day)
Stool Erythrocyte
destruction
GlobinAmino
(120 days) acids

Macrophages (MPS)

FIGURE 19-14  Metabolism of Bilirubin Released by Heme Breakdown. MPS, Mononuclear

­phagocyte system.

Development of Leukocytes the cell develops cellular surface elongations and branches that pro-
All leukocytes arise from stem cells in the bone marrow (their pathways gressively fragment into platelets. Like erythrocytes, platelets released
of differentiation are shown in Figure 19-7). Lymphoid progenitor cells from the bone marrow lack nuclei.
develop into lymphocytes, which are released into the bloodstream to An optimal number of platelets and committed platelet precur-
undergo further maturation in the primary and secondary lymphoid sors (megakaryoblasts) in the bone marrow is maintained primarily
organs (see Chapter 6). Monocyte progenitors develop into monocytic by thrombopoietin, with other factors such as GM-CSF, produced
cells, which continue maturing into macrophages after release into the by the liver and kidney. These factors affect the rate of differentiation
bloodstream and entrance into various tissues.20 Progenitor cells for into megakaryocytes and the rate of platelet release.6 About two thirds
granulocytes normally fully mature in the marrow into neutrophils, of platelets enter the circulation, and the remainder resides in the
eosinophils, and basophils and are released into the blood. splenic pool. Platelets circulate in the bloodstream for about 10 days
The bone marrow selectively retains immature granulocytes as a before beginning to lose their ability to carry out biochemical reac-
reserve pool that can be rapidly mobilized in response to the body’s tions. Senescent platelets are sequestered and destroyed in the spleen
needs.3 Further maturation is under the control of several hematopoi- by mononuclear cell phagocytosis.
etic growth factors, including interleukins, granulocyte-macrophage
colony-stimulating factor (GM-CSF), and granulocyte colony-­
MECHANISMS OF HEMOSTASIS
stimulating factor (G-CSF).
Leukocyte production increases in response to infection, to the Hemostasis means arrest of bleeding. As a result of hemostasis, dam-
presence of steroids, and to reduction or depletion of reserves in the aged blood vessels may maintain a relatively steady state of blood
marrow. It is also associated with strenuous exercise, convulsive sei- volume, pressure, and flow. Three equally important components of
zures, heat, intense radiation, increased heart rates, pain, nausea and the control of hemostasis are platelets, blood proteins (clotting fac-
vomiting, and anxiety. tors), and the vasculature (endothelial cells and subendothelial matrix)
­(Figure 19-15). The role of platelets is to (1) contribute to regulation
Development of Platelets
Platelets (thrombocytes) are derived from stem cells and progenitor
cells that differentiate into megakaryocytes.6 During thrombopoiesis, Vasculature
the megakaryocyte progenitor is programmed to undergo an endomi-
totic cell cycle (endomitosis) during which DNA replication occurs,
but anaphase and cytokinesis are blocked (see Chapter 1) (see Figures
19-4 and 19-7). Thus, the megakaryocyte nucleus enlarges and becomes
Blood proteins
extremely polyploidy (up to 100-fold or more of the normal amount
(clotting factors) Platelets
of DNA) without cellular division. Concurrently, the numbers of cyto-
plasmic organelles (e.g., internal membranes, granules) increase, and FIGURE 19-15  Three Hemostatic Compartments.
490 CHAPTER 19  Structure and Function of the Hematologic System

TABLE 19-5 TYPES OF BLEEDING: SOURCES, VESSEL SIZE, AND SEALING REQUIREMENTS

TYPES AND SOURCES OF BLEEDING INVOLVED VESSEL SIZE SEALING REQUIREMENTS
Pinpoint petechial hemorrhage (blood leakage from Capillary Smallest Generally direct-sealing
small vessels) Venule Mostly fused platelets
Arteriole Mostly fused platelets
Ecchymosis (large, soft tissue bleeding) Vein Vascular contraction, fused platelets, perivascular
and intravascular hemostatic factor activation
(see Figure 19-16)
Rapidly expanding “blowout” hemorrhage Artery Greater vascular contraction, more fused platelets,
greater perivascular, and intravascular hemostatic
factor activation
Largest

Modified from Harmening DM, editor: Clinical hematology and fundamentals of hemostasis, ed 3, Philadelphia, 1997, FA Davis.

of blood flow into a damaged site through induction of vasoconstric- through the receptor complex GPIb/IX/V. Progressively the platelets
tion (vasospasm), (2) initiate platelet-to-platelet interactions resulting undergo further aggregation through platelet-to-platelet adhesion
in formation of a platelet plug to stop further bleeding, (3) activate the involving further fibrinogen bridging between receptors (particularly
coagulation (or clotting) cascade to stabilize the platelet plug, and (4) GPIIb/IIIa) on adjacent platelets.
initiate repair processes including clot retraction and clot dissolution As a result of interactions with the endothelium or the subendothe-
(fibrinolysis) (see Figures 19-18 and 19-19). lial matrix, as well as exposure to inflammatory mediators produced by
The relative importance of the hemostatic mechanisms clearly var- the endothelium and other cells, the platelets are activated.23 Activation
ies with vessel size. Damage to large vessels cannot easily be controlled results in dynamic changes in platelet shape from smooth spheres to
by hemostasis but requires vascular contraction and dramatically those with spiny projections and degranulation (also called the platelet-
decreased blood flow into the damaged vessels (Table 19-5). release reaction) resulting in the release of various potent biochemicals.

Function of Platelets and Blood Vessels

The normal platelet count ranges from 150,000 to 400,000/mm3, and a
count below 150,000/mm3 is defined as thrombocytopenia. However,
the thrombocytopenia is usually asymptomatic unless the count drops HEALTH ALERT
below 100,000/mm3, at which time abnormal bleeding may occur in Sticky Platelets, Genetic Variations,
response to trauma. Spontaneous major bleeding episodes do not gen- and Cardiovascular Complications
erally occur unless the platelet count falls below 20,000/mm3.
Platelets normally circulate freely, suspended in plasma, in an unac- Investigators report that a genetic trait induces some people to make sticky
tivated state. The state of platelet activation is primarily under the con- platelets. People with platelets that tend to stick together have an increased
trol of endothelial cells lining the vessels. Endothelial products, such risk of suffering complications from heart procedures. After individuals received
as nitric oxide (NO) and the prostaglandin derivative prostacyclin I2 angioplasty, in which a balloon-tipped catheter opens a blocked artery, inves-
(PGI2), maintain platelets in an inactive state. When a vessel is dam- tigators compared complications in the group with more sticky, or reactive,
aged, platelet activation may be initiated. Activation proceeds through platelets with those with less reactive platelets. Of 112 participants, 3 months
a process of increasing platelet adhesion, aggregation, and activation.21 after the procedure, 15 individuals with sticky platelets experienced chest pain
Initially, platelets adhere weakly to the vessel wall, followed by increased or a heart attack; 4 individuals with less reactive platelets experienced such
strength of adherence to the vessels, adherence between platelets (aggre- complications. In addition, 10 people with sticky platelets needed another
gation), and finally the development of an immobilizing meshwork of angioplasty, compared with only 2 from the less reactive platelet group.
platelets and fibrin (Figure 19-16) (see Health Alert: Sticky Platelets, In another study, investigators analyzed the receptor glycoprotein GP11b/111a
Genetic Variations, and Cardiovascular Complications). for weaknesses that might direct attempts to prevent clotting, heart attack, and
This process can begin in several ways. If the vessel lining remains stroke. Blood samples from 1340 people revealed that 72% had inherited from
intact in an area of inflammation, the endothelial cells may become both parents a gene for a version of GP11b/111a called P1A1, whereas 28% had
activated and begin expressing new proteins on their surface. Several inherited 1 or 2 copies of a gene encoding a version called P1A2. The blood from
of these, particularly P-selectin, bind specifically yet weakly with recep- the group with two copies of P1A1 clotted less readily than did the blood of the
tors on the surface of inactive platelets (e.g., GPIb) (Figure 19-17). As other group. The degree of clotting also depended on fibrinogen levels in the
inflammation progresses, the platelets adhere more avidly through blood. In individuals with unusually high fibrinogen levels, the presence of P1A1
additional receptors that bind through a fibrinogen bridge with the glycoprotein seemed to increase clotting more than did P1A2. Thus, testing for
endothelial cell surface.22 The principal fibrinogen receptor is the inte- platelet stickiness and GP11b/111a status could determine which people need
grin αIIbβ3 (also known as GPIIb/IIIa). anticlotting drugs and for how long.
During vessel damage, the endothelial layer is frequently compro-
Data from Furlan M: Sticky and promiscuous plasma proteins maintain
mised resulting in exposure of the underlying matrix that contains col- the equilibrium between bleeding and thrombosis, Swiss Med Wkly
lagen and other components including fibronectin. The matrix also 132(15–16):181–189, 2002; Lohse J et al: Platelet function in obese
contains von Willebrand factor (vWF), and the exposed collagen can children and adolescents, Hamostaseologie 30(suppl 1):S126–S132,
bind additional vWF from the circulation (see Figure 19-17). Platelets 2010; Mammen EF: Sticky platelet syndrome, Semin Thromb Hemost
adhere strongly to collagen through the receptor GPVI and to vWF 25(4):361–365, 1999.
 CHAPTER 19  Structure and Function of the Hematologic System 491

A B

C
FIGURE 19-16  Platelet Activation. A, After endothelial denudation, platelets and leukocytes adhere
to the subendothelium in a monolayer fashion. B, Higher-power view showing leukocytes and platelets
adherent to the subendothelium. C, High magnification of a thrombus showing a mixture of red cells
and platelets incorporated into the fibrin meshwork. (A and B from Libby P et al: Braunwald’s heart
disease: a textbook of cardiovascular medicine, ed 8, Philadelphia, 2007, Saunders; as reproduced
from Faggiotto A, Ross R: Studies of hypercholesterolemia in the nonhuman primate. II. Fatty streak
conversion to fibrous plaque, Arteriosclerosis 4(4):341–356, 1984; C from Damjanov I, Linder J, editors:
Anderson’s pathology, ed 10, St Louis, 1996, Mosby.)

Platelets contain three types of granules: lysosomes, dense bodies, acid to TXA2. Aspirin, particularly at low doses, specifically and irre-
and alpha granules. The contents of the dense bodies and alpha gran- versibly inhibits COX-1, decreasing production of TXA2 and decreas-
ules are particularly important in hemostasis. The dense bodies con- ing platelet activation.
tain ADP, serotonin, and calcium. ADP reacts with specific receptors If blood vessel injury is minor, hemostasis is achieved tempo-
on platelets to induce further adherence and subsequent degranulation rarily by formation of the platelet plug, which usually forms within
of nearby platelets and causing their plasma membranes to become 3 to 5 minutes of injury. Platelet plugs seal the many minute rup-
ruffled and sticky. The activated platelets cause a platelet plug to seal tures that occur daily in the microcirculation, particularly in cap-
the injured endothelium. Serotonin is a vasoactive amine that func- illaries. With too few platelets, numerous small hemorrhagic areas
tions like histamine and has immediate effects on smooth muscle in called purpuras develop under the skin and throughout the tissues
the vascular endothelium, causing an immediate temporary constric- (see Chapter 20).
tion of the injured vessel (see Chapter 5). Vasoconstriction reduces
blood flow and diminishes bleeding. Vasodilation soon follows, per- Function of Clotting Factors
mitting the inflammatory response to proceed (see Figures 22-24 and A blood clot is a meshwork of protein strands that stabilizes the plate-
22-25). Calcium is necessary for many of the intracellular signaling let plug and traps other cells, such as erythrocytes, phagocytes, and
mechanisms that control platelet activation. microorganisms (Figure 19-18). The strands are made of fibrin, which
Alpha granules contain a large number of clotting factors (e.g., is produced by the clotting (coagulation) system. The clotting system
fibrinogen, factor V), growth factors (e.g., platelet-derived growth was described in Chapter 5 and consists of a family of proteins that
factor), and heparin-binding proteins (e.g., platelet factor 4). Many circulate in the blood in inactive forms. Initiation of the system results
of these mediators either promote or inhibit platelet activity and the in sequential activation (cascade) of multiple members of the system
eventual process of clot formation (see Figure 19-17). Platelet-derived until a fibrin clot is created. As was described for the clotting, comple-
growth factor stimulates smooth muscle cells and promotes tissue ment, and kinin systems (see Chapter 5), each is usually diagrammed
repair. Heparin-binding proteins enhance clot formation at the site of with multiple pathways of activation that unite in a common pathway.
injury. This organization is purely for convenience, and many members of
Platelets also begin producing the prostaglandin derivative throm- each pathway may be activated by several alternative means and mem-
boxane A2 (TXA2), which counters the effects of prostacyclin I2 (PGI2), bers of one system frequently activate members of another (e.g., acti-
produced by endothelial cells (see Figure 19-17). TXA2 causes vaso- vated members of the complement system can activate members of the
constriction and promotes the degranulation of platelets, whereas clotting system).
PGI2 promotes vasodilation and inhibiting platelet degranulation. In The clotting system is usually presented as two pathways of initia-
platelets, an isoform of cyclooxygenase (COX-1) converts arachidonic tion (intrinsic and extrinsic pathways) that join in a common pathway.
492 CHAPTER 19  Structure and Function of the Hematologic System

Endothelial sloughing
I. Subendothelial exposure
Platelets
• Occurs after endothelial sloughing PGI2
• Platelets begin to fill endothelial gaps
• Promoted by thromboxane A2 (TXA2)
• Inhibited by prostacyclin I2 (PGI2)
• Platelet function depends on many
factors, especially calcium Collagen

II. Adhesion
GPIIb/IIIa
GPIa/IIa
• Adhesion is initiated by loss of endothelial cells
(or rupture or erosion of atherosclerotic plaque), Sticky
Endothelium GPIb platelets
which exposes adhesive glycoproteins such as
collagen and von Willebrand factor (vWF) in
the subendothelium. vWF and, perhaps, other
adhesive glycoproteins in the plasma deposit Collagen VWF
on the damaged area. Platelets adhere to the ACTIVATION
subendothelium through receptors that bind to VWF
the adhesive glycoproteins (GPIb, GPIa/IIa,
Fibrinogen
GPIIb/IIIa).
Collagen

III. Activation Collagen

Platelets
• After platelets adhere they undergo an activation
process that leads to a conformational change in
GPIIb/IIIa receptors, resulting in their ability to
bind adhesive proteins, including fibrinogen and
von Willebrand factor
• Changes in platelet shape
• Formation of pseudopods
• Activation of arachidonic pathway Collagen

IV. Aggregation RBC Platelets

• Induced by release of TXA2

• Adhesive glycoproteins bind simultaneously to
GPIIb/IIIa on two different platelets
• Stabilization of the platelet plug (blood clot)
occurs by activation of coagulation factors,
thrombin, and fibrin
Fibrin
• Heparin neutralizing factor enhances clot formation Fibrin Thrombin
mesh

V. Platelet plug formation

• RBCs and platelets enmeshed in fibrin

Platelet plug (blood clot)

VI. Clot retraction and clot dissolution Fibrin degradation Thrombin

Plasmin Plasminogen Activated protein

• Clot retraction, using large number of platelets, activators
joins the edges of the injured vessel
• Clot dissolution is regulated by thrombin and
plasminogen activators

FIGURE 19-17  Blood Vessel Damage, Blood Clot, and Clot Dissolution.
 CHAPTER 19  Structure and Function of the Hematologic System 493

The intrinsic pathway is activated when Hageman factor (factor XII) Retraction and Lysis of Blood Clots
in plasma contacts negatively charged subendothelial substances After a clot is formed, it retracts, or “solidifies.” Fibrin strands shorten,
exposed by vascular injury. The extrinsic pathway is activated when becoming denser and stronger, which approximates the edges of the
tissue thromboplastin, a substance released by damaged endothelial injured vessel wall and seals the site of injury. Retraction is facilitated
cells, reacts with clotting factors, particularly factor VII. Both pathways by the large numbers of platelets trapped within the fibrin meshwork.
lead to the common pathway and activation of factor X (Stuart-Prower The platelets contract and “pull” the fibrin threads closer together
factor), which proceeds to clot formation. As with complement and while releasing a factor that stabilizes the fibrin. Contraction expels
kinin systems, the clotting system is complex with a large number of protein-free serum from the fibrin meshwork (see Figure 19-18). This
alternative activators and inhibitors. Also, there is interaction between process usually begins within a few minutes after a clot has formed,
the pathways so that an activated member of one pathway may activate and most of the serum is expelled within 20 to 60 minutes.
a member of the other pathway. Lysis (breakdown) of blood clots is carried out by the fibrinolytic
Activated platelets are important participants in clotting. During system (Figure 19-19). Another plasma protein, plasminogen, is con-
activation, phospholipids in the platelet plasma membrane undergo verted to plasmin by several products of coagulation and inflamma-
redistribution so that a particular phospholipid, phosphatidyl serine tion (e.g., activated factor XII, thrombin, lysosomal enzymes). Plasmin
(PS), is greatly enriched on the platelet surface. PS provides a matrix for is an enzyme that dissolves clots (fibrinolysis) by degrading fibrin and
formation of several important complexes of clotting factors, includ- fibrinogen into fibrin degradation products (FDPs).24 The fibrinolytic
ing the tenase complex (factor X and activated factors VIII and IX) system removes clotted blood from tissues and dissolves small clots
that activates factor X and the prothrombinase complex (prothrombin (thrombi) in blood vessels. A balance between the amounts of thrombin
and activated factors X and V) that activated prothrombin into throm- and plasmin in the circulation maintains normal coagulation and lysis.
bin. Thrombin then converts fibrinogen into fibrin, which polymerizes Blood tests for evaluating the hematologic system are listed in
into a fibrin clot (e.g., factor VIIa of the extrinsic pathway can directly Table 19-6.
activate factor IX of the intrinsic pathway).
A variety of substances, some of which are products of the coagula-
tion system itself, control coagulation. For example, excess thrombin
4 QUICK CHECK 19-5
is inactivated by antithrombin III. Other anticoagulants, most nota- 1. Why are platelets necessary to stop bleeding?
bly heparin, are produced and secreted locally by tissue mast cells and 2. Briefly describe the steps of platelet adhesion and aggregation.
basophils activated by the injury (see Chapter 5). 3. How does plasminogen initiate fibrinolysis?

RBCs enmeshed in fibrin

Damaged tissue cells

Injur
Injury 2 Prothrombin
Extrinsic
3

Clotting Prothrombin
factors activator
Fibrin mesh (blood clot)
Calcium
Blood clot
Intrinsic
Thrombin

1 Fibrinogen Fibrin

Sticky platelets

Platelet plug

FIGURE 19-18  Blood Clotting Mechanism. A, The complex clotting mechanism can be distilled
into three basic steps: (1) release of clotting factors from both injured tissue cells and sticky plate-
lets at the injury site (which form temporary platelet plug), (2) series of chemical reactions that
eventually result in the formation of thrombin, and (3) formation of fibrin and trapping of blood cells
to form a clot. B, An electron micrograph showing entrapped RBCs in a fibrin clot. (A from Patton
KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby; B copyright Dennis Kunkel
Microscopy, Inc.)
494 CHAPTER 19  Structure and Function of the Hematologic System

TABLE 19-6 COMMON BLOOD TESTS FOR HEMATOLOGIC DISORDERS

POSSIBLE HEMATOLOGIC CAUSE
CELL TYPE AND TEST PROPERTY EVALUATED BY TEST OF ABNORMAL FINDINGS
Erythrocyte
Red cell count Number (in millions) of erythrocytes/μl of blood Altered erythropoiesis, anemias, hemorrhage, Hodgkin
disease, leukemia
Mean corpuscle volume (MCV) Size of erythrocytes Anemias, thalassemias
Mean corpuscle hemoglobin (MCH) Amount of hemoglobin in each erythrocyte Anemias, hemoglobinopathy
(by weight)
Mean corpuscular hemoglobin Concentration of hemoglobin in each erythrocyte (per- Anemias, hereditary spherocytosis
concentration (MCHC) centage of erythrocyte occupied by hemoglobin)
Hemoglobin determination Amount of hemoglobin (by weight)/dl of blood Anemias
Hematocrit determination Percentage of a given volume of blood that is occupied Hemorrhage, polycythemia, erythrocytosis, anemias,
by erythrocytes leukemia
Reticulocyte count Number of reticulocytes/μl of blood (also expressed Hyperactive or hypoactive bone marrow function
as percentage of reticulocytes in total red blood cell
count)
Erythrocyte osmotic fragility test Cellular shape (biconcavity), structure of plasma Anemias, hemolytic disease caused by ABO or Rh
membrane incompatibility, Hodgkin disease, polycythemia vera,
thalassemia major
Hemoglobin electrophoresis Relative percentage of different types of hemoglobin in Sickle cell disease, sickle cell trait, hemoglobin C disease,
erythrocytes hemoglobin C trait, thalassemias
Sickle cell test Presence of hemoglobin S in erythrocytes Sickle cell trait, sickle cell anemia
Glucose-6-phosphate dehydrogenase Deficiency of G6PD in erythrocytes Hemolytic anemia
(G6PD) deficiency test

Hemoglobin Metabolism
Serum ferritin determination Depletion of body iron (potential deficiency of heme Iron deficiency anemias
synthesis)
Total iron-building capacity (TIBC) Amount of iron in serum plus amount of transferrin Hemorrhage, iron deficiency anemia, hemochromatosis,
available in serum (μγ/δγ) hemosiderosis, iron overload, anemias, thalassemia
Transferrin saturation Percentage of transferrin that is saturated with iron Acute hemorrhage, hemochromatosis, hemosiderosis, sid-
eroblastic anemia, iron deficiency anemia, iron overload,
thalassemia
Porphyrin analysis (protoporphyrin Concentration of protoporphyrin in erythrocytes Megaloblastic anemia, congenital erythropoietic porphyria
analysis) (mcg/dl), an indicator of iron-deficient erythropoiesis
Direct antiglobulin test (DAT) Antibody binding to erythrocytes Hemolytic disease of newborn, autoimmune hemolytic
­anemia, drug-induced hemolytic anemia, transfusion
reaction
Antibody screen test (indirect Coombs Detection of antibodies to erythrocyte antigens (other Same as for DAT
test) than ABO antigens)
See below See below

Leukocytes: Differential White Cell Count (Absolute Number of A Type of Leukocyte/μl of Blood
Neutrophil count Neutrophils/μl Myeloproliferative disorders, hematopoietic disorders,
hemolysis, infection
Lymphocyte count Lymphocytes/μl Infectious lymphocytosis, infectious mononucleosis, hema-
topoietic disorders, anemias, leukemia, lymphosarcoma,
Hodgkin disease
Plasma cell count Plasma cells/μl Infectious mononucleosis, lymphocytosis, plasma cell
leukemia
Monocyte count Monocytes/μl Hodgkin disease, infectious mononucleosis, monocytic
leukemia, non-Hodgkin lymphoma, polycythemia vera
Eosinophil count Eosinophils/μl Hematopoietic disorders
Basophil count Basophils/μl Chronic myelogenous leukemia, hemolytic anemias,
­Hodgkin disease, polycythemia vera
 CHAPTER 19  Structure and Function of the Hematologic System 495

TABLE 19-6 COMMON BLOOD TESTS FOR HEMATOLOGIC DISORDERS—cont’d

POSSIBLE HEMATOLOGIC CAUSE
CELL TYPE AND TEST PROPERTY EVALUATED BY TEST OF ABNORMAL FINDINGS
Platelets and Clotting Factors
Platelet count Number of circulating platelets (in thousands)/μl of Anemias, multiple myeloma, myelofibrosis, polycythemia
blood vera, leukemia, disseminated intravascular coagulation
(DIC), hemolytic disease of the newborn, transfusion
reaction, lymphoproliferative disorders
Bleeding time Duration of bleeding following a standardized superfi- Leukemia, anemias, DIC, fibrinolytic activity, purpuras, hem-
cial puncture wound of skin, integrity of platelet plug, orrhagic disease of the newborn, infectious mononucleo-
measured in minutes following puncture sis, multiple myeloma, clotting factor deficiencies, throm-
basthenia, thrombocytopenia, von Willebrand disease
Clot retraction test Platelet number and function, fibrinogen quantity and Acute leukemia, aplastic anemia, factor XIII deficiency,
use, measured in hours required for expression of increased fibrinolytic activity, Hodgkin disease, hyperfi-
serum from a clot incubated in a test tube brinogenemia or hypofibrinogenemia, idiopathic thrombo-
cytopenic purpura, multiple myeloma, polycythemia vera,
secondary thrombocytopenia, thrombasthenia
Platelet adhesion studies Ability of platelets to adhere to foreign surfaces Anemia, macroglobulinemia, Bernard-Soulier syndrome,
multiple myeloma, myeloid metaplasia, plasma cell
dyscrasias, thrombasthenia, thrombocytopathy, von Wil-
lebrand disease
Platelet aggregation tests Ability of platelets to adhere to one another Afibrinogenemia, Bernard-Soulier syndrome, thrombasthe-
nia, hemorrhagic thrombocythemia, myeloid metaplasia,
plasma cell dyscrasias, platelet release defects, poly-
cythemia vera, preleukemia, sideroblastic anemia, von
Willebrand disease, Waldenström macroglobulinemia,
hypercoagulability
Whole blood clotting time (Lee-White Overall ability of blood to clot, as measured in minutes Afibrinogenemia, clotting factor deficiencies, excessive
coagulation time) in a test tube fibrinolysis, hemorrhagic disease of the newborn, hypofi-
brinogenemia, hypoprothrombinemia, leukemia
Circulating anticoagulants (immuno- Presence of antibodies that neutralize clotting factors Afibrinogenemia, presence of fibrin-fibrinogen degradation
globulin G [IgG] antibodies that inhibit and inhibit coagulation, as indicated by prolonged products, macroglobulinemia, multiple myeloma, DIC,
coagulation) clotting time, prothrombin time, or partial thrombo- plasma cell dyscrasias
plastin time
Partial thromboplastin time (PTT) Effectiveness of clotting factors (except factors VII and Presence of circulating anticoagulants, DIC, clotting factor
VIII), effectiveness of intrinsic pathway of coagulation deficiencies, excessive fibrinolysis, hemorrhagic disease
cascade, as measured by a test tube (in seconds) of the newborn, hypofibrinogenemia and afibrinogen-
emia, prothrombin deficiency, von Willebrand disease,
acute hemorrhage
Prothrombin time Effectiveness of activity of prothrombin, fibrinogen, Hypofibrinogenemia, dysfibrinogenemia, and afibrinogen-
and factors V, VII, and X; effectiveness of vitamin K– emia; presence of circulating anticoagulants; DIC; defi-
dependent coagulation factors of extrinsic and com- ciency of factors V, VII, or X; presence of fibrin degradation
mon pathways of coagulation cascade as measured products, increased fibrinolytic activity, hemolytic jaundice,
in a test tube (in seconds) hemorrhagic disease of the newborn; acute leukemia, poly-
cythemia vera, prothrombin deficiency, multiple myeloma
Thrombin time Quantity and activity of fibrinogen as measured in a Hypofibrinogenemia, dysfibrinogenemia, and afibrinogenemia;
test tube (in seconds) presence of circulating anticoagulants; hemorrhagic disease
of the newborn, polycythemia vera; increase in fibrinogen-
fibrin degradation products; increased fibrinolytic activity
Fibrinogen assay Amount of fibrinogen available for fibrin formation Acute leukemia, congenital hypofibrinogenemia or afi-
brinogenemia, DIC, increased fibrinolytic activity, severe
hemorrhage
Fibrin-fibrinogen degradation products Fibrinogenic activity as measured by levels of fibrin- Transfusion reactions, DIC, internal hemorrhage in the
(fibrin-fibrinogen split products) fibrinogen degradation products (in μl/ml of blood) newborn, deep vein thrombosis, pulmonary embolism

Data from Bick RL et al: Hematology: clinical and laboratory practice, St Louis, 1993, Mosby; Byrne CJ et al: Laboratory tests: implications for
­nursing care, Menlo Park, Calif, 1986, Addison-Wesley.
496 CHAPTER 19  Structure and Function of the Hematologic System

normal erythrocyte life span is 60 to 80 days; in premature infants, it

t-PA
may be as short as 20 to 30 days; and in children and adolescents, it is
the same as that in adults—120 days.
The postnatal fall in hemoglobin and hematocrit values is more
Plasminogen Plasmin
marked in premature infants than it is in full-term infants. In pre-
school and school-aged children, hemoglobin, hematocrit, and red
blood cell counts gradually rise. Metabolic processes within the eryth-
u-PA rocytes of neonates differ significantly from those found in erythro-
cytes of normal adults. The relatively young population of erythrocytes
u-PAR Fibrin clot Fibrin degradation in newborns consumes greater quantities of glucose than do erythro-
products cytes in adults.
The lymphocytes of children tend to have more cytoplasm and
less compact nuclear chromatin than do the lymphocytes of adults. A
possible explanation is that children tend to have more frequent viral
Vascular
infections, which are associated with atypical lymphocytes. Minor
endothelium
infections, in which the child fails to exhibit clinical manifestations of
FIGURE 19-19  The Fibrinolytic System. Fibrinolysis is initiated by illness, and the administration of immunizations also may account for
the binding of plasminogen to fibrin. Although tissue plasminogen
the lymphocyte changes.
activator (t-PA) initiates intravascular fibrinolysis, urokinase plas-
minogen activator (u-PA) is the major activator of fibrinolysis in tis- At birth the lymphocyte count is high, and it continues to rise dur-
sue (extravascular). Plasmin digests the fibrin into smaller soluble ing the first year of life. Then it steadily declines until the lower value
pieces (fibrin degradation products). u-PAR, Urokinase-like plasmin- seen in adults is reached. It is unknown whether these developmental
ogen activator receptor. variations are physiologic or a pathologic response to frequent viral
infection and immunizations in children.
The neutrophil count, like the lymphocyte count, is high at birth
and rises during the first days of life. After 2 weeks, the neutrophil
count falls to within or below the normal adult range. By approxi-
 PEDIATRICS & HEMATOLOGIC VALUE CHANGES
mately 4 years of age, the neutrophil count is the same as that of an
Blood cell counts tend to rise above adult levels at birth and then decline adult.
gradually throughout childhood. Table 19-7 lists normal ranges during The eosinophil count is high in the first year of life and higher in
infancy and childhood. The immediate rise in values is the result of children than in teenagers or adults. Monocyte counts too are high in
accelerated hematopoiesis during fetal life and the increased numbers the first year of life but then decrease to adult levels. Platelet counts
of cells that result from the trauma of birth and cutting of the umbili- in full-term neonates are comparable with platelet counts in adults and
cal cord. remain so throughout infancy and childhood.
Average blood volume in the full-term neonate is 85 ml/kg of body
weight. The premature infant has a slightly larger blood volume of 90
ml/kg of body weight, with the mean increasing to 150 ml/kg during
AGING & HEMATOLOGIC VALUE CHANGES
the first few days after birth. In both full-term and premature infants, Blood composition changes little with age. The erythrocyte life span
blood volume decreases during the first few months. Thereafter the in elderly persons is normal, although the erythrocytes are replenished
average blood volume is 75 to 77 ml/kg, which is similar to that of older more slowly after bleeding, probably because of iron depletion. Total
children and adults. serum iron, total iron-binding capacity, and intestinal iron absorption
The hypoxic intrauterine environment stimulates erythropoietin are all decreased somewhat in elderly persons. Iron deficiency is often
production in the fetus and accelerates fetal erythropoiesis, produc- responsible for the low hemoglobin levels noted in elderly persons. The
ing polycythemia (excessive proliferation of erythrocyte precursors) plasma membranes of erythrocytes become increasingly fragile, with
in the newborn. After birth, the oxygen from the lungs saturates arte- portions being lost, presumably because of physical trauma inflicted
rial blood, and more oxygen is delivered to the tissues. In response to during circulation.
the change from a placental to a pulmonary oxygen supply during the Lymphocyte function decreases with age (see Chapters 6 and 7),
first few days of life, levels of erythropoietin and the rate of blood cell causing changes in cellular immunity and some decline in T cell func-
formation decrease. The active rate of fetal erythropoiesis is reflected tion. The humoral immune system is less able to respond to antigenic
by the large numbers of immature erythrocytes (reticulocytes) in the challenge.
peripheral blood of full-term neonates. After birth, the number of No changes in platelet numbers or structure have been observed in
reticulocytes decreases about 50% every 12 hours, so it is rare to find elderly persons, yet evidence shows that platelet adhesiveness probably
an elevated reticulocyte count after the first week of life. During this increases. Although fibrinogen levels and factors V, VII, and IX tend to
period of rapid growth, the rate of erythrocyte destruction is greater be increased in elderly people, evidence concerning hypercoagulability
than that in later childhood and adulthood. In full-term infants, the is inconclusive.
 CHAPTER 19  Structure and Function of the Hematologic System
TABLE 19-7 HEMATOLOGIC VALUES FROM BIRTH TO ADULTHOOD
DIFFERENTIAL COUNTS
LEUKOCYTES PLATELETS
HEMOGLOBIN HEMATOCRIT RETICULOCYTES (WBC/mm3): NEUTROPHILS LYMPHOCYTES EOSINOPHILS MONOCYTES (103/mm3):
AGE (g/dl): MEAN (%): MEAN (%): MEAN MEAN (%): MEAN (%): MEAN (%): MEAN (%): MEAN MEAN
Newborn (cord 16.8 55 5.0 18,000 61 31 2 6 290
blood)
2 wk 16.5 50 1.0 12,000 40 48 3 9 252
3 months 12.0 36 1.0 12,000 30 63 2 5 140-340
6 months to 6 yr 12.0 37 1.0 10,000 45 48 2 5 140-340
7-12 yr 13.0 38 1.0 8,000 55 38 2 5 140-340
Adult 13.0 40 1.0 8,000 55 35 2 5 140-340
Female 14 41 0.8-4.1 7,400 54-62 25-33 1-4 3-7 140-340
Male 16 47 0.8-2.5 7,400 54-62 25-33 1-4 3-7 140-340

497
498 CHAPTER 19  Structure and Function of the Hematologic System

DID YOU UNDERSTAND?

Components of the Hematologic System 6. Erythropoiesis depends on the presence of vitamins (especially vitamin
1. Blood consists of a variety of components: about 92% water and 8% B12, folate vitamin, vitamin B6, riboflavin, pantothenic acid, niacin, ascorbic
­solutes. In adults, the total blood volume is approximately 5.5 L. acid, and vitamin E).
2. Plasma, a complex aqueous liquid, contains two major groups of plasma 7. Regulation of erythropoiesis is mediated by erythropoietin. Erythropoietin
proteins: (a) albumins and (b) globulins. is secreted by the kidneys in response to tissue hypoxia and causes a com-
3. The cellular elements of blood are the red blood cells (erythrocytes), white pensatory increase in erythrocyte production if the oxygen content of the
blood cells (leukocytes), and platelets. blood decreases because of anemia, high altitude, or pulmonary disease.
4. Erythrocytes are the most abundant cells of the blood, occupying approxi- 8. Maintenance of optimal levels of granulocytes and monocytes in the blood
mately 48% of the blood volume in men and approximately 42% in women. depends on the availability of pluripotential stem cells in the marrow,
Erythrocytes are responsible for tissue oxygenation. induction of these into committed stem cells, and timely release of new
5. Leukocytes are fewer in number than erythrocytes and constitute approxi- cells from the marrow.
mately 5000 to 10,000 cells/mm3 of blood. Leukocytes defend the body 9. Specific humoral colony-stimulating factors (CSFs) are necessary for the
against infection and remove dead or injured host cells. adequate growth of myeloid, erythroid, lymphoid, and megakaryocytic
6. Leukocytes are classified as either granulocytes (neutrophils, basophils, lineages.
eosinophils) or agranulocytes (monocytes/macrophages, lymphocytes). 10. Platelets develop from megakaryocytes by a process called endomitosis.
7. Platelets are not cells but disk-shaped cytoplasmic fragments. Platelets are In endomitosis, the megakaryocytes undergo DNA replication but not cell
essential for blood coagulation and control of bleeding. division; thus, the cell does not divide into two daughter cells.
8. The lymphoid organs are sites of residence, proliferation, differentiation, or
function of lymphocytes and mononuclear phagocytes. Mechanisms of Hemostasis
9. The spleen is the largest lymphoid organ and functions as the site of fetal 1. Hemostasis, or arrest of bleeding, involves (a) vasoconstriction (vasospasm),
hematopoiesis, filters and cleanses the blood, and acts as a reservoir for (b) formation of a platelet plug, (c) activation of the clotting cascade, (d) for-
lymphocytes and other blood cells. mation of a blood clot, and (e) clot retraction and clot dissolution.
10. The lymph nodes are the site of development or activity of large numbers of 2. The normal vascular endothelium prevents clotting by producing factors such
lymphocytes, monocytes, and macrophages. as nitric oxide (NO) and prostacyclin I2 (PGI2) that relax the vessels and pre-
11. The mononuclear phagocyte system (MPS) is composed of monocytes in vent platelet activation.
bone marrow and peripheral blood and macrophages in tissue. 3. Lysis of blood clots is the function of the fibrinolytic system. Plasmin, a pro-
12. The MPS is the main line of defense against bacteria in the bloodstream teolytic enzyme, splits fibrin and fibrinogen into fibrin degradation products
and cleanses the blood by removing old, injured, or dead blood cells; anti- that dissolve the clot.
gen-antibody complexes; and macromolecules.
Pediatrics & Hematologic Value Changes
Development of Blood Cells 1. Blood cell counts tend to rise above adult levels at birth and then decline
1. Hematopoiesis, or blood cell production, occurs in the liver and spleen of the gradually throughout childhood.
fetus and in the bone marrow after birth. 2. The lymphocytes of children tend to have more cytoplasm and less compact
2. Hematopoiesis involves two stages: (a) proliferation and (b) differentiation, nuclear chromatin than do the lymphocytes of adults.
or maturation. Each type of blood cell has parent cells called stem cells.
3. Hematopoiesis continues throughout life to replace blood cells that grow old Aging & Hematologic Value Changes
and die, are killed by disease, or are lost through bleeding. 1. Blood composition changes little with age. Erythrocyte replenishment may be
4. Bone marrow consists of blood vessels, nerves, mononuclear phagocytes, delayed after bleeding, presumably because of iron deficiency.
stem cells, blood cells in various stages of differentiation, and fatty 2. Lymphocyte function appears to decrease with age. Particularly affected is a
tissue. decrease in cellular immunity.
5. Hemoglobin, the oxygen-carrying protein of the erythrocyte, enables the 3. Platelet adhesiveness probably increases with age.
blood to transport 100 times more oxygen than could be transported dis-
solved in plasma alone.
 CHAPTER 19  Structure and Function of the Hematologic System 499

 KEY TERMS
•  granulocyte  480
A •  ranulocyte  480
G •  xyhemoglobin  487
O
• Albumin  478 • Hematopoiesis  483 • Phagocyte  480
• Basophil  480 • Hematopoietic stem cell  483 • Plasma  477
• Blood clot  491 • Heme  487 • Plasma protein  477
• Bone marrow (myeloid tissue)  483 • Hemoglobin (Hb)  486 • Plasmin  493
• Clotting (coagulation) system  491 • Hemostasis  489 • Platelet (thrombocyte)  481
• Clotting factor  480 • Immunocyte  480 • Platelet-release reaction  490
• Collagen  490 • Integrin αIIbβ3 (GPIIb/IIIa)  490 • Proerythroblast  486
• Colony-stimulating factor (CSF, hemato- • Leukocyte (white blood cell)  480 • Prostacyclin I2 (PGI2)  490
poietic growth factor)  485 • Lipoprotein  480 • Protoporphyrin  487
• Cyclooxygenase (COX-1)  491 • Lymph node  482 • Reticulocyte  486
• Deoxyhemoglobin  487 • Lymphocyte  481 • Serum  477
• Endomitosis  489 • Macrophage  481 • Spleen  482
• Eosinophil  480 • Marginating storage pool  485 • Stromal cell  484
• Erythroblast (normoblast)  486 • Methemoglobin  487 • Stromal stem cell  484
• Erythrocyte (red blood cell)  480 • Monocyte  481 • Thrombopoietin (TPO)  481
• Erythropoiesis  485 • Mononuclear phagocyte system • Thromboxane A2 (TXA2)  491
• Erythropoietin  485 (MPS)  483 • Tissue thromboplastin  493
• Fibrin degradation product (FDP)  493 • Myoglobin  487 • Transferrin  488
• Fibrinolysis  490 • Natural killer (NK) cells  481 • von Willebrand factor (vWF)  490
• Fibrinolytic system  493 • Neutrophil (polymorphonuclear neutro-
• Globin  486 phil [PMN])  480
• Globulin  478 • Nitric oxide (NO)  490

REFERENCES 14. Lippi G, Franchini M, Favaloro EJ: Thrombotic complications of

­erythropoiesis-stimulating agents, Semin Thromb Hemost 36(5):537–549,
1. Chuang VT, Otagiri M: Recombinant human serum albumin, Drugs 2010.
Today (Barc) 43(8):547–561, 2007. 15. Schechter AN: Hemoglobin research and the origins of molecular medi-
2. Mohandas N, Gallagher PG: Red cell membrane: past, present, and future, cine, Blood 112(10):3927–3938, 2008.
Blood 112(10):3939–3948, 2008. 16. Mozzarelli A, et al: Haemoglobin-based oxygen carriers: research and real-
3. Borregaard N: Neutrophils, from marrow to microbes, Immunity ity towards an alternative to blood transfusions, Blood Transfus 8(suppl 3):
33(5):657–670, 2010. s59–s68, 2010.
4. Bochner BS, Gleich GJ: What targeting eosinophils has taught us about 17. Edison ES, Bajel A, Chandy M: Iron homeostasis: new players, newer
their role in diseases, J Allergy Clin Immunol 126(1):16–25, 2010. insights, Eur J Haematol 1(6):411–424, 2008.
5. Karasuyama H, et al: Role for basophils in systemic anaphylaxis, Chem 18. West AR, Oates PS: Mechanisms of heme iron absorption: current ques-
Immunol Allergy 95:85–97, 2010. tions and controversies, World J Gastroenterol 14(26):4101–4110, 2008.
6. Stasi R, et al: Thrombopoietic agents, Blood Rev 24(4–5):179–190, 2010. 19. Antonelou MH, Kriebardis AG, Papassideri IS: Aging and death signaling
7. Turley SJ, Fletcher AL, Elpek KG: The stromal and haematopoietic in mature red cells: from basic science to transfusion practice, Blood Transfus
antigen-presenting cells that reside in secondary lymphoid organs, Nat 8(suppl 3):s39–s47, 2010.
Rev Immunol 10(12):813–825, 2010. 20. Geissmann F, et al: Development of monocytes, macrophages, and den-
8. Gatto D, Brink R: The germinal center reaction, J Allergy Clin Immunol dritic cells, Science 27(5966):656–661, 2010.
126(5):898–907, 2010. 21. Kunicki TJ, Nugent DJ: The genetics of normal platelet reactivity, Blood
9. van de Pavert SA, Mebius RE: New insights into the development of lym- 116(15):2627–2634, 2010.
phoid tissues, Nat Rev Immunol 10(9):664–674, 2010. 22. Li Z, Delaney MK, O’Brien KA, et al: Signaling during platelet adhesion
10. Hume DA: The mononuclear phagocyte system, Curr Opin Immunol and activation, Arterioscler Thromb Vasc Biol 30(12):2341–2349, 2010.
18(1):49–53, 2005. 23. Totani L, Evangelista V: Platelet-leukocyte interactions in cardiovascular
11. National Institutes of Health: Stem cell information, Bethesda, Md, 2010, disease and beyond, Arterioscler Thromb Vasc Biol 30(12):2357–2361,
National Institutes of Health, U.S. Department of Health and Human 2010.
Services [cited January 10, 2011]. Available at http://stemcells.nih.gov/info 24. Weisel JW, Litvinov RI: The biochemical and physical process of fibri-
2010. nolysis and effects of clot structure and stability on the lysis rate, Cardiovasc
12. Ratajczak MZ: Phenotypic and functional characterization of hematopoi- Hematol Agents Med Chem 6(3):161–180, 2008.
etic stem cells, Curr Opin Hematol 15(4):293–300, 2008.
13. Del Fattore A, Capannolo M, Rucci N: Bone and bone marrow: the same
organ, Arch Biochem Biophys 503(1):28–34, 2010.
CHAPTER

20
Alterations of Hematologic Function
Anna Schwartz, Neal S. Rote, and Kathryn L. McCance

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
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CHAPTER OUTLINE
Alterations of Erythrocyte Function, 500 Alterations of Lymphoid Function, 515
Classification of Anemias, 500 Lymphadenopathy, 515
Macrocytic-Normochromic Anemias, 502 Malignant Lymphomas, 516
Microcytic-Hypochromic Anemias, 504 Alterations of Splenic Function, 521
Normocytic-Normochromic Anemias, 505 Alterations of Platelets and Coagulation, 523
Myeloproliferative Red Cell Disorders, 506 Disorders of Platelet Function, 523
Polycythemia Vera, 506 Alterations of Platelet Function, 526
Iron Overload, 508 Disorders of Coagulation, 526
Alterations of Leukocyte Function, 508
Quantitative Alterations of Leukocytes, 508
Qualitative Alterations of Leukocytes, 512

Alterations of erythrocyte function involve either insufficient or exces- from alterations in any of the three main components of the clotting
sive numbers of erythrocytes in the circulation or normal numbers of process.
cells with abnormal components. Anemias are conditions in which
there are too few erythrocytes or an insufficient volume of erythro-
ALTERATIONS OF ERYTHROCYTE FUNCTION
cytes in the blood. Polycythemias are conditions in which erythrocyte
numbers or volume is excessive. All of these conditions have many Strictly speaking, anemia is a reduction in the total number of circulat-
causes and are pathophysiologic manifestations of a variety of disease ing erythrocytes or a decrease in the quality or quantity of hemoglobin.
states. The causes of anemia are (1) altered production of erythrocytes, (2)
Many disorders involving leukocytes range from increased num- blood loss, (3) increased erythrocyte destruction, or (4) a combination
bers of leukocytes (i.e., leukocytosis) in response to infections to pro- of all three.
liferative disorders (such as leukemia). Many hematologic disorders
are malignancies, and many nonhematologic malignancies metastasize Classification of Anemias
to bone marrow, affecting leukocyte production. Thus a large portion Anemias are classified by their causes (e.g., anemia of chronic disease)
of this chapter is devoted to malignant disease. or by the changes that affect the size, shape, or substance of the eryth-
The primary role of clotting (hemostasis) is to stop bleeding rocyte. The most common classification of anemias is based on the
through an interaction of endothelium lining the vessels, platelets, and changes that affect the cell’s size and hemoglobin content (Table 20-1).
clotting factors. A large number of disease states may be associated Terms used to identify anemias reflect these characteristics. Terms that
with a clinically significant increase or decrease in clotting resulting end with cytic refer to cell size, and those that end with chromic refer to

500
 CHAPTER 20  Alterations of Hematologic Function 501

TABLE 20-1 MORPHOLOGIC CLASSIFICATION OF ANEMIAS

MORPHOLOGY OF REMAINING
ERYTHROCYTES NAME AND MECHANISM OF ANEMIA PRIMARY CAUSE
Macrocytic-normochromic anemia: large, Pernicious anemia: lack of vitamin B12; abnormal DNA and Congenital or acquired deficiency of intrinsic
­abnormally shaped erythrocytes, normal RNA synthesis in erythroblast; premature cell death factor (IF); genetic disorder of DNA
hemoglobin concentrations synthesis
Folate deficiency anemia: lack of folate; premature cell death Dietary folate deficiency
Microcytic-hypochromic anemia: small, Iron deficiency anemia: lack of iron for hemoglobin; insufficient Chronic blood loss, dietary iron deficiency,
abnormally shaped erythrocytes and hemoglobin disruption of iron metabolism or iron cycle
reduced hemoglobin concentration
Sideroblastic anemia: dysfunctional iron uptake by erythroblasts Congenital dysfunction of iron metabolism in
and defective porphyrin and heme synthesis erythroblasts, acquired dysfunction of iron
metabolism as result of drugs or toxins
Thalassemia: impaired synthesis of α- or β-chain of hemoglobin Congenital genetic defect of globin synthesis
A; phagocytosis of abnormal erythroblasts in marrow
Normocytic-normochromic anemia: normal Aplastic anemia: insufficient erythropoiesis Depressed stem cell proliferation
size, normal hemoglobin concentration
Posthemorrhagic anemia: blood loss Increased erythropoiesis; iron depletion
Hemolytic anemia: premature destruction (lysis) of mature erythro- Increased fragility of erythrocytes
cytes in circulation
Sickle cell anemia: abnormal hemoglobin synthesis, abnormal cell Congenital dysfunction of hemoglobin
shape with susceptibility to damage, lysis, and phagocytosis synthesis
Anemia of chronic inflammation; abnormally increased demand for Chronic infection or inflammation; malignancy
new erythrocytes

DNA, Deoxyribonucleic acid; RNA, ribonucleic acid.

hemoglobin content. Additional terms describing erythrocytes found Tissue hypoxia creates additional demands and effects on the pul-
in some anemias are anisocytosis (assuming various sizes) and poi- monary and hematologic systems. The rate and depth of breathing
kilocytosis (assuming various shapes). increases in an effort to increase oxygen availability accompanied by an
increase in the release of oxygen from hemoglobin. All of these com-
CLINICAL MANIFESTATIONS  The fundamental alteration of ane- pensatory mechanisms may cause individuals to experience shortness
mia is a reduced oxygen-carrying capacity of the blood resulting in of breath (dyspnea), a rapid and pounding heartbeat, dizziness, and
tissue hypoxia. Symptoms of anemia vary, depending on the body’s fatigue. In mild chronic cases, these symptoms may be present only
ability to compensate for the reduced oxygen-carrying capacity. Ane- when there is an increased demand for oxygen (e.g., during physical
mia that is mild and starts gradually is usually easier to compensate for exertion), but in severe cases, symptoms may be experienced even at
and may cause problems for the individual only during physical exer- rest.
tion. As red cell reduction continues, symptoms become more pro- Manifestations of anemia may be seen in other parts of the body.
nounced and alterations in specific organs and compensation effects The skin, mucous membranes, lips, nail beds, and conjunctivae
are more apparent. Compensation generally involves the cardiovascu- become either pale because of reduced hemoglobin concentration or
lar, respiratory, and hematologic systems (Figure 20-1). yellowish (jaundiced) because of accumulation of end products of red
A reduction in the number of blood cells in the blood causes a cell destruction (hemolysis) if that is the cause of the anemia. Tissue
reduction in the consistency and volume of blood. Initial compensa- hypoxia of the skin results in impaired healing and loss of elasticity, as
tion for cellular loss is movement of interstitial fluid into the blood well as thinning and early graying of the hair. Nervous system manifes-
causing an increase in plasma volume. This movement maintains an tations may occur where the cause of anemia is a deficiency of vitamin
adequate blood volume, but the viscosity (thickness) of the blood B12. Myelin degeneration occurs, causing a loss of nerve fibers in the
decreases. The “thinner” blood flows faster and more turbulently than spinal cord, resulting in paresthesias (numbness), gait disturbances,
normal blood, causing a hyperdynamic circulatory state. This hyper- extreme weakness, spasticity, and reflex abnormalities. Decreased oxy-
dynamic state creates cardiovascular changes— increased stroke vol- gen supply to the gastrointestinal (GI) tract often produces abdomi-
ume and heart rate. These changes may lead to cardiac dilation and nal pain, nausea, vomiting, and anorexia. Low-grade fever (<101° F)
heart valve insufficiency if the underlying anemic condition is not occurs in some anemic individuals and may result from the release of
corrected. leukocyte pyrogens from ischemic tissues.
Hypoxemia, reduced oxygen level in the blood, further contrib- When the anemia is severe or acute in onset (e.g., hemorrhage), the
utes to cardiovascular dysfunction by causing dilation of arterioles, initial compensatory mechanism is peripheral blood vessel constric-
capillaries, and venules, thus increasing flow through them. Increased tion, diverting blood flow to essential vital organs. Decreased blood
peripheral blood flow and venous return further contributes to an flow detected by the kidneys activates the renin-angiotensin response,
increase in heart rate and stroke volume in a continuing effort to meet causing salt and water retention in an attempt to increase blood vol-
normal oxygen demand and prevent cardiopulmonary congestion. ume. These situations are considered to be emergencies and require
These compensatory mechanisms may lead to heart failure. immediate intervention to correct the underlying problem that caused
502 CHAPTER 20  Alterations of Hematologic Function

Etiologic events
(↓ erythropoiesis)
(blood loss)
(↑ destruction)

↓ Red blood cells, ↓ hemoglobin

(anemic condition)

↓ Oxygen-carrying capacity
(hypoxemia) Liver
(fatty changes; fatty
Ischemia Tissue hypoxia changes can also occur
in heart and kidney)

Respiratory Central nervous system

Claudication Weakness, Pallor (skin/ (↑ respiratory rate, depth, (dizziness, fainting,
(muscle) ↑ Fatigue mucous membrane) “exertional dyspnea”) lethargy)

Compensatory
Heart mechanisms
(angina)

↑ Heart rate Cardiovascular Capillary Renal ↑ DPG in cells

↑ Oxygen demands dilation
for work of heart
↑ SV ↑ Renin-aldosterone
response
↑ Erythropoietin ↑ Salt and H2O
retention
Stimulates ↑ Extracellular fluid
bone marrow
↑ Extracellular
Hyperdynamic fluid
circulation
Cardiac High-output ↑ Release of oxygen
murmurs cardiac failure from hemoglobin in tissues
FIGURE 20-1  Progression and Manifestations of Anemia. DPG, 2,3-Diphosphoglycerate; SV, stroke volume.

the acute blood loss; therefore, long-term compensatory mechanisms and cell division is blocked or delayed. However, ribonucleic acid
do not develop. (RNA) replication and protein (hemoglobin) synthesis proceed nor-
Therapeutic interventions for slowly developing anemic conditions mally. Asynchronous development leads to an overproduction of
require treatment of the underlying condition and palliation of asso- hemoglobin during prolonged cellular division, creating a larger than
ciated symptoms.1 Therapies include transfusion, dietary correction, normal erythrocyte with a disproportionately small nucleus. With each
and administration of supplemental vitamins or iron. cell division, the disproportion between RNA and DNA becomes more
apparent.
Macrocytic-Normochromic Anemias
The macrocytic (megaloblastic) anemias are characterized by unusu- Pernicious Anemia
ally large stem cells (megaloblasts) in the marrow that mature into Pernicious anemia (PA), the most common type of macrocytic ane-
erythrocytes that are unusually large in size (macrocytic), thickness, mia, is caused by vitamin B12 deficiency, which often accompanies the
and volume.2 The hemoglobin content is normal, thus allowing them end stage of type A chronic atrophic (autoimmune) gastritis (Figure
to be classified as normochromic. 20-2, C).3 Pernicious means highly injurious or destructive and reflects
These anemias are the result of ineffective erythrocyte deoxyribo- the fact that this condition was once fatal. It most commonly affects
nucleic acid (DNA) synthesis, commonly caused by deficiencies of individuals over the age of 30 who are of Northern European descent,
vitamin B12 (cobalamin) or folate (folic acid). These defective eryth- as well as blacks and Hispanics. Females are more prone to develop PA,
rocytes die prematurely, which decreases their numbers in the circula- with black females having an earlier onset.
tion, causing anemia.
Defective DNA synthesis in megaloblastic anemias causes red cell PATHOPHYSIOLOGY  The underlying alteration in PA is the absence
growth and development to proceed at unequal rates. DNA synthesis of intrinsic factor (IF), an enzyme required for gastric absorption of
 CHAPTER 20  Alterations of Hematologic Function 503

CLINICAL MANIFESTATIONS  Pernicious anemia develops slowly

(over 20 to 30 years), so by the time an individual seeks treatment,
it is usually severe. Early symptoms are often ignored because they
are nonspecific and vague and include infections, mood swings, and
gastrointestinal, cardiac, or kidney ailments. When the hemoglobin
A B C level has decreased to 7 to 8 g/dl, the individual experiences the classic
symptoms of anemia: weakness, fatigue, paresthesias of feet and fin-
gers, difficulty walking, loss of appetite, abdominal pain, weight loss,
and a sore tongue that is smooth and beefy red. The skin may become
“lemon yellow” (sallow), caused by a combination of pallor and jaun-
dice. Hepatomegaly, indicating right-sided heart failure, may be pres-
ent in the elderly along with splenomegaly, which is nonpalpable.
D E F
EVALUATION AND TREATMENT  Evaluation is based on blood
tests, bone marrow aspiration, serologic studies, gastric biopsy, clini-
cal manifestations, and the Schilling test. The Schilling test uses cobalt
radioisotopes and labeled B12 to evaluate IF production. The test is per-
formed by administering radioactive cobalamin and then measuring
its excretion in the urine. Low urinary excretion is significant for PA.
G H I Serologic studies show the presence of antibodies against gastric cells
and gastric biopsy reveals achlorhydria, a total absence of hydrochloric
acid (HCl).
Untreated PA is fatal, usually because of heart failure. With replace-
ment therapy of vitamin B12, mortality has decreased significantly.
Death from PA is now rare and relapses are often the result of non-
compliance with therapy. Initial replacement of vitamin B12 is accom-
J K L plished by weekly injections until the deficiency is corrected. Monthly
injections are then required for the remainder of an individual’s life.
Conventional wisdom and practice determined that oral preparations
were ineffective because there was no IF to facilitate absorption of B12.
However, recent practice has shown that oral administration of higher
doses of B12 is beneficial. Apparently, an alternative mechanism for B12
M N O absorption exists that is independent of IF. PA is not curable; therefore,
treatment must be continued throughout the individual’s lifetime.
FIGURE 20-2  Appearance of Red Blood Cells in Various Dis-
orders. A, Normal blood smear. B, Hypochromic-microcytic ane- Folate Deficiency Anemias
mia (iron deficiency). C, Macrocytic anemia (pernicious anemia). Folate (folic acid) is an essential vitamin required for RNA and DNA syn-
D, Macrocytic anemia in pregnancy. E, Hereditary elliptocytosis.
thesis within the erythrocyte. Humans are totally dependent on dietary
F, Myelofibrosis (teardrop). G, Hemolytic anemia associated with
prosthetic heart valve. H, Microangiopathic anemia. I, Stomato- intake to meet the daily requirement of 50 to 200 mg/day. Increased
cytes. J, Spherocytes (hereditary spherocytosis). K, Sideroblastic amounts are required for lactating and pregnant females. Folate is
anemia; note the double population of red blood cells. L, Sickle cell absorbed from the upper small intestine and does not require any other
anemia. M, Target cells (after splenectomy). N, Basophil stippling in element (i.e., IF) to facilitate absorption. After absorption, folate circu-
case of unexplained anemia. O, Howell-Jolly bodies (after splenec- lates through and is stored in the liver. Folate deficiency occurs more
tomy). (From Wintrobe MM et al: Clinical hematology, ed 8, Phila- often than B12 deficiency, particularly in alcoholics and individuals who
delphia, 1981, Lea & Febiger.) are malnourished because of fad diets or diets low in vegetables. It is
estimated that at least 10% of North Americans are folate deficient.
Clinical manifestations are similar to the malnourished appearance
dietary vitamin B12, a vitamin essential for nuclear maturation and of individuals with PA, except for the absence of neurologic symptoms.
DNA synthesis in red blood cells. Deficiency of IF may be congenital or Specific manifestations include cheilosis (scales and fissures of the
may be the result of adult-onset gastric mucosal atrophy in which the mouth), stomatitis (inflammation of the mouth), and painful ulcer-
parietal cells are destroyed. Subsequently, all secretions of the stom- ations of the buccal mucosa and tongue. Dysphagia, flatulence, and
ach—hydrochloric acid, pepsin, and IF—are deficient. PA is associated watery diarrhea also may be present, as well as histologic changes in
with autoimmune conditions that affect the endocrine system. Gastric the GI tract suggestive of sprue (chronic absorption disorder). Neuro-
atrophy may be caused by type A chronic gastritis, an autoimmune logic manifestations, if present, may be caused by thiamine deficiency,
disorder that causes destruction of parietal and zymogenic cells. These which often accompanies folate deficiency.
destroyed cells are replaced with mucus-containing cells (intestinal Evaluation of folate deficiency is based on blood tests, measurement
metaplasia). In addition, PA may be caused by heavy alcohol inges- of serum folate levels, and clinical manifestations. Treatment requires
tion, hot tea, and cigarette smoking. Complete or partial removal of administration of oral folate preparations until adequate blood levels
the stomach (gastrectomy) causes IF deficiency and results in PA. Indi- are obtained and manifestations are reduced or eliminated. Long-
viduals with chronic gastritis are at risk for the development of gastric term therapy is not necessary except for maintenance of an adequate
cancer and must be followed regularly to prevent this condition. daily intake of folate. Folate is essential for reducing blood levels of
504 CHAPTER 20  Alterations of Hematologic Function

homocysteine, which has been recently recognized as a risk factor for

the development of coronary artery disease.

Microcytic-Hypochromic Anemias
The microcytic-hypochromic anemias are characterized by abnor-
mally small erythrocytes that contain abnormally reduced amounts of
hemoglobin (see Figure 20-2, B). Hypochromia occurs even in cells of
normal size.
FIGURE 20-3  Pallor and Iron Deficiency. Pallor of the skin,
Microcytic-hypochromic anemia can result from (1) disorders of
mucous membranes, and palmar creases in an individual with
iron metabolism, (2) disorders of porphyrin and heme synthesis, or hemoglobin level of 9 g/dl. Palmar creases become as pale as the
(3) disorders of globin synthesis. Specific conditions include iron defi- surrounding skin when the hemoglobin level approaches 7 g/dl.
ciency anemia, sideroblastic anemia, and thalassemia. (From Hoffbrand AV, Pettit JE: Sandoz atlas of clinical hematology,
London, 1988, Gower Medical.)
Iron Deficiency Anemia
Iron deficiency anemia (IDA) is the most common type of anemia
throughout the world, occurring in both developing and developed
countries.2,4 The overall incidence of IDA is difficult to establish
because of the lack of standardized methods and techniques to deter-
mine hypoferremia and IDA. Certain populations are at high risk
for developing hypoferremia and IDA and include individuals living
in poverty, women of childbearing age, and children. Females in the
United States have a higher incidence than males for both hypofer-
remia and IDA, with the peak incidence occurring in the reproductive
years and decreasing at menopause. Males have a higher incidence dur-
ing childhood and adolescence. Children under 2 years of age are often
affected because of their increased demand for iron during growth.
FIGURE 20-4  Koilonychia. The nails are concave, ridged, and brit-
tle. (From Hoffbrand AV, Pettit JE: Sandoz atlas of clinical hematol-
PATHOPHYSIOLOGY  In developed countries, pregnancy and a con- ogy, London, 1988, Gower Medical.)
tinuous loss of blood are the most common causes of IDA. A blood loss
of 2 to 4 ml/day (1 to 2 mg of iron) is enough to cause IDA. Males may
experience bleeding as a result of ulcers, hiatal hernia, esophageal varices,
cirrhosis, hemorrhoids, ulcerative colitis, or cancer. Menorrhagia (exces-
sive menstrual bleeding) causes primary IDA in females. Other causes of
blood loss for both genders include: (1) use of medications that cause GI
bleeding; (2) surgical procedures that decrease stomach acidity, intes-
tinal transit time, and absorption (e.g., gastric bypass); (3) insufficient
dietary intake of iron; and (4) eating disorders such as pica—the craving
and eating of nonnutritional substances, such as dirt, chalk, and paper.
Iron in the form of hemoglobin is in constant use in the body. An
important attribute of iron is that it can be recycled; therefore, the body
maintains a balance between iron that is in use as hemoglobin and iron
that is stored and available for future hemoglobin synthesis (see Figure
19-13). Blood loss disrupts this balance by creating a need for more
iron, thus depleting the iron stores more rapidly to replace the iron lost
from bleeding.
IDA develops slowly through three overlapping stages. In stage I, FIGURE 20-5  Glossitis. Tongue of individual with iron deficiency
the body’s iron stores for red cell production and hemoglobin syn- anemia has bald, fissured appearance (arrow) caused by loss of
thesis are depleted. Red cell production proceeds normally with the papillae and flattening. (From Hoffbrand AV, Pettit JE: Sandoz atlas
hemoglobin content of red cells also remaining normal. In stage II, of clinical hematology, London, 1988, Gower Medical.)
insufficient amounts of iron are transported to the marrow, and iron-
deficient red cell production begins. Stage III begins when the hemo-
globin-deficient red cells enter the circulation to replace normal, aged As the condition progresses and becomes more severe, structural
erythrocytes that have been destroyed. The manifestations of IDA and functional changes occur in epithelial tissue. The fingernails
appear in stage III when there is an insufficient iron supply and dimin- become brittle and “spoon shaped” or concave (koilonychia) (Figure
ished hemoglobin synthesis. 20-4). Tongue papillae atrophy and cause soreness along with redness
and burning (Figure 20-5). These changes can be reversed within 1 to
CLINICAL MANIFESTATIONS  The onset of symptoms is gradual, 2 weeks of iron replacement. The corners of the mouth become dry
and individuals usually do not seek medical attention until hemoglobin and sore (angular stomatitis), and an individual may experience dif-
levels drop to 7 or 8 g/dl. Early symptoms are nonspecific and include ficulty with swallowing because of a “web” that develops from mucus
fatigue, weakness, shortness of breath, and pale earlobes, palms, and and inflammatory cells at the opening of the esophagus. These lesions
conjunctiva (Figure 20-3). have the potential to become cancerous.
 CHAPTER 20  Alterations of Hematologic Function 505

Iron is a component of many enzymes in the body, and lack of iron antituberculous agents (isoniazid [INH], pyrazinamide, cycloserine,
may alter other physiologic processes and contribute to the clinical and chloramphenicol), which interfere with B12 metabolism or directly
manifestations. Individuals with IDA exhibit gastritis, neuromuscular injure the mitochondria. Copper deficiency also causes reversible SA
changes, irritability, headache, numbness, tingling, and vasomotor dis- by interfering with conversion of ferric iron to ferrous iron. This is
turbances. Gait disturbances are rare. In the elderly, mental confusion, extremely rare and is associated with gastrectomy and prolonged par-
memory loss, and disorientation may be wrongly perceived as normal enteral nutrition without copper supplements. Hypothermia causes
events associated with aging. decreased heme synthesis and incorporation into hemoglobin.

EVALUATION AND TREATMENT  Evaluation is based on clinical CLINICAL MANIFESTATIONS  Along with the cardiovascular and
manifestations and laboratory tests. Iron stores are measured directly, respiratory manifestations common to all anemias, individuals with SA
by bone marrow biopsy, or indirectly, by tests that measure serum may show signs of iron overload (hemosiderosis), including mild to
ferritin, transferrin saturation, or total iron-binding capacity. A sen- moderate enlargement of the liver (hepatomegaly) and spleen (spleno-
sitive indicator of heme synthesis is the amount of free erythrocyte megaly); however, liver function remains normal or only mildly affected.
protoporphyrin (FEP) within erythrocytes. A test that determines the Occasionally the skin may become abnormally colored (bronze-tinted).
concentration of soluble fragment transferrin receptor differentiates Neurologic and skin alterations associated with other anemias are absent.
primary IDA from IDA that is associated with chronic disease. Hemosiderosis of cardiac tissue may result in heart rhythm disturbances,
The first step in treatment of IDA is to find and eliminate, or rule which is a significant but uncommon complication and generally occurs
out, sources of blood loss. If this is not done, replacement therapy is late in the course of the disease. Growth and development impairment
ineffective. Iron replacement therapy is required and very effective. may occur in infants and young children who are severely affected.
Initial doses are 150 to 200 mg/day and are continued until the serum
ferritin level reaches 50 mg/L, indicating that adequate replacement EVALUATION AND TREATMENT  Initially, SA may be mistaken for
has occurred. A rapid decrease in fatigue, lethargy, and other associ- deficiency of stem cells in the marrow (hypoplastic anemia) or iron
ated symptoms is generally seen within the first month of therapy. deficiency anemia. The diagnosis of SA is established by bone marrow
Replacement therapy usually continues for 6 to 12 months after the biopsy, which documents the presence of sideroblasts and confirms the
bleeding has stopped but may continue for as long as 24 months. Men- diagnosis.
struating females may need daily oral iron replacement therapy (325 Hereditary SA is initially treated with pyridoxine therapy (50 to 200
mg/day) until menopause. mg/day), which is effective in approximately one third of individuals
treated; however, response is variable. An optimal response is reticulo-
Sideroblastic Anemia cytosis with normal levels of hemoglobin and FEP returning within 1
Sideroblastic anemias (SAs) are a heterogeneous group of disor- to 2 months; cellular morphologic abnormalities do not disappear. A
ders characterized by anemia of varying severity because of ineffi- less optimal response is an elevated hemoglobin level that stabilizes at
cient iron uptake, resulting in abnormal hemoglobin synthesis. SA less than normal levels. A therapeutic response to pyridoxine may be
is characterized by the presence of ringed sideroblasts in the bone maintained with lifelong administration of a reduced dosage. Nonre-
marrow. These are red cells that contain iron granules that have not sponse to pyridoxine requires blood transfusions for symptom relief
been synthesized into hemoglobin but instead are arranged in a circle and to promote growth and development.
around the nucleus. Individuals with SA also have increased tissue Evidence of iron overload requires iron depletion therapy to pre-
levels of iron. vent or minimize organ damage. Phlebotomy, or removal of blood
from the circulation, is used in individuals with mild to moderate
PATHOPHYSIOLOGY  Sideroblastic anemias have various causes anemia without other complications (i.e., heart disease). After iron
but all share the commonality of altered heme synthesis in the ery- removal, maintenance phlebotomies are continued. Severely anemic
throid cells in bone marrow. SAs are either acquired or hereditary. individuals who may require transfusions become extremely iron over-
Acquired sideroblastic anemias, which are the most common, occur loaded, which mandates use of deferoxamine, an iron-chelating agent,
as a primary disorder with no known cause (idiopathic) or are associ- to reduce iron levels.
ated with other myeloproliferative or myeloplastic disorders. Another Individuals with acquired SA are less likely to respond to pyridox-
form is described as reversible SAs; these are secondary to various ine, but SA rarely incapacitates them. When SA is secondary to an
conditions such as alcoholism, drug reactions, copper deficiency, and identifiable cause, treatment or removal of the cause is essential. In
hypothermia. the absence of blood cell abnormalities and iron overload, progression
Hereditary sideroblastic anemias are rare and occur almost exclu- takes place over years. Transfusion and iron overload therapy is the
sively in males, supporting a recessive X-linked transmission; however, same as for hereditary SA when indicated.
autosomal transmission affecting females has been reported. Other Death from SA is rare and often secondary to complications such
genetic, chromosomal, or enzyme dysfunctions also have been asso- as infection, bone marrow failure, liver failure, or cardiac failure, or
ciated with hereditary SA. In all instances, SA anemia is present in arrhythmias. Idiopathic SA has the potential to convert to myelodys-
infancy or childhood but may remain undetected until midlife, when plastic syndrome, or abnormal marrow proliferation, which may then
other conditions, such as diabetes or cardiac failure from iron over- convert to acute myeloblastic leukemia.
load, cause it to be manifest.
Reversible sideroblastic anemia, associated with alcoholism, Normocytic-Normochromic Anemias
results from nutritional deficiencies of folate. Alcohol impairs heme Normocytic-normochromic anemias (NNAs) are characterized by
synthesis by reducing the activity of specific enzymes along the bio- erythrocytes that are relatively normal in size and hemoglobin content
synthetic pathway and also by direct effects of alcohol or acetal- but insufficient in number.5 These anemias do not share any com-
dehyde, or both, on the heme biosynthetic steps or mitochondrial mon etiology, pathologic mechanism, or morphologic characteris-
metabolism. Some specific drugs also cause reversible SA and include tics. They are less common than the macrocytic-normochromic and
506 CHAPTER 20  Alterations of Hematologic Function

the microcytic-hypochromic anemias. Five distinct anemias—aplas- (Table 20-3). Polycythemia exists in two forms: relative and absolute.
tic, posthemorrhagic, hemolytic, sickle cell, and anemia of chronic Relative polycythemia results from hemoconcentration of the blood
inflammation—exemplify the diversity of the NNA characteristics associated with dehydration. It is of minor consequence and resolves
and are summarized in Table 20-2. (Sickle cell anemia is discussed in with fluid administration or treatment of underlying conditions.
Chapter 21.) Absolute polycythemia consists of two forms: primary and sec-
ondary. Secondary polycythemia, the most common of the two, is a
physiologic response resulting from erythropoietin secretion caused by
4 QUICK CHECK 20-1 hypoxia. This hypoxia is noted in individuals living at higher altitudes
(>10,000 ft), smokers with increased blood levels of CO, and indi-
1. How do cell size and content determine classification of anemia?
2. Why is iron important to hemoglobin synthesis, and why is iron deficiency viduals with chronic obstructive pulmonary disease or coronary heart
related to anemia? failure, or both. Abnormal types of hemoglobin (e.g., San Diego, Ches-
3. How is anemia diagnosed? apeake), which have a greater affinity for oxygen, also cause second-
ary polycythemia, as does inappropriate secretion of erythropoietin by
certain tumors (e.g., renal cell carcinoma, hepatoma, and cerebellar
hemangioblastomas). The absolute primary form of polycythemia is
MYELOPROLIFERATIVE RED CELL DISORDERS referred to as polycythemia vera.
Hematologic dysfunction results from an overproduction of cells, as
well as a deficiency. One or more marrow elements may be produced in Polycythemia Vera
excess, responding to exogenous (e.g., exposure to radiation, drugs) or Polycythemia vera (PV) is a chronic, clonal alteration characterized
endogenous (e.g., physiologic compensatory response, immune disor- by overproduction of red cells (frequently with increased white cells
der) signals. Excessive red cell production is classified as polycythemia and platelets) accompanied by splenomegaly.6 Hypercellularity of bone

TABLE 20-2 NORMOCYTIC-NORMOCHROMIC ANEMIAS

EVALUATION
ANEMIA PATHOPHYSIOLOGY CLINICAL MANIFESTATIONS AND TREATMENT
Aplastic Rare; may result from infiltrative disorders of bone Classic cardiovascular and respiratory Bone marrow biopsy determines
marrow, autoimmune diseases, renal failure, splenic manifestations with thrombocytopenia, whether anemia is caused by pure
dysfunction, vitamin B12 or folate deficiency, parvo- hemorrhage into tissues, leukopenia, and red cell aplasia or hypoplasia
virus infection, or exposure to radiation, drugs, and infection Treat underlying disorder or prevent
toxins; also may be congenital further exposure to causative agent
Common stem cell population may be altered so it can- Blood transfusions, marrow trans-
not proliferate or differentiate, or stem cell environ- plant, and pharmacologic stimula-
ment is altered to inhibit erythropoiesis tion of bone marrow function
Outcome ranges from death to minimal manifestations
Posthemorrhagic Caused by sudden blood loss with normal iron stores Often obscured by cardiovascular manifes- Restoration of blood volume by
tations of acute hemorrhage intravenous administration of saline,
Severe shock, lactic acidosis, and death dextran, albumin, or plasma
can occur if blood loss exceeds 40-50% Transfusion of whole blood also
of plasma volume required occasionally
Hemolytic Acquired: caused by infection, systemic disease, drugs Splenomegaly, jaundice, aplastic hemo- Blood and bone marrow studies
or toxins, liver disease, kidney disease, abnormal lytic, or megaloblastic crises can develop Erythroid hyperplasia is found in mar-
immune responses with viral infection row and blood smears
Hereditary: caused by abnormalities of RBC membrane With severe disease, bones become de- Treatment of acquired disease
or cytoplasmic contents; present at birth formed and pathologic fractures occur involves removing cause or treating
Hemolysis: in blood vessels or lymphoid tissues that Cardiovascular and respiratory manifesta- underlying disorder
filter blood (e.g., spleen, liver) tions correspond with severity of anemia Other forms of treatment are transfu-
Erythrocytes: rigid, slowing their passage and making sions, splenectomy, and steroids
them vulnerable to phagocytosis or folate
Types: warm antibody disease (mediated by IgG anti-
body specific for erythrocyte antigens), cold antibody
disease (mediated by IgM), and drug induced
Anemia of chronic Associated with chronic infections (e.g., AIDS), chronic Manifestations fewer and milder than Blood tests show iron deficiency in
inflammation inflammatory diseases (e.g., rheumatoid arthritis, most other anemias marrow despite normal or increased
SLE), and malignancies General disability caused by chronic dis- iron stores elsewhere
Causes are decreased erythrocyte life span, failure ease limits physical activity so hemoglo- No treatment is needed unless ane-
of mechanisms of compensatory erythropoiesis, or bin levels adequate; if they drop, signs of mia becomes symptomatic
disturbance of iron cycle iron deficiency anemia develop Erythropoietin may be used

AIDS, Acquired immunodeficiency syndrome; RBC, red blood cell; SLE, systemic lupus erythematosus.
 CHAPTER 20  Alterations of Hematologic Function 507

TABLE 20-3 DISORDERS CLASSIFIED AS POLYCYTHEMIA

TYPE OF POLYCYTHEMIA MECHANISM OF INCREASED ERYTHROPOIESIS CAUSE OF ASSOCIATED DISORDER
Primary polycythemia (polycythemia Excessive proliferation of erythroid precursors in marrow; Possible mutation in erythropoietin receptor
vera) increased sensitivity of stem cell to erythropoietin
Secondary polycythemia Physiologic increase in erythropoietin secretion by kidneys in Tissue hypoxia caused by cardiopulmonary disorders
response to underlying systemic disorder (chronic obstructive pulmonary disease, congestive heart
failure), decreased barometric pressure, cardiovascular
malformations causing mixing of arterial and venous
blood, methemoglobinemia, carboxyhemoglobinemia,
smoking, obesity
“Nonphysiologic”* increase in erythropoietin secretion Renal disorders, cerebellar hemangioblastomas, hepatoma
(liver tumor), ovarian carcinoma, uterine leiomyoma,
pheochromocytoma, adrenocortical hypersecretion
Familial polycythemia Genetically induced increase in erythroid precursors of marrow Genetic defect
Abnormal Hb† with increased oxygen affinity
Decreased 2,3-DPG
Increased sensitivity of stem cells to erythropoietin
Increased erythropoietin in secretion

*Nonphysiologic means that there is no obvious physiologic explanation for hypersecretion of erythropoietin.
†2,3-DPG, 2,3-Diphosphoglycerate; Hb, hemoglobin.

marrow, along with hyperplasia of myeloid, erythroid, and megakaryo- however, increased blood volume does increase blood pressure.
cytes, is a distinguishing feature. PV is quite rare, occurring mostly in Coronary blood flow may be affected, precipitating angina, although
white males of Eastern European Jewish origin from 55 to 80 years of cardiovascular infarctions are uncommon. Other cardiovascular
age, with a median age of 55 to 60 years, but it has been observed in manifestations include Raynaud phenomenon and thromboangiitis
females and individuals less than 40 years of age. It is rarely seen in chil- obliterans.
dren or in multiple members of a single family; however, an autosomal A unique feature of PV, and helpful in diagnosis, is the develop-
dominant form exists that causes increased secretion of erythropoietin. ment of intense, painful itching that appears to be intensified by heat or
exposure to water (aquagenic pruritus) so that individuals avoid expo-
PATHOPHYSIOLOGY  PV is a neoplastic, nonmalignant condition sure to water, particularly warm water when bathing or showering. The
characterized by an abnormal proliferation of bone marrow stem cells intensity of itching is related to the concentration of mast cells in the
with subsequent self-destructive expansion of red cells. This aberrant skin and is generally not responsive to antihistamines or topical lotions.
proliferation occurs despite normal to below normal erythropoietin
levels. The underlying cause remains unknown, with the most likely EVALUATION AND TREATMENT  Blood and laboratory findings,
etiology thought to be an acquired genetic stem cell alteration of the characterized by an absolute increase in red blood cells and in total
erythropoietin receptor that causes the abnormal proliferation. Labo- blood volume, confirm the diagnosis. Erythrocytes appear normal, but
ratory studies have found red cell precursors that are capable of growth anisocytosis may be present. There also may be moderate increases in
independent of erythropoietin. These red blood cell precursors also white blood cells and platelets. A bone marrow examination may be
demonstrate sensitivity to other growth factors, such as interleukin-3 done; however, it cannot definitively confirm the diagnosis. Treatment
(IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), of PV consists of reducing red cell proliferation and blood volume,
or insulin-like growth factor. controlling symptoms, and preventing clogging and clotting of the
blood vessels. Phlebotomy (approximately 300 to 500 ml) is used to
CLINICAL MANIFESTATIONS  Clinical manifestations of PV are due reduce red cell mass and blood volume. Initial phlebotomies are done
to increased blood volume, which increases blood viscosity, creating two to three times a week until hematocrit levels drop sufficiently and
a hypercoagulable state resulting in clogging and occlusion of blood then are repeated every 3 to 4 months to maintain appropriate hema-
vessels. Tissue injury (ischemia) and death (infarction) is the outcome tocrit levels (<45%). Frequent phlebotomies also reduce iron levels,
of blood vessel blockage, and this occurs about 40% of the time. These a condition that impedes erythropoiesis, but they also may contribute
outcomes are directly correlated with hematocrit levels. Increases in to the development of thrombosis; thus, use of phlebotomies needs to
numbers of thrombocytes, as well as production of dysfunctional be individualized. Smokers are urged to quit smoking, and individuals
platelets, also contribute to this hypercoagulable condition. with congestive heart failure and chronic obstructive pulmonary dis-
Circulatory alterations caused by the thick, sticky blood give rise ease require appropriate drug intervention.
to other manifestations, such as plethora (ruddy, red color of the face, Hydroxyurea, a nonalkylating myelosuppressive, is the drug of
hands, feet, ears, and mucous membranes) and engorgement of retinal choice for myelosuppression because of a reduced incidence to cause
and cerebral veins. Other symptoms may include headache, drowsi- leukemia and thrombosis. Radioactive phosphorus (32P) also is used
ness, delirium, mania, psychotic depression, chorea, and visual distur- as an effective and easily tolerated intervention to suppress erythro-
bances. Death from cerebral thrombosis is approximately five times poiesis. Its effects may last up to 18 months. Side effects of 32P include
greater in individuals with PV.6,7 suppression of hematopoiesis resulting in anemia, leukopenia, and
Cardiovascular function, despite the vascular alterations, remains thrombocytopenia. Acute leukemia is also a side effect, although most
relatively normal. Cardiac workload and output remain constant; often it occurs only after 7 or more years of treatment, making its use
508 CHAPTER 20  Alterations of Hematologic Function

in elderly persons more common. Interferon is gaining popularity as CLINICAL MANIFESTATIONS  Clinical manifestations of HH
an effective drug therapy because of its ability to inhibit growth of the include symptoms such as fatigue, malaise, abdominal pain, arthralgias
abnormal clone, which diminishes the clinical and laboratory mani- and impotence, and clinical findings of hepatomegaly, abnormal liver
festations of myeloproliferation. Interferon use for this purpose is still enzymes, bronzed skin, diabetes, and cardiomegaly. Many individu-
new, and long-term effects are as yet unknown. als are diagnosed as a result of serum iron studies as part of a health
Survival for 10 to 15 years is common. However, without proper screening panel. Most (>75%) are asymptomatic and have a low fre-
treatment, 50% of individuals with PV die within 18 months of the quency (<25%) of cirrhosis, diabetes, or skin pigmentation.
onset of initial symptoms because of thrombosis or hemorrhage. A sig-
nificant potential outcome of PV is the conversion to acute myeloid EVALUATION AND TREATMENT  Laboratory findings in individuals
leukemia (AML), occurring spontaneously in 10% of individuals and with HH show elevations in serum iron levels, transferrin saturation,
generally being resistant to conventional therapy. Conversion to AML and ferritin levels. Documentation of iron overload relies on quantita-
is most likely related to treatment methods associated with cytotoxic tive phlebotomy with calculation of the amount of iron removed or
myelosuppressive agents, chlorambucil, and busulfan. Although PV is liver biopsy with determination of quantitative hepatic iron. With the
a chronic disorder, appropriate therapy results in remissions and pre- advent of genetic testing, individuals who are C282Y homozygous or
vention of significant pathologic outcomes. compound heterozygous, less than 40 years old, and have normal liver
functions, no further workup is necessary.
Iron Overload Treatment of HH is simple and consists of phlebotomy of 550 ml of
Iron overload can be primary, as in hereditary hemochromatosis (HH), whole blood, which is equivalent to 200 to 250 mg of iron. Frequency
or secondary. The secondary causes of iron overload include anemias of phlebotomy depends on ferritin levels and should continue until
with inefficient erythropoiesis (e.g., sideroblastic anemia, aplastic ane- the ferritin level is between 20 and 50 ng/ml. Initially, phlebotomy
mia), dietary iron overload, or conditions that require repeated blood may be needed weekly but once therapeutic ferritin levels are reached,
transfusions or iron dextran injections. phlebotomy may only be needed every 2 to 3 months. Blood banks
now accept blood donations from persons with documented HH. Iron
Hereditary Hemochromatosis chelating agents are sometimes used in addition to phlebotomy, but
Hereditary hemochromatosis (HH) is a common inherited, auto- this is not the mainstay of treatment. Individuals with HH should be
somal recessive disorder of iron metabolism,8 and is characterized instructed to refrain from taking iron and vitamin C supplements and
by increased gastrointestinal iron absorption with subsequent tissue consuming raw shellfish; in addition, alcohol should be used in mod-
iron deposition. Excess iron is deposited in the liver, pancreas, heart, eration. Family screening is recommended and necessary for all first-
joints, and endocrine gland causing tissue damage that can lead to degree relatives of a person with HH.
diseases such as cirrhosis, diabetes, heart failure, arthropathies, and
impotence.
HH is caused by two genetic base-pair alterations, C282Y and
ALTERATIONS OF LEUKOCYTE FUNCTION
H63D. These are mutations in the HFE gene on chromosome 6. Leukocyte function is affected if too many or too few white cells are
Homozygosity of C282Y is the most common genotype and accounts present in the blood or if the cells that are present are structurally
for 82% to 90% of HH cases. The remaining cases appear to be caused or functionally defective. Phagocytic cells (granulocytes, monocytes,
by environmental factors or other genotypes. HFE mutations are com- macrophages) may lose their ability to act as effective phagocytes, and
mon in the United States with 1 in 10 white persons heterozygous for the lymphocytes may lose their ability to respond to antigens. (Disrup-
HFE C282Y mutation and 4.4 in 1000 homozygous for the C282Y tions of inflammatory and immune processes caused by leukocyte dis-
mutation. C282Y homozygosity is much lower among Hispanics (0.27 orders are described in Chapter 5.) Other leukocyte alterations include
in 1000), Asian Americans (<0.001 per 1000), Pacific islanders (0.12 infectious mononucleosis and cancers of the blood—leukemia and
per 1000), and black persons (0.14 per 1000). multiple myeloma.

PATHOPHYSIOLOGY  Mouse studies have confirmed that the HFE Quantitative Alterations of Leukocytes
gene is responsible for HH. HFE protein, found in the crypt cells of Quantitative alterations are increases or decreases in numbers of leu-
the duodenum, facilitates transferring receptor-dependent iron uptake kocytes in the blood. Leukocytosis is present when the count is higher
into crypt cells. Mutant HFE protein loses its functional ability and than normal; leukopenia is present when the count is lower than nor-
causes a relative iron deficiency in duodenal crypt cells. The deficiency mal. Leukocytosis and leukopenia may affect a specific type of white
results in an increase in the expression of an iron transport protein, blood cell and may result from a variety of physiologic conditions and
divalent metal ion transporter 1 (DMT-1), which is responsible for alterations.
dietary iron absorption in the villus cells of the small intestine. This Leukocytosis occurs as a normal protective response to physiologic
inappropriate intestinal iron absorption leads to iron overload and, stressors, such as invading microorganisms, strenuous exercise, emo-
eventually, end-organ damage that can result in cirrhosis, diabetes tional changes, temperature changes, anesthesia, surgery, pregnancy,
mellitus, hypothyroidism, cardiomyopathies, and arthritis. and some drugs, hormones, and toxins. It also is caused by pathologic
Although the natural history of HH is not well understood, there conditions, such as malignancies and hematologic disorders. Unlike
appears to be a long latent period with individual variation in bio- leukocytosis, leukopenia is never normal. When the leukocyte count
chemical expression modified by environmental factors, such as blood falls to less than 1000/mm3, the risk of infection increases drastically.
loss from menstruation or donation, alcohol intake, and diet. Cirrho- With counts below 500/mm3, the possibility for life-threatening infec-
sis is a late-stage development of HH that can shorten life expectancy. tions is high. Leukopenia may be caused by radiation, anaphylactic
Cirrhosis also is a risk factor for hepatocellular carcinoma that occurs shock, autoimmune disease (e.g., systemic lupus erythematosus),
between 40 and 60 years old. Cirrhosis prevention is a major goal of immune deficiencies (see Chapter 7), and certain chemotherapeutic
HH screening and treatment. agents.
 CHAPTER 20  Alterations of Hematologic Function 509

Chemotherapeutic agents used to treat hematologic and other malig-

Granulocyte and Monocyte Alterations nancies cause bone marrow suppression. Several other drugs cause
Increased levels of circulating granulocytes (neutrophils, eosinophils, agranulocytosis, which occurs rarely but carries a high mortality rate
basophils) and monocytes are chiefly a physiologic response to micro- of 10% to 48%. Clinical manifestations of agranulocytosis include
bial invasion. Increased numbers also occur as a result of myelopro- infection (particularly of the respiratory system), general malaise,
liferative disorders (polycythemia vera, chronic myelocytic leukemia septicemia, fever, tachycardia, and ulcers in the mouth and colon. If
[CML]) that increase stem cell proliferation in the bone marrow.9 untreated, sepsis results in death within 3 to 6 days. Other conditions
Decreases occur when infectious processes deplete the supply of associated with neutropenia are identified in Table 20-4.
circulating granulocytes and monocytes, drawing them out of the Eosinophilia is an absolute increase (>450/mm3) in the total num-
circulation and into infected tissues faster than they can be replaced. ber of circulating eosinophils. Allergic disorders (type 1) associated with
Decreases also can be caused by disorders that suppress marrow func- asthma, hay fever, and drug reactions often cause eosinophilia. Hyper-
tion, such as Shwachman-Diamond syndrome, severe congenital neu- sensitivity reactions trigger the release of eosinophilic chemotaxic factor
tropenia, or immune-related neutropenia.10 of anaphylaxis (ECF-A) and histamine from mast cells, attracting eosino-
Granulocytosis—an increase in granulocytes (neutrophils, eosino- phils to the area. Areas with abundant mast cells, such as the respiratory
phils, or basophils)—begins when stored blood cells are released. Neu- and GI tracts, are commonly affected. Eosinophilia also may occur in der-
trophilia is another term that may be used to describe granulocytosis matologic disorders, eosinophilia-myalgia syndrome, and parasitic inva-
because neutrophils are the most numerous of the granulocytes (Table sion. Other conditions that cause eosinophilia are detailed in Table 20-4.
20-4). Neutrophilia is seen in the early stages of infection or inflam- Eosinopenia, a decrease in circulating eosinophils, generally is
mation and is established when the absolute count exceeds 7500/mm3. caused by migration of eosinophils into inflammatory sites. It may be
Release and depletion of stored neutrophils stimulates granulopoiesis seen in Cushing syndrome and as a result of stress caused by surgery,
to replenish neutrophil reserves. Specific conditions associated with shock, trauma, burns, or mental distress. Other conditions that cause
neutrophilia are identified in Table 20-4. eosinopenia are detailed in Table 20-4.
When the demand for circulating mature neutrophils exceeds the Basophilia is a response to inflammation and immediate hyper-
supply, immature neutrophils (and other leukocytes) are released from sensitivity reactions. Basophils contain histamine that is released
the bone marrow. Premature release of the immature cells is respon- during an allergic reaction. Increased basophils are seen in myelopro-
sible for the phenomenon known as a shift-to-the-left or leukemoid liferative disorders, such as chronic myeloid leukemia and myeloid
reaction. This refers to the microscopic detection of disproportion- metaplasia. Other conditions that are associated with basophilia are
ate numbers of immature leukocytes in peripheral blood smears. To listed in Table 20-4.
understand this phenomenon, visualize cellular differentiation, matu- Basopenia is seen in hyperthyroidism, acute infection, and long-
ration, and release (see Figure 19-7) as progressing from left to right term therapy with steroids. Other conditions associated with basope-
instead of vertically. The early release of immature white cells prevents nia are listed in Table 20-4.
the completion of the sequence and shifts the distribution of leuko- Monocytosis, an increase in monocytes, is often transient and
cytes in the blood toward those on the left side of the diagram. This correlates poorly with disease states. It is usually associated with neu-
phenomenon is also seen in the blood smear of individuals with leuke- tropenia during bacterial infections, particularly in the late stages or
mia, hence the term leukemoid reaction. As infection or inflammation recovery stage, when monocytes are needed to phagocytize surviving
diminishes, and granulopoiesis replenishes circulating granulocytes, a microorganisms and debris. Increased monocytes also may indicate
shift-to-the-right, or return to normal, occurs. marrow recovery from agranulocytosis. Monocytosis is often seen in
Neutropenia is a condition associated with a reduction in circu- chronic infections such as tuberculosis (TB) and subacute bacterial
lating neutrophils and exists clinically when the neutrophil count is endocarditis (SBE), and it has been found to correlate with the extent
less than 2000/mm3. Reduction in neutrophils occurs in severe pro- of myocardial damage following myocardial infarctions. Other condi-
longed infections when production of granulocytes cannot keep up tions associated with monocytosis are identified in Table 20-4. Mono-
with demand.9,10 cytopenia, a decrease in monocytes, is rare but has been identified with
Other causes of neutropenia, in the absence of overwhelming infec- hairy cell leukemia and prednisone therapy.
tion, may be (1) decreased neutrophil production or ineffective granu-
lopoiesis, (2) reduced neutrophil survival, and (3) abnormal neutrophil Lymphocyte Alterations
distribution and sequestration. Hematologic disorders that cause inef- Quantitative alterations of lymphocytes occur when lymphocytes are
fective or decreased production include hypoplastic or aplastic anemia, activated by antigenic stimuli, usually microorganisms (see Chapter 6).
megaloblastic anemias, leukemia, or drug-/toxin-induced neutropenia. Lymphocytosis is rare in acute bacterial infections and is seen most com-
Neutropenia also is seen in starvation and anorexia nervosa because of an monly in acute viral infections, particularly those caused by the Epstein-
inadequate supply of protein building blocks. Decreased neutrophil sur- Barr virus (EBV)—a causative agent in infectious mononucleosis. Other
vival is seen in autoimmune disorders (e.g., systemic lupus erythematosus, specific disorders associated with lymphocytosis are listed in Table 20-4.
rheumatoid arthritis). Abnormal neutrophil distribution and sequestra- Lymphocytopenia may be attributed to (1) abnormalities of lym-
tion are associated with hypersplenism and a pseudoneutropenia, which phocyte production associated with neoplasias and immune deficien-
in the presence of rheumatoid arthritis constitute Felty syndrome. Viral cies and (2) destruction by drugs, viruses, or radiation. It is also known
infections (human immunodeficiency virus [HIV], Epstein-Barr virus to occur without any detectable cause. Conditions associated with
[EBV]) also may cause neutropenia, as does chemotherapy and other lymphocytopenia are identified in Table 20-4. The lymphocytopenia
toxic drugs received for cancer treatment and transplantation. associated with heart failure and other acute illnesses may be caused
If neutrophils are drastically reduced (<500/mm3) and the entire by elevated levels of cortisol. Lymphocytopenia is a major problem
granulocyte count is extremely low, granulocytopenia or agranulo- in acquired immunodeficiency syndrome (AIDS). AIDS-related lym-
cytosis results. Usually, when this occurs, hematopoiesis is arrested phocytopenia is caused by HIV, which destroys T-helper lymphocytes.
in the bone marrow or cell destruction increases in the circulation. (For a detailed discussion of AIDS, see Chapter 7.)
510 CHAPTER 20  Alterations of Hematologic Function

TABLE 20-4 OTHER CONDITIONS ASSOCIATED WITH NEUTROPHILS, EOSINOPHILS,

BASOPHILS, MONOCYTES, AND LYMPHOCYTES
CONDITION CAUSE EXAMPLE
Neutrophil
Neutrophilia Inflammation or tissue Surgery, burns, MI, pneumonitis, rheumatic fever, rheumatoid arthritis
(granulocytosis) necrosis
Infection Bacterial: gram-positive (staphylococci, streptococci, pneumococci), gram-negative
(Escherichia coli, Pseudomonas species)
Physiologic Exercise, extreme heat or cold, third-trimester pregnancy, emotional distress
Hematologic Acute hemorrhage, hemolysis, myeloproliferative disorder, chronic granulocytic leukemia
Drugs or chemicals Epinephrine, steroids, heparin, histamine, endotoxin
Metabolic Diabetes (acidosis), eclampsia, gout, thyroid storm
Neoplasm Liver, GI tract, bone marrow
Neutropenia Decreased marrow Radiation, chemotherapy, leukemia, aplastic anemia, abnormal granulopoiesis
production
Increased destruction Splenomegaly, hemodialysis, autoimmune disease
Infection Gram-negative (typhoid), viral (influenza, hepatitis B, measles, mumps, rubella), severe infections,
protozoal infections (malaria)

Eosinophil
Eosinophilia Allergy Asthma, hay fever, drug sensitivity
Infection Parasites (trichinosis, hookworm), chronic (fungal, leprosy, TB)
Malignancy CML, lung, stomach, ovary, Hodgkin disease
Dermatosis Pemphigus, exfoliative dermatitis (drug-induced)
Drugs Digitalis, heparin, streptomycin, tryptophan (eosinophilia-myalgia syndrome), penicillins, propranolol
Eosinopenia Stress response Trauma, shock, burns, surgery, mental distress
Drugs Steroids (Cushing syndrome)

Basophil
Basophilia Inflammation Infection (measles, chickenpox), hypersensitivity reaction (immediate)
Hematologic Myeloproliferative disorders (CML, polycythemia vera, Hodgkin lymphoma, hemolytic anemia)
Endocrine Myxedema, antithyroid therapy
Basopenia Physiologic Pregnancy, ovulation, stress
Endocrine Graves disease

Monocyte
Monocytosis Infection Bacterial (subacute bacterial endocarditis, TB), recovery phase of infection
Hematologic Myeloproliferative disorders, Hodgkin disease, agranulocytosis
Physiologic Normal newborn
Monocytopenia Rare

Lymphocyte
Lymphocytosis Physiologic 4 months to 4 years
Acute infection Infectious mononucleosis, CMV infection, pertussis, hepatitis, mycoplasma pneumonia, typhoid
Chronic infection Congenital syphilis, tertiary syphilis
Endocrine Thyrotoxicosis, adrenal insufficiency
Malignancy ALL, CLL, lymphosarcoma cell leukemia
Lymphocytopenia Immunodeficiency AIDS, agammaglobulinemia
syndrome
Lymphocyte destruction Steroids (Cushing syndrome), radiation, chemotherapy
Hodgkin lymphoma
CHF, renal failure, TB, SLE,
aplastic anemia

AIDS, Acquired immunodeficiency syndrome; ALL, acute lymphocytic leukemia; CHF, congestive (left) heart failure; CLL, chronic lymphocytic leu-
kemia; CML, chronic myelogenous leukemia; CMV, cytomegalovirus; GI, gastrointestinal; MI, myocardial infarction, SLE, systemic lupus erythema-
tosus; TB, tuberculosis.
 CHAPTER 20  Alterations of Hematologic Function 511

Hematopoietic
stem cell

Common myeloid Common lymphoid

progenitor progenitor

AML AML AML AML AML Precursor B cell ALL Precursor T cell
Acute Acute Acute Acute Acute lymphoma lymphoma
basophilic eosinophilic myelomonocytic megakaryocytic erythroid
leukemia leukemia leukemia leukemia leukemia ALL ALL

Precursor Precursor Precursor

Basophil Eosinophil Granulocyte/ Megakaryocyte Erythroid B cell NK cell T cell
progenitor progenitor Monocyte progenitor progenitor
progenitor
Burkitt lymphoma Blastic Lymphoblastic
NK cell lymphoma
B cell CLL lymphoma
AML AML Hodgkin lymphoma
Acute Acute
myeloblastic monocytic
leukemia leukemia
Mature Secondary Mature
Granulocyte Monocyte B cell lymphoid organs T cell
progenitor progenitor
Mantle cell lymphoma Peripheral
Chronic myelogenous leukemia T cell
Follicular lymphoma
lymphoma
Diffuse B cell lymphoma

Waldenström
macroglobulinemia
Basophil Eosinophil Platelet Erythrocyte
NK cell
Multiple myeloma
Neutrophil Monocyte

Effector
Plasma cell T cell
FIGURE 20-6  Origins of Leukemias and Lymphomas. Differentiation pathways of blood-forming
cells and reported sites from which specific leukemias and lymphomas originate. Tumors of similar
types are given the same background coloring. ALL, Acute lymphocytic leukemia; AML, acute myelog-
enous leukemia; CLL, chronic lymphocytic leukemia; NK, natural killer.

The virus initially infects the oropharynx, nasopharynx, and salivary

Infectious Mononucleosis epithelial cells with later extension into lymphoid tissues and B cells.
Infectious mononucleosis (IM) is an acute infection of B lymphocytes Unaffected B cells produce antibodies (IgG, IgA, IgM) against the virus.
(B cells) with Epstein-Barr virus (EBV).11 Infections with EBV are Cytotoxic T lymphocytes (Tc cells) are activated and multiply to assist the
common in children, particularly those from low socioeconomic envi- B cells in attacking the virus and virus-infected cells directly (see Chapter
ronments. Approximately 50% to 85% of these children are infected 6). The production of B and T cells and the process of removing dead and
with EBV by age 4, and more than 90% of adults have indications of damaged leukocytes are largely responsible for lymphoid tissue swelling
exposure to EBV. These early infections are usually asymptomatic and (lymph nodes, spleen, tonsils, and, occasionally, liver). Sore throat and
provide immunity to EBV; thus children with an early infection rarely fever, two initial manifestations of IM, are caused by inflammation and
develop IM. Mononucleosis may arise when the initial infection with infection at the site of initial viral entry—the mouth and throat.
EBV occurs during adolescence or later, but it results in mononucleo-
sis in only 35% to 50% of these individuals. CLINICAL MANIFESTATIONS  The incubation period for IM is
The incidence of IM is approximately 45 in 10,000 individuals and approximately 30 to 50 days. Early flulike symptoms, such as head-
is most commonly seen in young adults between 15 and 35 years of age, ache, malaise, joint pain, and fatigue, may appear during the first 3 to
with the peak incidence between 15 and 19 years. It is rarely seen in 5 days, although some individuals are without symptoms. At the time
individuals over 40 years, and when it does occur, is more commonly of diagnosis, the individual commonly presents with the classic group
caused by cytomegalovirus (CMV). of symptoms: fever, sore throat, cervical lymph node enlargement, and
Transmission of EBV is usually through saliva from close personal fatigue. As the condition progresses, generalized lymph node enlarge-
contact (e.g., kissing, hence the term kissing disease). The virus also ment also may develop as well as enlargement of the spleen and liver
may be secreted in other mucosal secretions of the genital, rectal, and (25% to 75% of individuals). Splenic rupture is rare and can occur
respiratory tract, as well as blood. Transmission through sneezing or spontaneously or as a result of mild trauma, occurring primarily in
coughing has not been documented. The infection begins with wide- males (90%) between day 4 and day 21 after symptom onset. It is
spread invasion of the B lymphocytes, which have receptors for EBV. the most common cause of death related to IM. Other causes of the
512 CHAPTER 20  Alterations of Hematologic Function

TABLE 20-5 ESTIMATED NEW CASES AND DEATHS FROM LEUKEMIA IN THE UNITED
STATES—2007
TOTAL NEW CASES NEW CASES BY GENDER DEATHS BY GENDER
TYPES OF LEUKEMIA (PROPORTION OF NEW CASES) MALE FEMALE MALE FEMALE
All types 43,050 (100%) 24,690 19,440 12,660 9,180
Acute lymphocytic leukemia 5,330 (12%) 3,150 2,180 790 630
Chronic lymphocytic leukemia 14,990 (35%) 8,870 6,120 2,650 1,740
Acute myelogenous leukemia 12,330 (29%) 6,590 5,740 5,280 3,670
Chronic myelogenous leukemia 4,870 (11%) 2,800 2,070 190 250
Other 5,530 (13%) 3,280 2,250 3,750 2,890

Data from American Cancer Society: Cancer facts and figures—2010, Atlanta, 2010, The Society.

rare fatalities associated with IM are hepatic failure, extensive bac-

terial infection, or viral myocarditis. Other organ systems are rarely
4 QUICK CHECK 20-2
1. Explain the relationship between the early release of premature white
involved, but such involvement may be present with characteristic blood cells and a “shift-to-the-left.”
manifestations, such as fulminant hepatitis with jaundice and anemia, 2. What is meant by “shift-to-the-right”?
encephalitis, meningitis, Guillain-Barré syndrome, and Bell palsy. Eye
manifestations may include eyelid and periorbital edema, dry eyes,
keratitis, uveitis, and conjunctivitis. Pulmonary involvement is rare, Qualitative Alterations of Leukocytes
although incidences of pneumonia and respiratory failure have been Leukemias
documented in immunocompromised individuals. Reye syndrome has Leukemia is a clonal malignant disorder of the blood and blood-­
been known to develop in children with EBV infection. forming organs.13 The common pathologic feature of all forms of
IM is usually self-limiting, and recovery occurs in a few weeks; leukemia is an uncontrolled proliferation of malignant leukocytes,
severe clinical complications are rare (5%). Fatigue may last for 1 to 2 causing an overcrowding of bone marrow and decreased production
months after resolution of other symptoms. and function of normal hematopoietic cells.
The classification of leukemia is based on (1) the predominant cell
EVALUATION AND TREATMENT  The blood of affected individuals of origin (either myeloid or lymphoid) and (2) the degree of differentia-
contains an increased number of white blood cells with many atypical tion that took place before the cell became malignant (acute, with a rapid
forms. Serologic tests to determine a heterophile antibody response growth of immature blood cells, or chronic, with a slow growth of more
are necessary to diagnose EBV infection.12 Heterophilic antibodies differentiated cells) (Figure 20-6). Thus there are four types of leukemia:
are a heterogeneous group of IgM antibodies that are agglutinins acute lymphocytic (ALL) or myelogenous (AML) and chronic lympho-
against nonhuman red blood cells (e.g., horse, sheep) and are detected cytic (CLL) or myelogenous (CML).13-15 Further classification of acute leu-
by qualitative (Monospot) or quantitative (heterophile antibody test) kemias is based on characteristics that may provide significant therapeutic
methods. Use of the Monospot test is limited because other infections prognostic information, such as structure, number of cells, genetics, iden-
(e.g., CMV, adenovirus) and toxoplasmosis also produce heterophilic tification of surface markers, and histochemical staining (see Figure 20-6).
antibodies. Thus 5% to 15% of Monospot tests yield false-positive Acute leukemia is characterized by undifferentiated or immature
results. Heterophilic antibodies in the blood increase as the condi- cells, usually a blast cell. The onset of disease is abrupt and rapid. Dis-
tion progresses, although some individuals and children under 4 years ease progression results in a short survival time. In chronic leukemia,
of age do not produce them. Diagnosis of EBV infection specifically the predominant cell is more mature but does not function normally.
may be increased with newer viral-specific tests that identify EBV- The onset of the disease is gradual, and the prolonged clinical course
specific antibodies. Because these tests are more expensive and labor results in a relatively longer survival time.
intensive, they are reserved for instances when the Monospot is not Leukemia occurs with varying frequencies at different ages and is
appropriate. more common in adults than in children. It is estimated that more
Treatment is supportive and consists of rest and alleviation of than 43,050 cases of leukemia will be newly diagnosed in 2010, with
symptoms with analgesics and antipyretics. Aspirin is avoided with males having a slightly higher incidence than females (Table 20-5).
children because of its association with Reye syndrome. Streptococ- ALL is the least common type (12% of all leukemias) overall, but it is
cal pharyngitis, which occurs in 20% to 30% of cases, is treated with the most common in children. Leukemia accounts for about 31% of
penicillin or erythromycin, not ampicillin—ampicillin is known to all childhood cancers; ALL accounts for almost 74% of all new cases
cause a rash. Bed rest with avoidance of strenuous activity and contact of leukemia in children. CLL and AML (35% and 29% of leukemias,
sports is indicated. Steroids are used when severe complications, such respectively) are the most common types in adults. CML (11% of leu-
as impending airway obstruction, or other organ involvement (central kemias) is found mostly in adults. The sites of highest overall incidence
nervous system [CNS] manifestations, thrombocytopenic purpura, are the United States, Canada, Sweden, and New Zealand.
myocarditis, pericarditis) is evident. Acyclovir has been used in immu- Over the past 2 decades, remission induction rate and survival in
nocompromised individuals but is not considered standard therapy. most forms of leukemia have increased. Current survival rates range
IM and EBV infection were thought to be associated with chronic from 23% for AML to 74% for CLL. This progress is the result of
fatigue syndrome, but that is no longer the case. more effective chemotherapeutic agents, improved blood product and
 CHAPTER 20  Alterations of Hematologic Function 513

chemotherapy for Hodgkin lymphoma, non-Hodgkin lymphoma,

Normal chromosomes Philadelphia translocation
multiple myeloma, ovarian cancer, and breast cancer. Acute leukemia
also may develop secondary to certain acquired disorders, including
CML, CLL, polycythemia vera, myelofibrosis, Hodgkin lymphoma,
multiple myeloma, ovarian cancer, and sideroblastic anemia.
The leukemia blasts literally “crowd out” the marrow and cause cel-
bcr q11 lular proliferation of the other cell lines to cease. Normal granulocytic-
monocytic, lymphocytic, erythrocytic, and megakaryocytic progenitor
22
cells cease to function, resulting in pancytopenia (a reduction in all
22 cellular components of the blood).
Acute leukemias. About 85% of ALL arise from the B cell line, and
abl q34 about 15% arise from T cell lineage. A small percentage of ALL cases
have neither B nor T cell origination and are called null cell. Acute
9
leukemias are seen in both genders and in all ages, with the incidence
increasing dramatically in individuals older than 50 years. Mortality
9 for all acute leukemias in the United States is about 7 per 100,000. In
children younger than 15 years, leukemia accounts for more deaths
FIGURE 20-7  Philadelphia Chromosome. Schema of the Philadel- than any other cancer. However, leukemia deaths have declined 76%
phia (Ph) translocation (+) seen in chronic myelocytic leukemia. The in children, ages newborn to 14 years, in the United States from 1969
Ph1 chromosome results from an exchange of materials between to 2007. North American and Scandinavian countries have the highest
chromosomes 9 and 22—that is, t(9;22)(q34;q11). Because chro- mortality; Eastern European countries, Asia (except Japan), and Cen-
mosome 22 loses much more of its long arm than is translocated tral America have the lowest mortality. In past years, Japan’s mortality
to it from chromosome 9, chromosome 22 becomes much abbre- has been higher because of the atomic bombs dropped in World War
viated and is known as Ph1. (From Damjanov I, Linder J, editors: II. Blacks have consistently shown a lower mortality than whites.
Anderson’s pathology, ed 10, St Louis, 1996, Mosby.)
CLINICAL MANIFESTATIONS  The clinical manifestations of all
varieties of acute leukemia are generally similar. Mechanisms associ-
antimicrobial support, and specialized nursing care. Chemotherapy ated with common manifestations are summarized in Table 20-6.
and bone marrow transplants have significantly increased the survival Signs and symptoms related to bone marrow depression include
time for individuals with acute leukemia. fatigue caused by anemia, bleeding resulting from thrombocytopenia,
and fever caused by infection. Bleeding may occur in the skin, gums,
PATHOPHYSIOLOGY  Although the exact cause of leukemia is mucous membranes, and GI tracts. Visible signs include petechiae
unknown, several risk factors and related genetic aberrations are asso- and ecchymosis, as well as discoloration of the skin, gingival bleeding,
ciated with the onset of malignancy. There is a statistically significant hematuria, and midcycle or heavy menstrual bleeding.
tendency for leukemia to reappear in families. There is also an increased Infection sites include the mouth, throat, respiratory tract, lower
incidence of leukemia in association with other hereditary abnormali- colon, urinary tract, and skin and may be caused by gram-negative
ties such as Down syndrome, Fanconi aplastic anemia, Bloom syn- bacilli (Escherichia coli), Pseudomonas, and Klebsiella. Fever is an early
drome, trisomy 13, Patau syndrome, and some immune deficiencies sign often accompanied by chills.
(ataxia-telangiectasia, Wiskott-Aldrich syndrome, congenital X-linked Anorexia is accompanied by weight loss, diminished sensitivity to
agammaglobulinemia; see Chapter 7). sour and sweet tastes, wasting of muscle, and difficulty swallowing.
Several genetic translocations (mitotic errors) are observed in leu- Liver, spleen, and lymph node enlargement occurs more commonly
kemic cells. One of these translocations, the Philadelphia chromosome, in ALL than in CML. Liver and spleen enlargement commonly occur
is observed in 95% of those with CML and 30% of adults with ALL together. The leukemic individual often experiences abdominal pain
(Figure 20-7). The Philadelphia chromosome results from a recipro- and tenderness and also breast tenderness.
cal translocation between the long arms of chromosomes 9 and 22. A Neurologic manifestations are common and may be caused by
unique protein (bcr-abl protein) is encoded from two genes (BCR from either leukemic infiltration or cerebral bleeding. Headache, vomiting,
chromosome 22 and ABL from chromosome 9) artificially linked at papilledema, facial palsy, blurred vision, auditory disturbances, and
the junction of translocation. The bcr-abl protein affects a variety of meningeal irritation can occur if leukemic cells infiltrate the cerebral or
cell cycle control genes leading to an increased rate of cellular division, spinal meninges. Because most chemotherapeutic agents do not pen-
inhibition of DNA repair, and other dysregulations of cell growth. etrate the blood-brain barrier, leukemia cells can grow easily in these
Risk factors for the onset of leukemia include environmental fac- locations.
tors as well as other diseases. Increased risk has been linked to cigarette
smoke, exposure to benzene, and ionizing radiation. Large doses of ion- EVALUATION AND TREATMENT  Because leukemia often is con-
izing radiation particularly result in an increased incidence of myelog- fused with other conditions, early detection is difficult. Persistent
enous leukemia. Infections with HIV or hepatitis C virus increase the symptoms need intensive medical investigation. The diagnosis is made
risk for leukemia, and it is now widely accepted that some types of through blood tests and examination of bone marrow.
leukemia are caused by infection with the human T cell leukemia/lym- Chemotherapy, used in various combinations, is the treatment of
phoma virus-1 (HTLV-1). Drugs that cause bone marrow depression choice for leukemia. Supportive measures include blood transfusions,
(e.g., chloramphenicol, phenylbutazone, and certain alkylating agents, antibiotics, antifungals, and antivirals. Allopurinol is used to prevent
such as Cytoxan) also can predispose an individual to leukemia. AML uric acid production and elevation that occurs because of cellular death
is the most frequently reported secondary cancer after high doses of caused by treatment. Bone marrow transplantation as a treatment has
514 CHAPTER 20  Alterations of Hematologic Function

TABLE 20-6 CLINICAL MANIFESTATIONS AND RELATED PATHOPHYSIOLOGY IN LEUKEMIA

CLINICAL LABORATORY
MANIFESTATIONS ABNORMALITIES CAUSE COMMENTS
Anemia Relative proportion of erythroblasts Decreased stem cell input or ineffective In acute leukemia, anemia is usually present from
to total count (decreased in erythropoiesis or both beginning, often first symptom noticed, and severe;
anemia) is key mild form without symptoms is common in CML
and CLL; hemorrhage common in acute forms, oc-
casional in CML, but rare in CLL
Bleeding (purpura, Decreased and possibly abnormal Reduction in megakaryocytes leading to Bleeding more common in acute than in chronic
petechiae, ecchymosis, platelets thrombocytopenia leukemia
hemorrhage)
Infection Increased multisegmented neu- Opportunistic organisms; decreased Major sites of infection: oral cavity, throat, lower
trophils protection resulting from granulocyto- colon, urinary tract, lungs, and skin; prevention of
penia or immune deficiency secondary infection focuses on restoration of host defenses,
to chemotherapy, corticosteroids, and decreasing invasive procedures, and reducing
disease process colonization of organisms
Weight loss Decreased 24-hr urinary creatinine Condition can be attributed to pain, Severe weight loss may be related to excess produc-
excretion; hypoalbuminemia depression, chemotherapy, radiation tion of TNF-α
therapy, loss of appetite, and altera-
tions in taste
Bone pain Often no radiographic evidence of Result of bone infiltration by leukemic If combination drug regimens are ineffective, radia-
bone problems cells or intramedullary infection tion therapy is used
Liver, spleen, and lymph Biopsy abnormal for liver and Leukemic cell infiltration; lymph nodes
node enlargement spleen also undergo leukemia proliferation
in CLL
Elevated uric acid level Normal excretion of uric acid is Increased catabolism of protein and Hyperuricemia is present in both acute leukemia
300-500 mg/day; leukemic indi- nucleic acid; urate precipitation and CML; increasing urine pH or decreasing acid
vidual can excrete 50 times more increased from dehydration caused by production with drug allopurinol
anorexia or fever and drug therapy

CLL, Chronic lymphocytic leukemia; CML, chronic myelocytic leukemia; RBC, red blood cell.

increased since the 1980s. Survival rates have dramatically increased CML can occur, depending on the lineage of the malignant cells (e.g.,
because of improvements in donor matching, transfusion support, chronic neutrophilic leukemia [CNL], chronic eosinophilic leukemia
conditioning regimens, and antibiotics. [CEL]). Unlike cells in acute leukemia, chronic leukemic cells are well
The 5-year survival rate for those with leukemia is 38%, largely differentiated and can be readily identified. Individuals with chronic
because of poor survival rates of individuals with certain types of leuke- leukemia have a longer life expectancy, usually extending several years
mia (e.g., acute myelogenous). Since the 1970s, 5-year survival rates for from the time of diagnosis.
those with ALL have increased from 38% to 66% for adults and from 53% The chronic leukemias account for the majority of cases in adults
to 91% for children. Factors influencing increased survival rate include (see Table 20-5). The incidences of CLL and CML increase significantly
the use of combined and multimodality treatment methods, improved in individuals over 40 years of age, with prevalence in the sixth through
supportive services such as blood banking and nutritional support, and eighth decades. CML is a group of diseases called myeloproliferative
antimicrobial treatment. The presence of the Philadelphia chromosome disorders, which also include polycythemia vera, primary thrombo-
(observed in about 5% of children with ALL, in 30% of adults with ALL, cytosis, and idiopathic myelofibrosis (invasion of bone marrow by
and occasionally in AML) is a poor prognostic indicator. fibrous tissue).
Stimulation of blood cell growth and development with hemato-
poietic drugs has increased neutrophil recovery during chemotherapy PATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONS  Chronic
and bone marrow transplant. Blood granulocyte numbers (e.g., eosino- leukemia advances slowly and insidiously. Individuals are generally
phils, neutrophils, basophils/mast cells) are normally in the range of unaware of the condition until symptoms appear. When symptoms
4000 to 6000 cells/μl, and susceptibility to infection develops below do appear, they present as splenomegaly, extreme fatigue, weight loss,
1000 cells/μl. During a natural response to a bacterial infection, granu- night sweats, and low-grade fever. Individuals with CML may progress
locytes usually rise in number to 10,000 to 20,000 cells/μl. Leukemia through three phases of the disease: a chronic phase lasting 2 to 5 years
itself as well as the chemotherapeutic agents used to treat the disease can during which symptoms may not be apparent, an accelerated phase of 6
result in dramatic decreases in circulating granulocytes. The advent and to 18 months during which the primary symptoms develop, and a ter-
administration of colony-stimulating factors (CSFs) (e.g., granulocyte- minal blast phase with a survival of only 3 to 6 months. The acceler-
stimulating factors) can stimulate bone marrow production and raise ated phase is characterized by excessive proliferation and accumulation
white cell numbers and afford protection from infections (Table 20-7). of malignant cells. Splenomegaly is prominent and becomes painful,
Chronic leukemias. The two main types of chronic leukemia are but lymphadenopathy generally is not present. Liver enlargement also
(1) myelogenous (CML) and (2) lymphocytic (CLL). Several forms of occurs, but liver function is rarely altered. Hyperuricemia is common
 CHAPTER 20  Alterations of Hematologic Function 515

TABLE 20-7 SOME EXAMPLES OF HUMAN COLONY-STIMULATING FACTORS

CSF CELL ORIGIN CELL STIMULATED
M-CSF Macrophage, Macrophage
fibroblast
GM-CSF T cell, Neutrophil,
macrophage, monocyte, macrophage,
fibroblast eosinophils
G-CSF Macrophage, Neutrophil,
fibroblast eosinophil,
basophil
IL-3 T cell Neutrophil,
macrophage
Erythropoietin Kupffer and Erythrocyte Morphologic Effects of Growth Factor. Marrow aspirate from a patient receiving
­peritubular granulocyte colony-stimulating factor (G-CSF) showing an early neutrophil response. There
kidney cells is a marked shift toward immaturity in the neutrophils with the majority at the promyelocyte
and early myelocyte stages of maturation. (Wright-Giemsa stain.) (Courtesy Laura Schmitz,
MD, Hennepin County Medical Center, Minneapolis, Minn. From Damjanov I, Linder J, edi-
tors: Anderson’s pathology, ed 10, St Louis, 1996, Mosby.)

and produces gouty arthritis. Infections, fever, and weight loss also are and combination chemotherapy, appears to increase the survival time
seen often. The terminal blast phase is characterized by rapid and pro- more significantly. Allogeneic bone marrow transplant survival rates
gressive leukocytosis with an increase in basophils. In the later stages of have increased from 20% to 30% in 1977 to approximately 55% in
the terminal phase, which then resembles AML, blast cells or promyelo- 2006 with the use of concurrent high-dose radiation, chemotherapy,
cytes predominate, and the individual experiences a “blast crisis.” and interferon therapy.
The Philadelphia chromosome is a useful diagnostic marker for When to begin treatment for CLL is difficult to determine and is
CML and is observed in 95% of individuals with CML. The median related to the degree of symptoms. Treatment consists of alkylating
age for persons with Philadelphia chromosome-positive CML is 40 to agent or purine analog chemotherapy. Steroids and, later, splenec-
45 years. The Philadelphia chromosome, although present in red cells, tomy also may be used to control leukocytosis and cytopenias. Radia-
white cells, and platelets, appears to affect only white cell function and tion therapy may be used to alleviate lymphadenopathy. Late stages
production. Although it is difficult to identify alterations within the of the disease require combination chemotherapy. Regardless of the
cell’s structure, absent or low levels of the enzyme neutrophil alkaline approach, cure rates for CLL are poor.
phosphatase, along with decreased phagocytic capabilities, indicate
that cells fail to differentiate normally. The only known cause of CML
is exposure to ionizing radiation. 4 QUICK CHECK 20-3
CLL involves predominantly malignant transformation of B cells; 1. How are leukemias classified?
rarely (<5%) are T cells involved. The malignant transformation is 2. What is the pathogenesis of ALL?
thought to be caused by failure of the normal mechanisms of pro- 3. What is the significance of the Philadelphia chromosome, and how is it
grammed cell destruction (apoptosis), allowing these cells to have an related to leukemia?
extended life, thus the chronic nature of the disease. These cells fail to
develop into antibody-producing cells and fail to respond to stimula-
tion by helper T cells. ALTERATIONS OF LYMPHOID FUNCTION
Suppression of normal antibody production is the most signifi-
cant effect in CLL. Individuals are thus at risk for recurrent bacterial Lymphadenopathy
and other infections that are commonly sensitive to antibodies. Ane- Lymphadenopathy is characterized by enlarged lymph nodes (­Figure
mia, thrombocytopenia, and neutropenia are typically present with 20-8). Lymph node enlargement occurs because of an increase in size
overt CLL. Invasion of most organs by leukemic cells is uncommon, and number of its germinal centers caused by proliferation of lympho-
but infiltration of lymph nodes, liver, spleen, and salivary glands is cytes and monocytes (immature phagocytes) or invasion by malignant
observed. Central nervous system involvement and elevated blood lev- cells. Normally, lymph nodes are not palpable or are barely palpable.
els of calcium are rare, whereas elevated levels of lactic dehydrogenase Enlarged lymph nodes are characterized by being palpable and often
(LDH) and uric acid are common. also may be tender or painful to touch, although not in all situations.
Localized lymphadenopathy (reactive lymph nodes) usually indi-
EVALUATION AND TREATMENT  Therapeutic approaches include cates drainage of an area associated with an inflammatory or infec-
bone marrow transplantation, biologic response modifiers, and com- tious lesion. Generalized lymphadenopathy, associated with infection,
bination chemotherapy. Alone, state-of-the-art chemotherapy for occurs less often and is generally seen in the presence of malignant
CML does not cure the disease, prevent blastic transformation, or pro- or nonmalignant disease. Lymphadenopathy is of more significance in
long the average survival time. New drugs, including imatinib mesy­ adult disease than in children. The location and size of the enlarged
late, which is highly specific for CML, are being utilized. Bone marrow nodes are important factors in diagnosing the cause of the lymphade-
transplantation, when compared with biologic response modifiers nopathy, as are the individual’s age, gender, and geographic location.
516 CHAPTER 20  Alterations of Hematologic Function

FIGURE 20-8  Lymphadenopathy. Individual with lymphocyte leu-

kemia with extreme but symmetric lymphadenopathy. (Courtesy
Dr. A.R. Kagan, Los Angeles. From del Regato JA, Spjut HJ, Cox
JD: Cancer: diagnosis, treatment, and prognosis, ed 6, St Louis,
1985, Mosby.) B
FIGURE 20-9  Lymph Nodes. A, Lymphocytes and histiocytes of
Hodgkin lymphoma, nodular type. Large nodules with small, round
Generalized lymphadenopathy occurs with non-Hodgkin lymphomas, lymphocytes, histiocytes, and scattered lymphocyte and histiocyte
chronic lymphocytic leukemia, histiocytosis, and disorders that pro- cells. B, Diagnostic Reed-Sternberg cell (arrow). A large multinucle-
duce lymphocytosis. In general, lymphadenopathy results from four ated or multilobed cell with inclusion body–like nucleoli surrounded
types of conditions: (1) neoplastic disease, (2) immunologic or inflam- by a halo of clear nucleoplasm. (From Damjanov I, Linder J, editors,
matory conditions, (3) endocrine disorders, or (4) lipid storage dis- Anderson’s pathology, ed 10, St Louis, 1996, Mosby.)
eases. Diseases of unknown cause, including autoimmune diseases and
reactions to drugs, also may lead to generalized lymphadenopathy.
incidence of non-Hodgkin lymphoma has nearly doubled. The exact
Malignant Lymphomas reason for this increase remains a mystery; however, a modest portion
Lymphomas consist of a diverse group of neoplasms that develop from of the increase had been attributed to lymphomas developing in asso-
the proliferation of malignant lymphocytes in the lymphatic system. The ciation with immune deficiencies, including AIDS and organ trans-
most recent classification of lymphomas was published by the World plants. Conversely, the incidence of Hodgkin lymphoma has declined
Health Organization (WHO) and is derived from the Revised European- over the same time period, especially among elderly persons. In chil-
American Lymphoma (REAL) Classification. This classification is based dren under 15 years, Hodgkin lymphoma accounts for about 7.2% of
on the cell type from which the lymphoma probably originated. The childhood cancer and non-Hodgkin lymphoma for 6.6%. Currently
groups include Hodgkin lymphoma and two that were previously clas- the 5-year survival rates for children are 79% for all childhood cancers
sified as non-Hodgkin lymphoma (B cell neoplasms, T cell and NK cell and 96% for Hodgkin lymphoma.
neoplasms). With the new classification, multiple myeloma, which was
previously classified independently, is included as a B cell lymphoma.
Incidence rates of lymphoma differ with respect to age, gender, geo- Hodgkin Lymphoma
graphic location, and socioeconomic class. The estimated new cases of PATHOPHYSIOLOGY  Hodgkin lymphoma (HL) is characterized by
lymphoma, including multiple myeloma, for 2010 are approximately its progression from one group of lymph nodes to another, the develop-
94,210 individuals. These consist of 8490 cases of Hodgkin lymphoma, ment of systemic symptoms, and the presence of Reed-Sternberg (RS)
65,540 cases of non-Hodgkin lymphoma (except multiple myeloma), cells (Figure 20-9).16 It is widely accepted that the RS cell represents the
and 20,180 cases of multiple myeloma. It is estimated that 32,180 malignant transformation of lymph cells.17 The RS cells are often large
people will die from these diseases in 2010. Since the early 1970s, the and binucleate, with occasional mononuclear variants. The RS cells
 CHAPTER 20  Alterations of Hematologic Function 517

TABLE 20-8 SUBTYPES OF CLASSIC HODGKIN LYMPHOMA

SUBTYPE INCIDENCE PRESENTATION
Nodular sclerosis HL Most common subtype in developing countries Large tumor nodules with RS cells surrounded by collagen and
Found in all ages but most common in adolescents and young fibrous bands
adults (median age of onset is about 28 yr)
Incidence in females exceeds that in males
Mixed ­cellularity HL Second most common subtype RS cells with mixed inflammatory cell (lymphocytes, monocytes/
Incidence in males exceeds that in females macrophages, eosinophils, plasma cells) infiltrate
Lymphocyte-rich classic HL Uncommon subtype Few RS cells and ­predominantly lymphocytic infiltration
Found in all ages but most common in adults Usually localized at diagnosis
Incidence in males exceeds that in females Survival is long with or without treatment
Lymphocyte depletion HL Uncommon subtype Large number of RS cells with less additional c­ ellular infiltrate
Most common type in elderly persons, HIV-positive Usually widespread disease: abdominal lymphadenopathy;
­individuals, and persons in nonindustrialized countries spleen, liver, and bone marrow involvement, without p­ eripheral
Incidence in males exceeds that in females ­lymphadenopathy
Stage is usually more advanced at diagnosis

are necessary for the diagnosis of HL; however, they are not specific to
HL. In rare instances, cells resembling RS cells can be found in benign
illnesses, as well as in other forms of cancer, including non-Hodgkin
lymphomas and solid tissue cancers and in infectious mononucleosis.
The incidence of HL is approximately 3.0/100,000 males and
2.6/100,000 females and peaks at two different times—during the sec-
ond and third decades of life and later during the sixth and seventh
decades. The incidence is greater in whites than blacks, with Denmark,
the Netherlands, and the United States having the highest incidence
and Japan and Australia having the lowest. The overall incidence is
lower in economically disadvantaged countries, although a greater
proportion of HL is observed in the elderly in those countries.
The triggering mechanism for the malignant transformation of
cells remains unknown. Classical HL appears to be derived from a B
cell in the germinal center that has not undergone successful immu-
noglobulin gene rearrangement (see Chapter 6) and would normally
be induced to undergo apoptosis. Survival of this cell may be linked
to infection with Epstein-Barr virus (EBV). Laboratory and epidemio-
logic studies have linked HL with EBV infections and EBV DNA, RNA,
and proteins are frequently observed in HL cells.18 The RS cells secrete
and release cytokines (e.g., IL-10, transforming growth factor-beta
[TGF-β]) that result in the accumulation of inflammatory cells that
produces the local and systemic effects. Classical HL is subclassified
into four types (Table 20-8) based on the morphology of RS cells, and
the characteristics of the inflammatory cell infiltrate in the tumor. FIGURE 20-10  Hodgkin Lymphoma and Enlarged Cervical
Lymph Node. Typical enlarged cervical lymph node in the neck
CLINICAL MANIFESTATIONS  Many clinical features of HL can be (arrow) of a 35-year-old woman with Hodgkin lymphoma. (From del
explained by the complex action of cytokines and other growth fac- Regato JA, Spjut HJ, Cox JD: Cancer: diagnosis, treatment, and
tors that are secreted and released by the malignant cells. These sub- prognosis, ed 6, St Louis, 1985, Mosby.)
stances induce infiltration and proliferation of inflammatory cells,
resulting in an enlarged, painless lymph node in the neck (often the staging classification system used for HL is able to establish a corre-
first sign of HL) (Figure 20-10). The discovery of an asymptomatic lation between the anatomic extent of the disease and the prognosis
mediastinal mass on routine chest x-ray is not uncommon. The cer- (Table 20-9). This classification system is based on the individual’s
vical, axillary, inguinal, and retroperitoneal lymph nodes are com- medical history, examination (presence of symptoms and palpa-
monly affected in HL (Figure 20-11). Local symptoms caused by ble lymph nodes), and other radiologic and hematologic results.
pressure and obstruction of the lymph nodes are the result of the Prognostic indicators include clinical stage, histologic type, tumor
lymphadenopathy. cell concentration and tumor burden, constitutional symptoms,
About a third of individuals will have some degree of systemic and age.
symptoms. Intermittent fever, without other symptoms of infec- Although HL rarely arises in the lung, mediastinal and hilar node
tion, drenching night sweats, itchy skin (pruritus), and fatigue are adenopathy can cause secondary involvement of the trachea, bronchi,
relatively common. These constitutional symptoms accompanied pleura, or lungs. Retroperitoneal nodes can involve vertebral bodies
by weight loss are associated with a poor prognosis. The Cotswold and nerves and also can cause displacement of ureters. Spinal cord
518 CHAPTER 20  Alterations of Hematologic Function

TABLE 20-9 DEFINITIONS OF STAGES OF

Epitrochlear HODGKIN DISEASE
and brachial
nodes STAGE CRITERIA
Left cervical I Involvement of a single lymph node region (I) or localized
supraclavicular Left axillary nodes involvement of a single extralymphatic organ or site (IE)*
nodes II Involvement of two or more lymph node regions on same side
Right cervical of diaphragm (II) or localized involvement of a single associ-
supraclavicular
ated extralymphatic organ or site and its regional lymph
nodes Retroperitoneal
Right axillary node(s), with or without involvement of other lymph node
nodes (located regions on same side of diaphragm (IIE)
nodes behind the
peritoneum) III Involvement of lymph node regions on both sides of dia-
Epitrochlear
phragm (III), which may also be accompanied by localized
and brachial Mesenteric nodes
nodes involvement of an associated extralymphatic organ or site
Right inguinal (IIIE), by involvement of spleen (IIIS), or by both (IIIE+S).
Left inguinal
nodes IV Disseminated (multifocal) involvement of one or more extra-
nodes
lymphatic organs, with or without associated lymph node
Common involvement, or isolated extralymphatic organ involvement
site with distant (nonregional) nodal involvement
Popliteal nodes Uncommon A: No systemic symptoms present
site B: Unexplained fevers >38° C, drenching night sweats, or weight loss >10%
of body weight

From NCCN: Hodgkin lymphoma. In NCCN practice guidelines in

oncology Cold Spring Publishing Huntington New York, vol 2, 2010.
(Originally adapted from Carbono PP et al: Report of the Committee on
Hodgkin’s Disease Staging Classification, Cancer Res 31[11]:
1860–1861, 1971.)
FIGURE 20-11  Common and Uncommon Involved Lymph *note: The number of lymph node regions involved may be indicated
Node Sites for Hodgkin Lymphoma. by a subscript (e.g., II3).

involvement is more common in the dorsal and lumbar regions than chemotherapy with or without additional radiation treatment. Those
in the cervical region. Skin lesions, although uncommon, include pso- with stage I or II disease are candidates for chemotherapy, combined
riasis and eczematoid lesions, causing itching and scratching. chemotherapy, or radiation therapy alone. The survival rate depends
As a result of direct invasion from mediastinal lymph nodes, peri- on many factors, including the age and gender of the individual, the
cardial involvement can cause pericardial friction rub, pericardial effu- stage of the disease, and other variables. The 5-year survival rate in
sion, and engorgement of neck veins. The GI tract and urinary tract are persons under age 20 is 96%; the survival rate for adults is 88%.
rarely involved. Anemia is often found in individuals with HL accom-
panied by a low serum iron level and reduced iron-binding capacity. Non-Hodgkin Lymphomas
Other laboratory findings include elevated sedimentation rate, leuko- The previously used generic classification of non-Hodgkin lymphoma
cytosis, and eosinophilia. Leukopenia occurs in advanced stages of HL. has been reclassified in the WHO/REAL scheme into (1) B cell neo-
Splenic involvement in HL depends on histologic type. In mixed plasms, a group that consists of a variety of lymphomas including
cellularity and lymphocytic deletion types of HL, the spleen is involved myelomas that originate from B cells at various stages of differentia-
in 60% of cases. With lymphocyte and nodular sclerosis types, 34% of tion, and (2) T cell and NK cell neoplasms, a group that includes lym-
cases involve the spleen. phomas that originate from either T or NK cells. These cancers are
differentiated from HL by lack of RS cells and other cellular changes
EVALUATION AND TREATMENT  Because of the variability in not characteristic of HL.
symptoms, early definitive detection may be difficult. Asymptomatic Because malignant changes can occur at various stages of B cell,
lymphadenopathy can progress undetected for several years. Careful T cell, or NK cell development, these cancers present with a variety
evaluation, including chest x-ray films, positron emission tomography of clinical states. In the following section, the types of tumors previ-
(PET) scans, and biopsy, should be carried out for individuals with ously classified as non-Hodgkin lymphoma are considered together,
fever of unknown origin and peripheral lymphadenopathy. A lymph and myeloma is described separately.
node biopsy with scattered RS cells and a cellular infiltrate is highly
indicative of HL. The effectiveness of treatment is related to the age PATHOPHYSIOLOGY  As with all cancers, lymphomas most likely
of the individual and the extent of the disease. Approximately 75% originate from mutations in cellular genes (many of which are envi-
of individuals diagnosed with HL can be cured, largely because of ronmentally induced) in a single cell that lead to loss of control of pro-
successful treatment of HL with irradiation and chemotherapy. The liferation and other aspects of cell growth. The most common type of
5-year survival rate is 83%. chromosomal alteration in non-Hodgkin lymphoma (NHL) is trans-
Persons with stage III or IV disease, bulky disease (>10-cm mass or location, which disrupts the genes encoded at the breakpoints. Risk
mediastinal disease with a transverse diameter exceeding 33% of the factors include a family history, exposure to a variety of mutagenic
transthoracic diameter), or presence of B symptoms require combined chemicals, irradiation, infection with certain cancer-related viruses
 CHAPTER 20  Alterations of Hematologic Function 519

TABLE 20-10 CLINICAL DIFFERENCES

BETWEEN NON-HODGKIN
LYMPHOMA AND HODGKIN
LYMPHOMA
NON-HODGKIN HODGKIN
CHARACTERISTICS LYMPHOMA LYMPHOMA
Nodal involvement Multiple peripheral Localized to single
nodes axial group of nodes
(i.e., cervical, medi-
astinal, paraaortic)
Mesenteric nodes and Mesenteric nodes and
Waldeyer ring Waldeyer ring rarely
commonly involved involved
Spread Noncontiguous Orderly spread by
contiguity
B symptoms* Uncommon Common
Extranodal involvement Common Rare
Extent of disease Rarely localized Often localized

*Fever, weight loss, night sweats. FIGURE 20-12  Burkitt Lymphoma. Burkitt lymphoma involving
the jaw in a young African boy. (Courtesy Dr. J.N.P. Davies, Albany,
NY. From del Regato JA, Spjut HJ, Cox JD: Cancer: diagnosis, treat-
(e.g., Epstein-Barr virus, human herpesvirus-8, HIV, HTLV-1, hepa- ment, and prognosis, ed 6, St Louis, 1985, Mosby.)
titis C), and immune suppression related to organ transplantation.
Gastric infection with Helicobacter pylori increases the risk for gastric in a variety of autoimmune diseases, including immune thrombocyto-
lymphomas. NHL is a disease of middle age, usually found in persons penia purpura, autoimmune anemias, systemic lupus erythematosus,
over 50 years old. and rheumatoid arthritis.
Burkitt lymphoma. Burkitt lymphoma is a B cell tumor with unique
CLINICAL MANIFESTATIONS  Clinical manifestations of NHL usu- clinical and epidemiologic features that accounts for 30% of childhood
ally begin as localized or generalized lymphadenopathy, similar to lymphomas worldwide. It occurs in children from east-central Africa
HL. Differences in clinical features are noted in Table 20-10. The cer- and New Guinea and is characterized by a facial mass around the jaw
vical, axillary, inguinal, and femoral chains are the most commonly (Figure 20-12). In the United States, Burkitt lymphoma is rare, usually
affected sites. Generally, the swelling is painless and the nodes have involves the abdomen, and is characterized by extensive bone marrow
enlarged and transformed over a period of months or years. Other sites invasion and replacement.
of involvement are the nasopharynx, GI tract, bone, thyroid, testes,
and soft tissue. Some individuals have retroperitoneal and abdominal PATHOPHYSIOLOGY  Epstein-Barr virus (EBV) is associated with
masses with symptoms of abdominal fullness, back pain, ascites (fluid almost all cases (>90%) of Burkitt lymphoma. It is suspected that sup-
in the peritoneal cavity), and leg swelling. pression of the immune system by other illnesses (e.g., HIV infection,
chronic malaria) increases the individual’s susceptibility to EBV. B
EVALUATION AND TREATMENT  Individuals with NHL can survive cells are particularly sensitive because of specific surface receptors for
for extended periods. Survival with nodular lymphoma ranges up to 15 EBV. As a result, the B cell undergoes chromosomal translocations that
years. Individuals with diffuse disease generally do not survive as long. result in overexpression of the c-myc proto-oncogene and loss of con-
Overall, the survival rates for NHL are less than those for Hodgkin trol of cell growth. The most common translocation (75% of individu-
lymphoma. For NHL, the survival rates are 1 year, 80%; 5 years, 67%; als) is between chromosomes 8 (containing the c-myc gene) and 14
and 10 years, 56%. Many investigators think that more aggressive treat- (containing the immunoglobulin heavy chain genes). Other transloca-
ment increases the cure rate. High-grade NHL is seen with increasing tions have been reported between chromosome 8 and chromosomes 2
frequency in persons with AIDS and has an extremely poor prognosis. or 22, which contain genes for immunoglobulin light chains.
Success of treatment is dependent on several parameters, including
the type of lymphoma, stage of disease, cell type, involvement of organs CLINICAL MANIFESTATIONS  In non-African Burkitt lymphoma
outside the lymph nodes, age of the person, and the severity of the the most common presentation is abdominal swelling. More advanced
body’s reaction to the disease (e.g., fever, night sweats, weight loss).19 disease may involve other organs—eyes, ovaries, kidneys, glandular
Treatment includes chemotherapy alone in many cases, although tissue (breast, thyroid, tonsil)—and presents with type B symptoms
radiation therapy is frequently included. Low-dose chemotherapy has (night sweats, fever, weight loss).
been followed by autologous stem cell transplantation in some indi-
viduals with NHL or for recurrent disease. Treatment of B cell lympho- EVALUATION AND TREATMENT  The distribution of tumors and
mas with rituximab has proven effective. Rituximab is a commercial the results of biopsy of enlarged lymph nodes or the bone marrow con-
monoclonal antibody against antigen CD20, which is expressed on taining malignant B cells are usually indicative of Burkitt lymphoma.
the surface of all B cells, including malignant ones. Administration of It is one of the most aggressive and quickly growing malignancies.
rituximab depletes most B cells and allows the replenishment of nor- However, the African variety in children has been successfully treated
mal B cells from the lymphoid stem cell pool. It has also proven useful with radiotherapy and cyclophosphamide (60% survival overall; 90%
520 CHAPTER 20  Alterations of Hematologic Function

cells return to either the bone marrow or other soft tissue sites. Their
return is aided by cell adhesion molecules that help them target favor-
able sites that promote continued expansion and maturation. Cyto-
kines, particularly interleukin-6 (IL-6), have been identified as essential
factors that promote the growth and survival of multiple myeloma
cells. (Lymphocytes and cytokines are described in Chapter 6.)
Myeloma cells in the bone marrow produce several cytokines them-
selves (e.g., IL-6, IL-1, TNF-α). IL-6 in particular acts as an osteoclast-
activating factor and stimulates osteoclasts to reabsorb bone. This
process results in bone lesions and hypercalcemia (high calcium levels
in the blood) attributable to the release of calcium from the breakdown
of bone.
The antibody produced by the transformed plasma cell is fre-
quently defective, containing truncations, deletions, and other abnor-
malities, and is often referred to as a paraprotein (abnormal protein in
FIGURE 20-13  Multiple Myeloma, Bone Marrow Aspirate. Nor- the blood). Because of the large number of malignant plasma cells, the
mal marrow cells are largely replaced by plasma cells, including abnormal antibody, called the M protein, becomes the most promi-
atypical forms with multiple nuclei (arrow), and cytoplasmic drop- nent protein in the blood (see Figure 20-15). Suppression of normal
lets containing immunoglobulin. (From Kumar V, Abbas AK, Fausto plasma cells by the myeloma results in diminished or absent normal
N: Robbins and Cotran pathologic basis of disease, ed 7, Philadel- antibodies. The excessive amount of M protein may also contribute
phia, 2005, Saunders.) to many of the clinical manifestations of the disease. If the myeloma
produces IgM (Waldenström macroglobulinemia), the excessive
amount of large molecule weight proteins (about 900,000 daltons) can
survival with limited disease). The American type is more resistant to lead to abnormally high blood viscosity (hyperviscosity syndrome).
treatment. Frequently, the myeloma produces free immunoglobulin light chain
Multiple myeloma. Multiple myeloma (MM) is a B cell cancer char- (Bence Jones protein) that is present in the blood and urine and con-
acterized by the proliferation of malignant plasma cells that infiltrate the tributes to damage of renal tubular cells.
bone marrow and aggregate into tumor masses throughout the skeletal
system (Figure 20-13).20 The reported incidence of MM has doubled in CLINICAL MANIFESTATIONS  The common presentation of MM is
the past 2 decades, possibly as a result of more sensitive testing used for characterized by elevated levels of calcium in the blood (hypercalce-
diagnosis. The annual incidence rate in the United States is 5/100,000, mia), renal failure, anemia, and bone lesions. The hypercalcemia and
with 20,180 new cases estimated for 2010. Multiple myeloma occurs bone lesions result from infiltration of the bone by malignant plasma
in all races, but the incidence in blacks is about twice that of whites. It cells and stimulation of osteoclasts to reabsorb bone. This process
rarely occurs before the age of 40 years—the peak age of incidence is results in the release of calcium (hypercalcemia) and development of
about 70 years. It is slightly more common in men (11,170 estimated “lytic lesions” (round, “punched out” regions of bone) (Figure 20-14).
new cases) than women (9010 new cases). It is estimated that approxi- Destruction of bone tissue causes pain, the most common present-
mately 10,650 people in the United States will die of MM in 2010. ing symptom, and pathologic fractures. The bones most commonly
Neoplastic cells of multiple myeloma reside in the bone marrow involved, in decreasing order of frequency, are the vertebrae, ribs,
and are usually not found in the peripheral blood. Occasionally, how- skull, pelvis, femur, clavicle, and scapula. Spinal cord compression,
ever, it may spread to other tissues, especially in very advanced disease. because of the weakened vertebrae, occurs in about 10% of individuals.
The basic defect is genetic, which may result from chronic stimulation Proteinuria is observed in 90% of individuals. Renal failure may be
of B cells with bacterial or viral antigens. either acute or chronic and is usually secondary to the hypercalcemia.
Bence Jones protein is present in about 80% of cases and may also lead
PATHOPHYSIOLOGY  Most, if not all, multiple myelomas involve to damage of the proximal tubules. Anemia is usually normocytic and
chromosomal translocations (breakpoints), which recur in many indi- normochromic and results from inhibited erythropoiesis caused by
viduals. In about half of MM cases, one of the chromosomal partners is tumor cell infiltration of the bone marrow.
14 (site of genes for the immunoglobulin heavy chain), which recom- The high concentration of paraprotein in the blood, particularly
bines with a number of other chromosomal sites of oncogenes, most associated with the large-molecular-weight IgM produced in Walden-
commonly 11(q13), 4(p16), 16(q23), 20(q11), and 6(p25), resulting ström macroglobulinemia, may lead to hyperviscosity syndrome. The
in probable dysregulation of the oncogenes. Breaks in 11q13 occur increased viscosity interferes with blood circulation to various sites
in about 25% of multiple myelomas and are associated with a more (brain, kidneys, extremities). IgM paraprotein may also result in cryo-
aggressive disease and a poorer prognosis. Deletions in chromosome globulins (proteins that precipitate from the blood at lower than body
13 are observed in about 50% of cases. The molecular pathogenesis of temperature). Hyperviscosity syndrome is observed in up to 20% of
multiple myeloma also involves proto-oncogene mutations and, more persons. Additional neurologic symptoms (e.g., confusion, headaches,
rarely, inactivation of tumor-suppressor genes. The precise timing and blurred vision) may occur secondary to hypercalcemia or hyperviscosity.
reason for the genetic alteration and accumulation are unknown. Suppression of the humoral (antibody-mediated) immune response
Malignant plasma cells arise from one clone of B cells that produce results in repeated infections, primarily pneumonias and pyelonephri-
abnormally large amounts of one class of immunoglobulin (usually tis. The most commonly involved organisms are encapsulated bacte-
IgG, occasionally IgA, and rarely IgM, IgD, or IgE). The malignant ria that are particularly sensitive to the effects of antibody; pneumonia
transformation may begin early in B cell development, possibly before caused by Streptococcus pneumoniae, Staphylococcus aureus, or Klebsi-
encountering antigen in the secondary lymphoid organs. The myeloma ella pneumoniae or pyelonephritis caused by Escherichia coli or other
 CHAPTER 20  Alterations of Hematologic Function 521

A recent addition to treatment of MM in individuals who have a

relapse after conventional chemotherapy is the drug thalidomide. The
use of thalidomide in treating MM is based on its suppression of TNF-α
and its anti-angiogenesis ability.

4 QUICK CHECK 20-4

1. Define multiple myeloma and discuss its pathogenesis.
2. Describe the features of a clonal disorder. Give an example.
3. How is lymphadenopathy related to infection?

Lymphoblastic lymphoma. Lymphoblastic lymphoma (LL) is a

relatively rare variant of NHL overall (2% to 4%) but accounts for
almost a third of cases of NHL in children and adolescents, with a male
predominance. The vast majority of LL (90%) is of T cell origin, and
the remainder arises from B cells. LL is similar to acute lymphoblastic
leukemia and may be considered a variant of that disease.

A B PATHOPHYSIOLOGY  The disease arises from a clone of relatively

immature T cells that becomes malignant in the thymus. As with most
FIGURE 20-14  Multiple (Plasma Cell) Myeloma. A, Roentgeno- lymphoid tumors, LL is frequently associated with translocations, pri-
gram of femur showing extensive bone destruction caused by
marily of the chromosomes that encode for the T cell receptor (chro-
tumor. Note absence of reactive bone formation. B, Gross speci-
men from same individual; myelomatous sections appear as dark
mosomes 7 and 14). These aberrations result in increased expression of
granular sections. (From Kissane JM, editor: Anderson’s pathology, a variety of transcription factors and loss of growth control.
ed 9, St Louis, 1990, Mosby.)
CLINICAL MANIFESTATIONS  The first sign of LL is usually a pain-
less lymphadenopathy in the neck. Peripheral lymph nodes in the
gram-negative organisms. Cell-mediated (T cell) function is relatively chest become involved in about 70% of individuals. Involved nodes
normal. Overwhelming infection is the leading cause of death from MM. are located mostly above the diaphragm. LL is a very aggressive tumor
that presents as stage IV in most people. T cell LL is associated with a
EVALUATION AND TREATMENT  Diagnosis of MM is made by symp- unique mediastinal mass (up to 75%) because of the apparent origin of
toms, radiographic and laboratory studies, and a bone marrow biopsy. the tumor in the thymus. The mass results in dyspnea and chest pain
Quantitative measurements of immunoglobulins (IgG, IgM, IgA) are and may cause compression of bronchi or the superior vena cava. The
usually performed. Typically, one class of immunoglobulin (the M pro- tumor may infiltrate the bone marrow in about half of those affected,
tein produced by the myeloma cell) is greatly increased, whereas the and suppression of bone marrow hematopoiesis leads to increased
others are suppressed. Serum electrophoretic analysis shows increased susceptibility to infections. Other organs, including the liver, kidney,
levels of M protein (Figure 20-15). Because the M protein is monoclo- spleen, and brain, may also be affected. Many individuals express type
nal, each molecule has the same electric charge and migrates at about B symptoms: fever, night sweats, and significant weight loss.
the same site on electrophoresis, resulting in a highly concentrated pro-
tein (M spike) (see Figure 20-15). Bence Jones protein is observed in EVALUATION AND TREATMENT  The most common therapeutic
the urine or serum by immunoelectrophoresis or in the serum using approach is combined chemotherapy. In early disease, the response
newly available enzyme-linked immunosorbent (ELISA) assays. Usu- rate is high with increased survival; the 5-year survival in children is
ally an intact antibody paraprotein coexists with Bence Jones protein. 80% to 90%, and it is 45% to 55% in adults. Disease-free survival rates
However, variants of MM include individuals in which free light chain at 5 years range from 70% to 90% in children and from 45% to 55% in
only is produced and a rare variant that produces only free heavy chain. adults. Although LL is easily treated, there is a high relapse rate: 40%
Measurement of another protein, free β2-microglobulin, is used as an to 60% of adults.
indicator of prognosis or effectiveness of therapy.
Although chemotherapy, radiation therapy, and marrow transplant
ALTERATIONS OF SPLENIC FUNCTION
have been used for treatment, the prognosis for persons with MM
remains poor. A mainstay of all treatments is corticosteroids (predni- In the past, splenomegaly (enlargement of the spleen) has been associ-
sone and/or dexamethasone). Autologous peripheral blood stem cell ated with various disease states. It is now recognized that splenomegaly
transplantation is preferred to bone marrow transplantation. Contro- is not necessarily pathologic; an enlarged spleen may be present in cer-
versial is whether tandem transplant offers the best outcome. Biphos- tain individuals without any evidence of disease. Splenomegaly may be,
phonate therapy is the primary treatment for bone lesions. However, however, one of the first physical signs of underlying conditions, and
individuals with multiple bone lesions, if untreated, rarely survive more its presence should not be ignored. In conditions where splenomegaly
than 6 to 12 months. Individuals with inactive (indolent) myeloma, is present, the normal functions of the spleen may become overactive,
however, can survive for many years. With chemotherapy and aggres- producing a condition known as hypersplenism.
sive management of complications, the prognosis can improve sig- Current diagnostic criteria for hypersplenism include: (1) ­anemia,
nificantly, with a median survival of 24 to 30 months and a 10-year leukopenia, thrombocytopenia, or combinations of these; (2) cel-
survival rate of 3%. The 3-year survival for all stages of MM is 58%. lular bone marrow; (3) splenomegaly; and (4) improvement after
522 CHAPTER 20  Alterations of Hematologic Function

Normal serum Monoclonal gammopathy serum

M spike in gamma region

PEL PEL

AIb 1 2   AIb 1 2  

PEL PEL

G G

A A
IFE IFE
M M

K K

L L
A B C
FIGURE 20-15  M Protein. Serum protein electrophoresis (PEL) is used to screen for M proteins
in multiple myeloma. A, In normal serum the proteins separate into several regions between albu-
min (Alb) and a broad band in the gamma (γ) region, where most antibodies (gamma globulins) are
found. Immunofixation (IFE) can identify the location of IgG (G), IgA (A), IgM (M), and kappa (K)
and lambda (L) light chains. B, Serum from an individual with multiple myeloma contains a sharp
M protein (M spike). The M protein is monoclonal and contains only one heavy chain and one light
chain. In this instance the IFE identifies the M protein as an IgG containing a lambda light chain.
C, Serum and urine protein electrophoretic patterns in an individual with multiple myeloma. Serum
demonstrates an M protein (immunoglobulin) in the gamma region, and the urine has a large amount
of the smaller-sized light chains with only a small amount of the intact immunoglobulin. (A and B
from Abeloff M et  al: Abeloff’s clinical oncology, ed 4, Philadelphia, 2008, Churchill Livingstone.
C from McPherson R, Pincus M: Henry’s clinical diagnosis and management by laboratory methods,
ed 21, Edinburgh, 2006, Saunders.)

splenectomy. Some individuals may seek treatment for problems even The white cells and platelets also are affected by sequestering,
though they have not met all the above clinical criteria; therefore, the although not to the same degree as the red cell. The degree of red cell
relevance and significance of hypersplenism are still uncertain. Primary destruction and the diluting effect are determined by the degree of
hypersplenism is recognized when no etiologic factor has been identified; spleen enlargement.
secondary hypersplenism occurs in the presence of another condition.
CLINICAL MANIFESTATIONS  Specific diseases or particular condi-
PATHOPHYSIOLOGY  Overactivity of the spleen results in hemato- tions related to the various classifications of splenomegaly are detailed
logic alterations that affect all three blood components. Splenic seques- in Box 20-1. Different pathologic processes that produce splenomegaly
tering of red cells, white cells, and platelets results in a reduction of are briefly described here.
all circulating blood cells. Up to 50% of red cells may be sequestered; Acute inflammatory or infectious processes cause splenomeg-
however, the rate of splenic pooling is directly related to spleen size and aly because of increased demand for defensive activities. An acutely
the degree of increased blood flow through it. Sequestering exposes the enlarged spleen secondary to infection may become so filled with
red cells to splenic activities, which accelerates their destruction, caus- erythrocytes that its natural rubbery resilience is lost and it becomes
ing further reductions in red cell concentration. Anemia is the result of fragile and vulnerable to blunt trauma. Splenic rupture is a complica-
these combined actions. Anemia is further potentiated by an increased tion associated with infectious mononucleosis.
blood volume, producing a dilutional effect on the already reduced red Congestive splenomegaly is accompanied by ascites, portal hyper-
cell concentration. tension, and esophageal varices and is most commonly seen in hepatic
 CHAPTER 20  Alterations of Hematologic Function 523

circulating platelets, and thrombocythemia, an increase in the num-

BOX 20-1 DISEASES RELATED TO
ber of platelets. Qualitative disorders affect the structure or function
CLASSIFICATION OF of individual platelets and can coexist with the quantitative disorders.
SPLENOMEGALY Qualitative disorders usually prevent platelet adherence and aggrega-
Inflammation or Infection tion, thereby preventing formation of a platelet plug.
Acute: viral (hepatitis, infectious mononucleosis, cytomegalovirus), bacterial
(salmonella, gram negative), parasitic (typhoid) Thrombocytopenia
Subacute or chronic: bacterial (subacute bacterial endocarditis, tuberculosis), Thrombocytopenia is defined as a platelet count below 150,000/mm3
parasitic (malaria), fungal (histoplasmosis), Felty syndrome, systemic lupus of blood, although most individuals do not consider the decrease
erythematosus, rheumatoid arthritis, thrombocytopenia significant unless it falls below 100,000/mm3, and the risk for hem-
orrhage associated with minor trauma does not appreciably increase
Congestive until the count falls below 50,000/mm3. Spontaneous bleeding without
Cirrhosis, heart failure, portal vein obstruction (portal hypertension), splenic trauma can occur with counts ranging from 10,000/mm3 to 15,000/
vein obstruction mm3. When this happens, skin manifestations (i.e., petechiae, ecchy-
moses, and larger purpuric spots) are observed or frank bleeding from
Infiltrative mucous membranes occurs. Severe bleeding results if the count falls
Gaucher disease, amyloidosis, diabetic lipemia below 10,000/mm3 and can be fatal if it occurs in the gastrointestinal
tract, respiratory tract, or central nervous system.
Tumors or Cysts
Before thrombocytopenia is diagnosed, the presence of a pseudo-
Malignant: polycythemia rubra vera, chronic or acute leukemias, Hodgkin lym-
thrombocytopenia must be ruled out. This phenomenon is seen in
phoma, metastatic solid tumors
approximately 1 in 1000 to 10,000 samples and results from an error in
platelet counting when a blood sample is analyzed by an automated cell
Nonmalignant: Hamartoma
counter. Platelets in the blood can become nonspecifically agglutinated
Cysts: true cysts (lymphangiomas, hemangiomas, epithelial, endothelial); false
by immunoglobulins in the presence of ethylenediaminetetraacetic acid
cysts (hemorrhagic, serous, inflammatory)
(EDTA) and are not counted, thus giving an apparent, but false, throm-
bocytopenia. Thrombocytopenia also may be falsely diagnosed because
of a dilutional effect observed after massive transfusion of platelet-poor
cirrhosis. Splenic hyperplasia develops in any disorder in which splenic packed cells to treat a hemorrhage. This is observed when more than
workload is increased and is most commonly associated with various 10 units of blood have been transfused within a 24-hour period. The
types of anemias (hemolytic) and chronic myeloproliferative disorders precipitating hemorrhage also depletes platelets, contributing to the
(i.e., polycythemia vera). pseudothrombocytopenic state. Splenic sequestering of platelets in
Infiltrative splenomegaly is caused by engorgement of the mac- hypersplenism also stimulates thrombocytopenia. Hypothermia (<25°
rophages with indigestible materials associated with various “storage C) also predisposes to a thrombocytopenic state, which is reversed when
diseases.” Tumors and cysts are neoplastic disorders that cause actual temperatures return to normal, suggesting sequestering and release.
growth of the spleen. Metastatic tumors of the spleen are rare and may
result from skin, lungs, breast, and cervical primary sites. PATHOPHYSIOLOGY  Thrombocytopenia results from decreased
platelet production, increased consumption, or both. The condition
EVALUATION AND TREATMENT  Treatment for hypersplenism is may also be either congenital or acquired and may be either primary
splenectomy; however, it may not always be indicated. A splenectomy or secondary to other conditions.21,22 Thrombocytopenia secondary to
is performed when its removal is considered necessary, eliminating its congenital conditions occurs in a large number of different diseases,
destructive effects on red cells. Clinical indicators should determine the although each is relatively rare.23 These include thrombocytopenia–
needs for splenectomy, not necessarily specific conditions. Splenectomy absent radius (TAR) syndrome, Wiskott-Aldrich syndrome (see Chap-
for splenic rupture is no longer considered mandatory because of the ter 7), various forms of MYH9 gene mutation (e.g., May-Hegglin
possibility of overwhelming sepsis after removal. Repair and preservation syndrome), X-linked thrombocytopenia, and many other examples.
should be considered before the decision to remove the spleen is made. Acquired thrombocytopenia is more common and may occur in
relationship to acute viral infections (EBV, rubella, CMV, and HIV),
drug reactions, autoimmune diseases, nutritional deficiencies, ane-
4 QUICK CHECK 20-5 mia (e.g., aplastic anemia), or cancer. Thrombocytopenia that results
1. Contrast the principal features of Hodgkin lymphoma with those of non- from decreased platelet production is usually the result of nutritional
Hodgkin lymphoma. deficiencies (vitamin B12 or folic acid, in particular), some infections
2. What is Burkitt lymphoma? (e.g., HIV), drugs (e.g., thiazides, estrogens, quinine-containing medi-
3. Identify the major causes of splenomegaly. How does it differ from cations, chemotherapeutic agents, ethanol), radiation therapy, bone
hypersplenism? marrow infiltration by some cancers, bone marrow hypoplasia (aplas-
tic anemia), or chronic renal failure.
Most common forms of thrombocytopenia are the result of
ALTERATIONS OF PLATELETS AND COAGULATION increased platelet consumption. Examples include heparin-induced
thrombocytopenia, idiopathic (immune) thrombocytopenia purpura,
Disorders of Platelet Function thrombotic thrombocytopenia purpura, and disseminated intravascu-
Quantitative or qualitative abnormalities of platelets can interrupt lar coagulation (discussed later in this chapter).
normal blood coagulation and prevent hemostasis. The quantitative Heparin-induced thrombocytopenia. Heparin is the most com-
abnormalities are thrombocytopenia, a decrease in the number of mon cause of drug-induced thrombocytopenia.24 Approximately 4%
524 CHAPTER 20  Alterations of Hematologic Function

of ­individuals treated with unfractionated heparin develop heparin- GPIa/IIa). The antibodies bind directly to the platelet antigens, after
induced thrombocytopenia (HIT). The incidence is lower (about which the antibody-coated platelets are recognized and removed from
0.1%) with the use of low-molecular-weight heparin. The onset of HIT the circulation by macrophages in the spleen.
is most common in people undergoing surgery. HIT is an immune-
mediated, adverse drug reaction caused by IgG antibodies primarily CLINICAL MANIFESTATIONS  Initial manifestations range from
against the heparin–platelet factor 4 complex. The IgG binds to plate- minor bleeding problems (development of petechiae and purpura)
let Fc receptors and activates platelet aggregation, release of additional over the course of several days to major hemorrhage from mucosal
platelet factor 4, and activation of thrombin, resulting in decreased sites (epistaxis, hematuria, menorrhagia, bleeding gums). Rarely will
platelet counts 5 to 10 days after heparin administration. If HIT is not an individual present with intracranial bleeding or other sites of inter-
recognized and treated, intravascular aggregation of platelets causes nal bleeding.
rapid development of arterial and venous thrombosis.
EVALUATION AND TREATMENT  Diagnosis is based on a history
CLINICAL MANIFESTATIONS  The hallmark of HIT is thrombocy- of bleeding and associated symptoms (weight loss, fever, headache).
topenia. However, 30% or more of those with thrombocytopenia are Physical examination includes notations on the types of bleeding,
also at risk for thrombosis. Venous thrombosis is more common and location, and severity of bleeding. In addition, evidence of infections
results in deep venous thrombosis and pulmonary emboli. Arterial (bacterial, HIV and other viral), medication history, family history,
thrombosis affects the lower extremities, causing limb ischemia. Car- and evidence of thrombosis are assessed. Other diagnostic tests include
diovascular accidents and myocardial infarctions also may be experi- complete blood count (CBC) and peripheral blood smear. Unlike
enced. Other major arteries (e.g., renal, mesenteric, upper limb) may some other forms of thrombocytopenia, there is usually no evidence
be affected too. of splenectomy. Testing for antiplatelet antibodies is usually not help-
ful. Although most cases of ITP are associated with elevated levels of
EVALUATION AND TREATMENT  Diagnosis is primarily based on IgG on platelets, other forms of thrombocytopenia also have a high
clinical observations. The individual presents with dropping platelet incidence of platelet-associated IgG; thus, the sensitivity is low (50%
counts after 5 days or longer of heparin treatment. On average, plate- to 65%). In addition, some cases of ITP will not present with elevated
let counts may reach 60,000/mm3. The onset of symptoms, including platelet-associated antibodies; the specificity is 75% to 94%, so that a
thrombosis, may be delayed until after release from the hospital. Most negative test does not rule out ITP.
individuals are affected by HIT following surgery; therefore other pos- Treatment is palliative, not curative, focusing on prevention of
sible causes of thrombocytopenia (e.g., infection, other drugs) must be platelet destruction by the spleen. Initial therapy for ITP is glucocor-
considered. ELISAs and other tests are available to measure anti-hepa- ticoids (e.g., prednisone), which suppress the immune response and
rin–platelet factor 4 antibodies. The sensitivity of this test is extremely prevent sequestering and further destruction of platelets. If steroid
high (>90%), but the specificity is less because of false-positive reac- therapy is ineffective, other reagents have been used. Treatment with
tions (e.g., those receiving dialysis). intravenous immunoglobulin (IVIg) is used to prevent major bleed-
Treatment is the withdrawal of heparin and use of alternative anti- ing. The response rate is 80%, but the effects are transient, lasting only
coagulants. A switch to low-molecular-weight heparin is not indi- days to a few weeks. Anti-Rho(D) (RhoGAM) has been used with lim-
cated, and warfarin should not be used until the symptoms of HIT ited success to treat individuals who are Rh positive.
have resolved because of an increased risk of initiating skin necrosis. If platelet counts do not increase appropriately, splenectomy is
The thrombocytopenia should then progressively resolve. The chance considered to remove the site of platelet destruction. However, sple-
of blood clots can be diminished using thrombin inhibitors (e.g., arg- nectomy is not without risks, and approximately 10% to 20% of indi-
atroban, lepirudin). viduals who undergo a splenectomy suffer a relapse and require further
Idiopathic (immune) thrombocytopenia purpura. Most of the lit- treatment. In that situation, it is believed that the liver has become
erature refers to thrombocytopenic purpura as idiopathic (no known the site for platelet destruction. If splenectomy is unsuccessful, more
cause) thrombocytopenia purpura (ITP), although the majority aggressive immunosuppressive medications (e.g., azathioprine, cyclo-
of cases are immune in nature.25 ITP may be acute or chronic. The phosphamide) are usually recommended. Because of potential compli-
acute form is frequently observed in children and typically lasts 1 to 2 cations, these medications are reserved for individuals who are severely
months with a complete remission. In some instances it may last for thrombocytopenic and refractive to other therapies.
up to 6 months, and some children (7% to 28%) may progress to the Thrombotic thrombocytopenia purpura. Thrombotic thrombocy-
chronic condition (see Chapter 19). Acute ITP is usually secondary topenia purpura (TTP) is a life-threatening multisystem disorder that
to infections (particularly viral) or other conditions (such as systemic is characterized by thrombotic microangiopathy, which includes micro-
lupus erythematosus [SLE]) that lead to large amounts of antigen in angiopathic hemolytic anemia and occlusion of arterioles and capillar-
the blood, such as exposure to some drugs. Under these conditions, the ies by aggregated platelets within the microcirculation.26,27 Aggregation
antigen usually forms immune complexes with circulating antibody, may lead to increased platelet consumption and organ ischemia. TTP
and it is thought that the immune complexes bind to Fc receptors on is relatively uncommon, occurring in about 5:1,000,000 individuals
platelets, leading to their destruction in the spleen. The acute form of per year. The incidence of TTP is increasing and does appear to be an
ITP usually resolves as the source of antigen is removed. actual increase and not just the result of improved recognition.
Chronic ITP is the primary form of the disease associated with the There are two types of TTP: familial and acquired idiopathic. The
presence of autoantibodies against platelet-associated antigens. This familial type is the more rare type and is usually chronic, relapsing,
form is more commonly observed in adults, being most prevalent in and usually seen in children. When recognized and treated early, the
women between 20 and 40 years old, although it can be found in all child experiences predictable recurring episodes approximately every
age categories. The chronic form tends to get progressively worse. 3 weeks that are responsive to treatment. Acquired TTP is more com-
The autoantibodies are generally of the IgG class and are against one mon and more acute and severe. It occurs mostly in females in their
or more of several platelet glycoproteins (e.g., GPIIb/IIIa, GPIIb/IX, thirties and is rarely observed in infants and the elderly.
 CHAPTER 20  Alterations of Hematologic Function 525

Most cases of TTP are related to a dysfunction of the plasma metal- adequately bind and remove thrombopoietin from the blood; thus
loprotease ADAMTS13. This enzyme is responsible for cutting large circulating levels remain high. Along with increased platelets, there
precursor molecules of von Willebrand factor (vWF) produced by may be a concomitant increase in the number of red cells, indicating a
endothelial cells into smaller molecules. Defects in ADAMTS13 result in myeloproliferative disorder; however, the increase in red cells is not to
expression of large-molecular-weight vWF on the endothelial cell sur- the extent seen in polycythemia vera.
face and the formation of large aggregates of platelets, which can break Secondary thrombocythemia may occur after splenectomy because
off and form occlusions in smaller vessels. People with TTP (about 80%) platelets that normally would be stored in the spleen remain in circu-
have <5% of normal plasma ADAMTS13 levels. Most individuals with lating blood. The increase in platelets may be gradual, with thrombo-
familial TTP are homozygous for mutations in ADAMTS13. Acquired cythemia not occurring for up to 3 weeks after splenectomy. Reactive
TTP of unexplained origin is associated in most (44% to 94%) people thrombocythemia may occur during some inflammatory conditions,
with an IgG autoantibody against ADAMTS13 that is able to neutralize such as rheumatoid arthritis and cancers. In these conditions, excessive
the enzyme’s activity and accelerate its clearance from the plasma. production of some cytokines (e.g., IL-6, IL-11) may induce increased
production of thrombopoietin in the liver, resulting in increased mega-
CLINICAL MANIFESTATIONS  TTP is clinically related to and must karyocyte proliferation. Reactive thrombocythemia may also occur
be distinguished from other thrombotic microangiopathic conditions, during a variety of physiologic conditions, such as after exercise.
including hemolytic uremic syndrome, malignant hypertension, pre-
eclampsia, and pregnancy-induced HELLP (hemolysis, elevated liver CLINICAL MANIFESTATIONS  Clinical manifestations vary among
enzymes, low platelet count) syndrome. Early diagnosis and treatment individuals. Those with ET are at risk for large-vessel arterial or venous
is essential because TTP may prove fatal within 90 days of onset if thrombosis, and ischemia in the fingers, toes, or cerebrovascular regions
untreated. is common. Digital ischemia is characterized by warm, congested red
Acute idiopathic TTP is characterized by a pentad of symptoms, extremities with a burning sensation, particularly on the forefoot sole
including extreme thrombocytopenia (<20,000/mm3), intravascular and toes. The lower extremities are affected more often, and only one
hemolytic anemia, ischemic signs and symptoms most often involving side may be involved. Standing, exercising, or applying heat precipi-
the central nervous system (about 65% present with memory distur- tates the pain, which is relieved by elevation and cooling of the affected
bances, behavioral irregularities, headaches, or coma), kidney failure extremity. In extreme situations, acrocyanosis and gangrene may result.
(65%), and fever (33%). Thrombosis of arteries is more common than of veins, and myocar-
dial and renal arteries may be involved. The carotid, mesenteric, and
EVALUATION AND TREATMENT  A routine blood smear usually subclavian arteries also may be affected. Myocardial ischemia and infarc-
shows fragmented red cells (schizocytes) produced by shear forces tion have occurred without clear evidence of coronary artery disease.
when red cells are in contact with the fibrin mesh in clots that form in Involvement of the nervous system is manifested by headache and
the vessels. As a result of tissue injury, serum levels of lactate dehydro- dizziness, with paresthesias, transient ischemic attacks, strokes, visual
genase (LDH) may be very high, and low-density lipoprotein (LDL) disturbances, and seizures also being reported. Major thrombotic
levels may be elevated. Tests for antibody on red cells are negative, events, not directly related to platelet count, occur in about 20% to
excluding immune hemolytic anemia. 30% of individuals with ET. Other risk factors (prior thrombosis, age,
Plasma exchange with fresh frozen plasma, which replenishes func- and duration of ET) are better predictors of future thrombosis.
tional ADAMTS13, is the treatment of choice, achieving a 70% to 80% Although thrombosis is the more common symptom, hemorrhage
response rate. Additionally, steroids (glucocorticoids) are admin- can also occur. Sites for bleeding include the GI tract, skin, urinary
istered. Nonresponse to conventional therapy may require a sple- tract, gums, joints, and brain. GI bleeding may be mistaken for a duo-
nectomy; however, postoperative hemorrhage remains a dangerous denal ulcer. Hemorrhage is not severe and generally occurs in the
complication. Immunosuppressive (azathioprine) therapy has been presence of very high platelet counts; transfusions are required only
successful in some individuals. Agents that target ADAMTS13 autoan- occasionally. Bleeding and clotting may occur simultaneously, and
tibody production by B cells (e.g., anti-CD20 monoclonal antibodies) individuals are not necessarily prone to one or the other.
are being studied and may potentially shorten the duration of plasma
exchange treatment and reduce relapses. EVALUATION AND TREATMENT  Initial diagnosis is not difficult; as
many as two thirds of cases are diagnosed from a routine complete
Thrombocythemia blood cell count (CBC). Secondary thrombocytosis also may occur as
Thrombocythemia (also called thrombocytosis) is defined as a a moderate rise in the platelet count that resolves with treatment or
platelet count greater than 400,000/mm3 of blood.28 Thrombocythe- resolution of the underlying condition.
mia may be primary or secondary (reactive) and is usually asymp- Essential thrombocythemia is diagnosed by a platelet count that
tomatic until the count exceeds 1 million/mm3. Then intravascular exceeds 600,000/mm3 and remains elevated, with no other indicated
clot formation (thrombosis), hemorrhage, or other abnormalities cause, such as arthritis, iron deficiency anemia, cancer, or splenec-
can occur. tomy. Many individuals present with a mild anemia and a slightly
elevated white blood cell count.
PATHOPHYSIOLOGY  Essential (primary) thrombocythemia (ET) Hydroxyurea (HU), a nonalkylating myelosuppressive agent, is
is a myeloproliferative disorder in which platelet production increases, used to suppress platelet production and at one time was the drug
resulting in platelet counts in excess of 600,000/mm3. It can occur in of choice for treating ET; however, long-term therapy with this drug
individuals at most any age. Manifestations include increased num- may cause progression to other myeloplastic disorders, particularly
bers of bone marrow megakaryocytes, splenomegaly, and periodic epi- acute myeloid leukemia. Other drugs used to treat ET include aspirin
sodes of hemorrhage or thrombosis, or both. The thrombocythemia is and interferon-alpha (IFNα). IFNα may not be effective for everyone
secondary to increased plasma thrombopoietin levels resulting from and aspirin, with its blood thinning properties, may cause hemor-
defects in the thrombopoietin receptor. The defective receptor cannot rhage. Anagrelide is now the drug of choice. Anagrelide interferes with
526 CHAPTER 20  Alterations of Hematologic Function

platelet maturation rather than production, thus not interfering with Disorders of Coagulation
red and white cell growth and development. Disorders of coagulation are usually caused by defects or deficiencies
of one or more of the clotting factors. (Normal function of the clot-
Alterations of Platelet Function ting factors is described in Chapter 19.) Qualitative or quantitative
Qualitative alterations in platelet function are characterized by an abnormalities interfere with or prevent the enzymatic reactions that
increased bleeding time in the presence of a normal platelet count. transform clotting factors, circulating as plasma proteins, into a stable
Associated clinical manifestations include spontaneous petechiae and fibrin clot (see Figure 19-17).
purpura and bleeding from the GI tract, genitourinary tract, pulmo- Some clotting factor defects are inherited and involve one single
nary mucosa, and gums. Congenital alterations in platelet function factor, such as the hemophilias and von Willebrand disease, caused
(thrombocytopathies) are quite rare and may be categorized into sev- by deficiencies of clotting factors. Other coagulation defects are
eral types of disorders: (1) platelet–vessel wall adhesion (e.g., defect acquired and tend to result from deficient synthesis of clotting fac-
in GPIb expression [Bernard-Soulier syndrome]), (2) platelet-plate- tors by the liver. Causes include liver disease and dietary deficiency
let interactions (e.g., defect in GPIIb/IIIa expression [Glanzmann of vitamin K.
thrombasthenia]), (3) platelet granules and secretion (e.g., receptor Other coagulation disorders are attributed to pathologic conditions
defects [ADP, collagen]), (4) arachidonic acid pathways (e.g., throm- that trigger coagulation inappropriately, engaging the clotting factors
boxane synthase deficiency), (5) cytoskeletal function (e.g., Wiskott- and causing detrimental clotting within blood vessels. For example,
Aldrich syndrome [see Chapter 7]), and (6) membrane phospholipid any cardiovascular abnormality that alters normal blood flow by accel-
regulation (coagulation protein-platelet interactions) (e.g., Scott eration, deceleration, or obstruction can create conditions in which
syndrome). coagulation proceeds within the vessels. An example of this is throm-
Acquired disorders of platelet function are more common than boembolic disease, in which blood clots obstruct blood vessels. Coagu-
the congenital disorders and may be categorized into three princi- lation is also stimulated by the presence of tissue factor that is released
pal causes: (1) drugs, (2) systemic conditions, and (3) hematologic by damaged or dead tissues. Vasculitis, or inflammation of the blood
alterations. vessels, along with vessel damage activates platelets, which in turn
Multiple drugs are known to affect platelet function by interfering activates the coagulation cascade. In extensive or prolonged vasculitis,
with platelet function in three ways: (1) inhibition of platelet membrane blood clot formation can suppress mechanisms that normally control
receptors, (2) inhibition of prostaglandin pathways, and (3) inhibition clot formation and dissolution, leading to clogging of the vessels. In
of phosphodiesterase activity. Aspirin is the most commonly used drug each of these acquired conditions, normal hemostatic function proves
that affects platelets. It irreversibly inhibits cyclooxygenase function detrimental to the body by consuming coagulation factors excessively
for several days after administration. Nonsteroidal anti-inflammatory or by overwhelming normal control of clot formation and breakdown
drugs also affect cyclooxygenase, although in a reversible fashion. Diet (fibrinolysis) (see Figure 19-19).
can affect platelet function (see Health Alert: Dark Chocolate, Wine,
and Platelet-Inhibitory Functions). Impaired Hemostasis
Systemic disorders that affect platelet function are chronic renal Impaired hemostasis, or the inability to promote coagulation and the
disease, liver disease, cardiopulmonary bypass surgery, and severe defi- development of a stable fibrin clot, is commonly associated with liver
ciencies of iron or folate. Hematologic disorders associated with plate- dysfunction, which may be caused by either specific liver disorders or
let dysfunction include chronic myeloproliferative disorders, multiple lack of vitamin K.
myeloma, leukemias, and myelodysplastic syndromes. Vitamin K deficiency. Vitamin K, a fat-soluble vitamin, is required
for the synthesis of prothrombin; the procoagulant factors II, VII,
IX, and X; and the anticoagulant factors (proteins C and S). Paren-
HEALTH ALERT teral administration of vitamin K is the treatment of choice and usu-
Dark Chocolate, Wine, and Platelet-Inhibitory ally results in correction of the deficiency. Fresh frozen plasma also
Functions may be administered but is usually reserved for individuals with life-­
threatening hemorrhages or those who require emergency surgery.
An increasing number of foods have been reported to have platelet-inhibitory Liver disease. Individuals who have liver disease present with a
functions. Recent studies showed flavanol-rich cocoa inhibited several mea- broad range of hemostatic derangements that may be characterized by
sures of platelet activity. Dark chocolate contains much more cocoa than does defects in the clotting or fibrinolytic system and by platelet dysfunc-
light chocolate. Additional cardioprotective effects may include antioxidant tion. The usual sequence of events is an initial reduction in clotting
properties and activation of nitric oxide (NO). Low to moderate consumption factors, which parallels the degree of liver cell damage or destruction.
of red wine reportedly has a greater benefit than other alcoholic beverages Factor VII is the first to decline because of its rapid turnover, followed
on cardioprotective mechanisms. Emerging are the effects of the polyphenol by a decrease in the levels of factors II and X. Factor IX levels are less
resveratrol known to be abundant in red wine. Investigators documented that affected and do not decline until the liver destruction is well advanced.
the polyphenolic antioxidants, resveratrol, and proanthocyanidins provide car- Protein C (an antithrombin) levels decline early, similar to levels of
dioprotection by their function in vivo as antioxidants. factor VII, and protein S (also an antithrombin) levels decline in the
later stages of liver disease. Declines of factor V levels are of special
Data from Corti R et al: Cocoa and cardiovascular health, Circulation importance because factor V plasma levels appear to be a direct reflec-
119(10):1433–1441, 2009; Djousse L et al: Chocolate consumption
tion of liver cell damage.
is inversely associated with prevalent coronary heart disease: The
National Health, Lung and Blood Institute Heart Study, Clin Nutr
Other alterations of hemostasis in liver disease include an increase
2010 Sept 9 [Epub ahead of print]; Flammer AJ et al: Dark chocolate in fibrinolytic activity that either is primary in origin or is a manifesta-
improves coronary vasomotion and reduces platelet reactivity, Circula- tion secondary to disseminated intravascular coagulation (DIC). This
tion 116(21):2376–2382, 2007; Pearson DA et al: Flavanols and platelet increased fibrinolysis results from excessive fibrinolytic activators and
reactivity, Clin Dev Immunol 12(1):1–9, 2005. decreased levels of inhibitors, such as α2-antiplasmin.
 CHAPTER 20  Alterations of Hematologic Function 527

Thrombocytopenia and thrombocytopathies are manifestations

BOX 20-2 CONDITIONS ASSOCIATED
of liver disease. Thrombocytopenia is caused by splenomegaly, which
often accompanies liver disease. Splenic pooling of platelets is the
WITH DIC
major cause of thrombocytopenia. Thrombocytopathies are associated Malignancy: acute leukemias, metastatic solid malignancies
with elevated levels of fibrin split products, ethanol, or drugs. Infections: bacterial (gram-negative endotoxin, gram-positive mucopolysac-
Treatment of hemostasis alterations in liver disease must be com- charides), viral (hepatitis, varicella, cytomegalovirus), fungal, parasitic
prehensive to cover all aspects of dysfunctions. Fresh frozen plasma Pregnancy complications: eclampsia/preeclampsia, placental abruption, amni-
(FFP) administration is the treatment of choice; however, not all indi- otic fluid embolism
viduals tolerate the volume needed to adequately replace all deficient Severe trauma: head injury, burns, crush injuries, tissue necrosis
factors. Alternative modalities include the addition of exchange trans- Liver disease: obstructive jaundice, acute liver failure
fusions and platelet concentration to FFP administration. Intravascular hemolysis: transfusion reactions, drug-induced hemolysis
Medical devices: aortic balloon, prosthetic devices
Consumptive Thrombohemorrhagic Disorders Hypoxia and low blood flow states: arterial hypotension secondary to shock,
Consumptive thrombohemorrhagic disorders are a heterogeneous cardiopulmonary arrest
group of conditions that demonstrate the entire spectrum of hemor-
Data from Bick RL et al: Hematology: clinical and laboratory practice,
rhagic and thrombotic pathologic findings. The symptoms of these
St Louis, 1993, Mosby.
disorders also range from the subtle to the devastating and are gener-
ally considered to be intermediary disease processes that complicate a
vast number of primary disease states. These disorders are also charac-
terized by confusion and controversy related to their diagnosis, treat- by several mechanisms. Widespread damage to vascular endothelium
ment, and management. No one term is capable of covering all the results in exposure of subendothelial tissue factor. Several types of cells
possible varieties of these disorders; however, DIC is most commonly either alter induction by cytokines or constitutively express TF on their
used in the clinical setting to describe a pathologic condition that is surface. Endothelial cells and monocytes do not normally express sur-
associated with hemorrhage and thrombosis. face TF unless stimulated by inflammatory cytokines (particularly IL-6
Disseminated intravascular coagulation. Disseminated intravas- and TNF-α). These cytokines are abundantly produced during many
cular coagulation (DIC) is an acquired clinical syndrome character- of the conditions listed in Box 20-2. Many tumors express surface TF
ized by widespread activation of coagulation, resulting in formation or produce cytokines that can stimulate TF expression by endothe-
of fibrin clots in medium and small vessels throughout the body.29 lium, monocytes, or both.
Widespread clotting may lead to blockage of blood flow to organs, TF binds clotting factor VII, which undergoes activation to factor
resulting in multiple organ failure. The magnitude of clotting may VIIa (also see Figure 19-18). The TF-VIIa complex is a potent activator
cause consumption of platelets and clotting factors, leading to severe of clotting factors IX and X, which leads to conversion of prothrombin
bleeding. to thrombin and formation of fibrin clots. This pathway appears to be
The clinical course of DIC is largely determined by the intensity of the primary route by which DIC is initiated; in animal models of DIC,
the stimulus, the response of the host, and the comorbidities, ranging inhibition of TF or factor VIIa completely prevents the generation of
from an acute, severe, life-threatening process that is characterized by thrombi by gram-negative bacterial endotoxin.
massive hemorrhage and thrombosis to a chronic, low-grade condi- Not only is the clotting system extensively activated in DIC, but
tion. The chronic condition is characterized by subacute hemorrhage also the predominant natural anticoagulants (tissue factor pathway
and diffuse microcirculatory thrombosis. DIC may be localized to one inhibitor, antithrombin III, protein C) are greatly diminished. Tissue
specific organ or generalized, involving multiple organs. factor pathway inhibitor (TFPI) in association with factor Xa inacti-
vates the TF-VIIa complex, preventing further activation of clotting.
PATHOPHYSIOLOGY  Coagulation is designed to function at local Antithrombin III (AT-III) is the principal inhibitor of thrombin,
areas of vascular damage, resulting in cessation of bleeding and activa- preventing further activation of fibrinogen to fibrin. Protein C is
tion of repair to the vessels. DIC results from abnormally widespread activated by thrombin to form activated protein C, which uses pro-
and ongoing activation of clotting. tein S as a cofactor to degrade factors Va and VIIIa. The rate of pro-
A variety of conditions are associated with DIC (Box 20-2). tein C activation increases dramatically if thrombin has first bound
Infectious disease, particularly involving sepsis, is the most com- to the membrane protein thrombomodulin on the endothelial cell
mon condition associated with DIC. Although all types of infections surface. During DIC, the activation of clotting is prolonged by the
may cause DIC, bacterial infections (both gram-negative and gram- increased rate of consumption, as well as decreased synthesis, of these
positive) are the most commonly observed underlying causes. DIC inhibitors and protein S and by cytokine-mediated decreased expres-
may occur in up to 50% of persons with gram-negative sepsis. Most sion of thrombomodulin on the endothelial cell surface. Thus clot-
solid tumors and hematologic cancers may trigger DIC. Approxi- ting is initiated concurrently with loss of regulation of the extent of
mately 15% of those with metastatic cancer or acute leukemia have thrombosis.
symptoms of DIC. Severe trauma, especially to the brain, can induce The rate of fibrinolysis is also diminished in DIC. The primary
DIC. DIC occurs in about two thirds of individuals with a systemic component of fibrinolysis is plasmin, which exists in the circulation as
inflammatory response to the trauma. Some complications of preg- an inactive precursor, plasminogen. Plasminogen is activated to plas-
nancy are also associated with DIC; incidences range from 50% min by a variety of substances, including thrombin, fibrin, tissue plas-
for women with placental abruptions to less than 10% for severe minogen activator (t-PA), and other molecules. Plasmin is an enzyme
preeclampsia. that digests fibrin clots, thus controlling the extent of fibrin deposition
Regardless of the underlying disease that initiates DIC, the common in the vessels. During DIC, the activity of plasmin is diminished by
pathway appears to be excessive and widespread exposure of tissue increased production of its natural inhibitor, plasminogen-activator
factor (TF or tissue thromboplastin) (Figure 20-16). This may occur inhibitor type I. Although some fibrinolytic activity remains, the level
528 CHAPTER 20  Alterations of Hematologic Function

Decreased natural anticoagulants Increased tissue factor Decreased fibrinolysis

contributes to contributes to

causes
consumption
causes
Thrombosis Increased clot formation

Thrombocytopenia
clot lysis
and clotting factor
deficiency

FDP

causes
decreased clearance

causes
Increased FDP Bleeding

inhibits hemostasis
FIGURE 20-16  Pathophysiology of Disseminated Intravascular Coagulation (DIC). Tissue factor
initiates clot formation and this effect is increased by a decrease in natural anticoagulants (tissue fac-
tor inhibitor, antithrombin-III, and protein C). There also is a reduction in clot breakdown or fibrinolysis
by plasmin. The combined effect is to cause thrombosis. The thrombotic activity consumes (uses up)
coagulation factors and platelets, which can increase bleeding. Slow degradation of the fibrin clot pro-
duces fibrin degradation products (FDPs). FDPs have inhibitory effects on thrombin and platelets. The
inhibition of coagulation, combined with the depletion of factors and platelets, then creates a bleeding
tendency. Uncontrolled DIC will eventually lead to multiple end-organ failure. For further details of these
mechanisms see Chapters 5 and 23. Inset is an example of DIC resulting from staphylococcal septice-
mia. Note the characteristic skin hemorrhage ranging from small purpuric lesions to larger ecchymoses.

is inadequate to control the systemic deposition of fibrin. The slow In addition to initiation of clotting by tissue factor, DIC may be
breakdown of fibrin by plasmin produces fibrin degradation products precipitated by direct proteolytic activation of factor X. This has
that are released into the blood. These are potent anticoagulants that been described as thrombin mimicry and is the result of proteases
are normally removed from blood by fibronectin and macrophages. directly converting fibrinogen to fibrin. These proteases may come
During DIC, the presence of fibrin degradation products is prolonged, from snake venom, some tumor cells, or the pancreas and liver,
probably because of diminished production of fibronectin. Low levels where they are respectively released during episodes of pancreatitis
of fibronectin suggest a poor prognosis. and various stages of liver disease. Direct proteolytic activity appears
Although thrombosis is generalized and widespread, individu- to be independent of any type of damage to the endothelium or
als with DIC are paradoxically at risk for hemorrhage. Hemorrhage tissue.
is secondary to the abnormally high consumption of clotting factors Whatever initiates the process of DIC, the cycle of thrombosis and
and platelets, as well as the anticoagulant properties of fibrin degra- hemorrhage persists until the underlying cause of the DIC is removed
dation products. Thrombin causes platelet activation and aggrega- or appropriate therapeutic interventions are used.
tion—an event that occurs early in the development of DIC—which
facilitates microcirculatory coagulation and obstruction in the initial CLINICAL MANIFESTATIONS  Clinical signs and symptoms of DIC
phase. However, platelet consumption exceeds production, resulting present a wide spectrum of possibilities, depending on the underly-
in a thrombocytopenia that increases bleeding. ing disease process that initiates DIC and whether the DIC is acute or
Activation of clotting also leads to activation of other inflamma- chronic in nature (Box 20-3). Most symptoms are the results of either
tory pathways, including the kallikrein-kinin and complement systems bleeding or thrombosis. Acute DIC presents with rapid development
(see Chapter 5). Factor XIIa, generated in DIC, converts prekallikrein of hemorrhaging (oozing) from venipuncture sites, arterial lines, or
to kallikrein, ultimately resulting in conversion to circulating kinins. surgical wounds or development of ecchymotic lesions (purpura, pete-
Activation of these systems contributes to increased vascular perme- chiae) and hematomas. Other sites of bleeding include the eyes (sclera,
ability, hypotension, and shock. Activated complement components conjunctiva), the nose, and the gums. Most individuals with DIC dem-
also induce platelet destruction, which initially contributes to the onstrate bleeding at three or more unrelated sites, and any combina-
thrombosis and later to the thrombocytopenia. tion may be observed. Shock of variable intensity, out of proportion to
The deposition of fibrin clots in the circulation interferes with the amount of blood loss, also may be observed. Hemorrhaging into
blood flow, causing widespread organ hypoperfusion. This condition closed compartments of the body also can occur and may precede the
may lead to ischemia, infarction, and necrosis, further potentiating development of shock.
and complicating the existing DIC process by causing further release Manifestations of thrombosis are not always as evident, even
of TF and eventually organ failure. though it is often the first pathologic alteration to occur. Several organ
 CHAPTER 20  Alterations of Hematologic Function 529

person must present with a clinical condition that is known to be asso-

BOX 20-3 CLINICAL MANIFESTATIONS
ciated with DIC. The most commonly used combination of labora-
ASSOCIATED WITH DIC* tory tests usually confirms thrombocytopenia or a rapidly decreasing
Integumentary System platelet count on repeated testing, prolongation of clotting times, the
Widespread hemorrhage and vascular lesions presence of fibrin degradation products, and decreased levels of coagu-
Oozing from puncture sites, incisions, mucous membranes lation inhibitors.
Acrocyanosis (irregular-shaped cyanotic patches) Platelet counts below 100,000/mm3 or a progressive decrease in
Gangrene platelet counts is very sensitive for DIC, although not greatly specific.
These changes usually indicate consumption of platelets.
Central Nervous System The standard coagulation tests (e.g., prothrombin time [PT], acti-
Subarachnoid hemorrhage vated partial thromboplastin time [aPTT]) also have a high degree of
Altered state of consciousness (slight confusion to convulsions and coma) sensitivity, but they are not highly specific for DIC. As a result of con-
sumption of circulating clotting factors, these tests are usually abnor-
Gastrointestinal System mal, ranging from shortened to prolonged times. However, conditions
Occult bleeding to massive gastrointestinal bleeding other than DIC may prolong clotting times.
Abdominal distention Detection of fibrin degradation products is more specific for DIC.
Malaise Detection of D-dimers is a widely used test for DIC. A D-dimer is a
Weakness molecule produced by plasmin degradation of cross-linked fibrin in
clots. D-dimers in the blood can be quantified using ELISA tests that
Pulmonary System
include commercially available and highly specific monoclonal anti-
Pulmonary infarctions
body against the D-dimer. Agglutination tests for other fibrin degrada-
ARDS
tion products are available. Fibrin degradation products are elevated
Cyanosis
in the plasma in 95% to 100% of cases; however, they are less specific
Tachypnea
for DIC than D-dimers and only document the presence of plasmin
Hypoxemia
and its action on fibrin. ELISAs for markers of thrombin activity are
Renal System sometimes used. For instance, ELISAs for fibrinopeptide A, a break-
Hematuria down product of fibrinogen produced during activation by thrombin,
Oliguria are available. However, these assays are also less specific for DIC.
Renal failure Levels of coagulation inhibitors (e.g., antithrombin III [AT-III],
protein C) can be measured by assays that rely on function or by
Modified from Bailes BK: Disseminated intravascular coagulation. Prin- ­ELISAs that quantify the amount of the specific inhibitor. AT-III levels
ciples, treatment, nursing management, AORN J 55(2):517–529, 1992. can provide key information for diagnosing and monitoring therapy of
ARDS, Adult respiratory distress syndrome; DIC, disseminated intra- DIC. Initial levels of functional AT-III are low in DIC because throm-
vascular coagulation. bin is irreversibly complexed with activated clotting factors and AT-III.
Treatment of DIC is directed toward (1) eliminating the underly-
ing pathologic condition, (2) controlling ongoing thrombosis, and (3)
systems are susceptible to microvascular thrombosis associated with maintaining organ function. Elimination of the underlying pathologic
dysfunction: cardiovascular, pulmonary, central nervous, renal, and condition is the initial intervention in the treatment phase in order to
hepatic systems. Acute and accurate clinical interpretations are criti- eliminate the trigger for activation of clotting. Once the stimulus is
cal to preventing progression of DIC that may lead to multisystem gone, production of coagulation factors in the liver leads to restoration
organ dysfunction and failure. (Multiple organ dysfunction and fail- of normal plasma levels within 24 to 48 hours.
ure are discussed further in Chapter 23.) Indicators of multisystem Control of thrombosis is more difficult to attain. Heparin has been
­dysfunction include changes in level of consciousness or behavior, used for this; however, its use is controversial because its mechanism
confusion, seizure activity, oliguria, hematuria, hypoxia, hypoten- of action is binding to and activating AT-III, which is deficient in many
sion, hemoptysis, chest pain, and tachycardia. Symmetric cyanosis of types of DIC. Currently, heparin is only indicated in certain types of
fingers and toes (blue finger/toe syndrome), nose, and breast may be situations related to DIC. For instance, heparin seems to be effective in
observed and indicates macrovascular thrombosis. This may lead to DIC caused by a retained dead fetus or associated with acute promy-
infarction and gangrene that may require amputation. Jaundice also is elocytic leukemia. Organ function is compromised by microthrombi,
observed and most likely results from red cell destruction rather than and there is a risk of losing an extremity because of vascular occlusion;
liver dysfunction. thus heparin is also indicated in these conditions. Heparin’s useful-
Individuals with chronic or low-grade DIC do not present with ness, however, for DIC that is precipitated by septic shock has not been
the overt manifestations of hemorrhaging and thrombosis but instead established and so is contraindicated in that instance; heparin is also
have subacute bleeding and diffuse thrombosis and are described as contraindicated when there is evidence of postoperative bleeding, pep-
having compensated DIC. The major characteristic of this state is an tic ulcer, or central nervous system bleeding.
increased turnover and decreased survival time of the components Replacement of deficient coagulation factors, platelets, and other
of hemostasis: platelets and clotting factors. Occasionally, diffuse or coagulation elements is gaining recognition as an effective treatment
localized thrombosis develops, but this is infrequent. modality. Their use is not without controversy, however, because a
major concern with replacement therapy is the possible risk of adding
EVALUATION AND TREATMENT  No single laboratory test can be components that will increase the rate of thrombosis. Clinical judg-
used to effectively diagnosis DIC. Diagnosis is based primarily on clini- ment is the key factor in determining whether replacement is to be
cal symptoms and confirmed by a combination of laboratory tests. The used as a treatment modality.
530 CHAPTER 20  Alterations of Hematologic Function

Several clinical trials are evaluating replacement of anticoagulants Therapy consists of removal or dissolution of the clot and sup-
(i.e., AT-III, protein C). Replacement of AT-III appears to be effective in portive measures. Anticoagulant therapy is effective in treating or pre-
DIC caused by sepsis. Low levels of AT-III correlate with sepsis-­initiated venting venous thrombosis; it is not as useful in treating or preventing
DIC, which makes a case for its use. AT-III inactivates thrombin, factor arterial thrombosis. Parenteral heparin is the major anticoagulant used
Xa, factor IXa, and other activated components of the clotting system. to treat thromboembolism. Oral coumarin drugs also are widely used,
Heparin augments AT-III, but the combination of heparin with AT-III particularly for individuals not hospitalized. More aggressive therapy
replacement has not been established. Antifibrinolytic drugs also are may be indicated for such conditions as pulmonary embolism, coro-
used in treatment but are limited to instances of life-threatening bleeding nary thrombosis, or thrombophlebitis. Streptokinase and urokinase
that have not been controlled by blood component replacement therapy. activate the fibrinolytic system and are administered to accelerate the
Maintenance of organ function is achieved by fluid replacement to lysis of known thrombi. Thrombolytic therapy has limited uses and is
sustain adequate circulating blood volume and maintain optimal tis- prescribed with a high degree of caution because it can cause hemor-
sue and organ perfusion. Fluids may be required to restore blood pres- rhagic complications.
sure, cardiac output, and urine output to normal parameters. The risk for developing spontaneous thrombi is related to several
factors, referred to as the Virchow triad: (1) injury to the blood vessel
Thromboembolic Disorders endothelium, (2) abnormalities of blood flow, and (3) hypercoagula-
Certain conditions within the blood vessels predispose an individual bility of the blood.
to develop clots spontaneously. A clot attached to the vessel wall is Endothelial injury to blood vessels can result from atherosclerosis
called a thrombus (Figure 20-17). A thrombus is composed of fibrin (plaque deposits on arterial walls) (see Chapter 23). Atherosclerosis
and blood cells and can develop in either the arterial or the venous initiates platelet adhesion and aggregation, promoting the develop-
system. Arterial clots form under conditions of high blood flow and are ment of atherosclerotic plaques that enlarge, causing further damage
composed mostly of platelet aggregates held together by fibrin strands. and occlusion. Other causes of vessel endothelial injury may be related
Venous clots form in conditions of low flow and are composed mostly to hemodynamic alterations associated with hypertension and turbu-
of red cells with larger amounts of fibrin and few platelets. lent blood flow. Injury also is caused by radiation injury, exogenous
A thrombus eventually reduces or obstructs blood flow to tissues chemical agents (e.g., toxins from cigarette smoke), endogenous agents
or organs, such as the heart, brain, or lungs, depriving them of essen- (e.g., cholesterol), bacterial toxins or endotoxins, or immunologic
tial nutrients critical to survival. A thrombus also has the potential of mechanisms. Whatever the precipitating cause of endothelial injury, it
detaching from the vessel wall and circulating within the bloodstream is a potent thrombogenic agent.
(referred to as an embolus). The embolus may become lodged in Sites of turbulent blood flow in the arteries and stasis of blood flow
smaller blood vessels, blocking blood flow into the local tissue or organ in the veins are at risk for thrombus formation. In areas of turbulence,
and leading to ischemia. Whether episodes of thromboembolism are platelets and endothelial cells may be activated, leading to thrombosis.
life-threatening depends on the site of vessel occlusion. In sites of stasis, platelets may remain in contact with the endothe-
lium for prolonged lengths of time, and clotting factors that would
normally be diluted with fresh flowing blood are not diluted and may
become activated. The most common clinical conditions that predis-
pose to venous stasis and subsequent thromboembolic phenomena
are major surgery (e.g., orthopedic surgery), acute myocardial infarc-
tion, congestive heart failure, limb paralysis, spinal injury, malignancy,
advanced age, the postpartum period, and bed rest longer than 1 week.
Turbulence and stasis occur with ulcerated atherosclerotic plaques
(myocardial infarction), hyperviscosity (polycythemia), and condi-
tions with deformed red cells (sickle cell anemia).
Hypercoagulability is the condition in which an individual is at
risk for thrombosis, but by itself it is a rare cause of thrombosis. Hyper-
coagulability is differentiated according to whether it results from pri-
mary (hereditary) or secondary (acquired) causes.
Hereditary hypercoagulability and thrombosis. Hereditary throm-
bophilias that increase the risk to develop thrombosis include factor V
Leiden mutation; prothrombin mutation; methylenetetrahydrofolate
reductase (MTHFR) mutation, leading to high homocysteine levels;
and deficiencies in protein C, protein S, and antithrombin III (AT-
III).30 Most are autosomal dominant. Factor V Leiden results from a
single nucleotide mutation that confers partial resistance to inactiva-
tion by activated protein C, resulting in prolonged high levels of acti-
vated factor V (factor Va) and overproduction of thrombin. It is the
most common hereditary thrombophilia and is primarily observed in
individuals of European ancestry. It is observed in about 5% of whites
FIGURE 20-17  Thrombus. Thrombus arising in valve pocket at in the United States and in about 30% of individuals presenting with
upper end of superficial femoral vein (arrow). Postmortem clot on deep venous thrombosis (DVT) or pulmonary embolism.
the right is shown for comparison. (From McLachlin J, Paterson Other hereditary thrombophilias are less common. Prothrom-
JC: Some basic observations on venous thrombosis and pulmonary bin mutation is observed in about 5% of individuals and leads to
embolism, Surg Gynecol Obstet 93[1]:1–8, 1951.) high levels of circulating prothrombin. More than 100 different
 CHAPTER 20  Alterations of Hematologic Function 531

known mutations lead to defects of protein C, protein S, and AT-III female and of reproductive age. Those with APS are at risk for both
and increase the risk of venous thrombosis. Mutations may lead arterial and venous thrombosis and a variety of obstetric complica-
to either quantitative (low levels of protein) or qualitative (pro- tions, including pregnancy loss and preeclampsia/eclampsia. The
duction of defective protein) changes. MTHFR mutation leads to pathophysiology is related to autoantibodies directly reacting with
alterations in the metabolism of the amino acid homocysteine into platelets or endothelial cells (increasing the risk for thrombosis)
methionine and abnormally elevated levels of that amino acid in the or the placental surface (resulting in damage to the placenta). The
blood (hyperhomocysteinemia). Acquired hyperhomocysteinemia predominant diagnostic tests measure prolongation of laboratory
may result from deficiencies in vitamins B6 or B12, endocrine dis- blood coagulation tests related to an antibody inhibitor (lupus anti-
eases (e.g., diabetes mellitus, hypothyroidism), pernicious anemia, coagulant) and specific ELISAs for antibodies against phospholipids
inflammatory bowel disease, renal failure, and therapy with some (e.g., anticardiolipin antibody) or proteins that bind to phospholipids
drugs. The mechanism of hypercoagulability conferred by hyper- (e.g., β2-glycoprotein I). Highly effective therapy (i.e., unfractionated
homocysteinemia is unclear but may be related to direct injury of or low-molecular-weight heparin with low-dose aspirin) is available to
endothelial cells or platelets or to alteration of some components of prevent the obstetric complications.
the clotting system.
Tests to diagnosis inherited thrombophilias include prothrombin
time, partial thromboplastin time, and levels of protein C, protein S,
and AT-III. More elaborate tests to detect precise mutations in factor
4 QUICK CHECK 20-6
1. Identify three pathologic causes of DIC, and describe the manifestations
V, prothrombin, or MTHFR may be indicated. associated with DIC.
Acquired hypercoagulability and thrombosis. Acquired hyperco- 2. Compare and contrast thrombocytopenia with thrombocytosis.
agulable states include antiphospholipid syndrome (APS).31 APS is 3. Why does vitamin K deficiency predispose an individual to a coagulation
an autoimmune syndrome characterized by autoantibodies against disorder?
plasma membrane phospholipids and phospholipid-binding proteins. 4. Compare and contrast a thrombus with an embolus.
As with most autoimmune diseases, the predominate individual is

DID YOU UNDERSTAND?

Alterations of Erythrocyte Function 12. Hemolytic anemia results from premature destruction of red cells and may
1. Anemia is generally defined as a reduction in the number or volume of cir- be acquired or hereditary. Of the acquired forms, autoimmune reaction and
culating red cells or an alteration in hemoglobin. drug-induced hemolysis are the most common causes.
2. The most common classification of anemias is based on changes in the cell 13. Anemia of chronic inflammation is associated with chronic infections,
size—represented by the suffix cytic—and changes in the cell’s hemoglo- chronic inflammatory diseases, and malignancies.
bin content—represented by the suffix chromic.
3. Clinical manifestations of anemia can be found in all organs and tis- Myeloproliferative Red Cell Disorders
sues throughout the body. Decreased oxygen delivery to tissues causes . Polycythemia vera is characterized by excessive proliferation of erythrocyte
1
fatigue, dyspnea, syncope, angina, compensatory tachycardia, and organ precursors in the bone marrow. Signs and symptoms result directly from
dysfunction. increased blood volume and viscosity. Therapeutic phlebotomy to remove
4. Macrocytic (megaloblastic) anemias are caused most commonly by defi- excessive blood volume and use of radioactive phosphorus have been helpful
ciency of vitamin B12. Pernicious anemia can be fatal unless vitamin B12 in decreasing the excessive red cell pool.
replacement is given. 2. Polycythemia vera may spontaneously convert to acute myelogenous
5. Microcytic-hypochromic anemias are characterized by abnormally small red leukemia.
cells with insufficient hemoglobin content. The most common cause is iron
deficiency. Alterations of Leukocyte Function
6. Iron deficiency anemia usually develops slowly, with a gradual insidious 1. Quantitative alterations of leukocytes (too many or too few) can be caused
onset of symptoms, including fatigue, weakness, dyspnea, alteration of by bone marrow dysfunction or premature destruction of cells in the circula-
various epithelial tissues, and vague neuromuscular complaints. tion. Many quantitative changes in leukocytes occur in response to invasion
7. Iron deficiency anemia is usually a result of a chronic blood loss or by microorganisms.
decreased iron intake. Once the source of blood loss is identified and cor- 2. Leukocytosis is a condition in which the leukocyte count is higher
rected, iron replacement therapy can be initiated. than normal and is usually a response to stress and invasion of
8. Sideroblastic anemia results from impaired iron metabolism and abnormal microorganisms.
sequestration of iron within the red cell. Treatment varies depending on the 3. Leukopenia is a condition in which the leukocyte count is lower than normal
cause. and is caused by pathologic conditions, such as malignancies and hemato-
9. Normocytic-normochromic anemias are characterized by insufficient num- logic disorders.
bers of normal erythrocytes. Included in this category are aplastic, post- 4. Granulocytosis (particularly as a result of an increase in neutrophils) occurs
hemorrhagic, and hemolytic anemia and anemia of chronic inflammation. in response to infection. The marrow releases immature cells, causing
10. In aplastic anemia, erythrocyte stem cells are underdeveloped, defective, a shift-to-the-left, when responding to an infection that has created a
or absent. Unless the cause is determined, bone marrow aplasia results in demand for neutrophils that exceeds the supply in the circulation.
death. 5. Eosinophilia results most commonly from parasitic invasion and ingestion
11. Posthemorrhagic anemia results from a sudden blood loss. Restoration of or inhalation of toxic foreign particles.
blood volume by plasma expanders or transfusions may diminish subjective 6. Basophilia is seen in hypersensitivity reactions because of the high content
symptoms of anemia. Hemoglobin restoration may take 6 to 8 weeks. of histamine and subsequent release.

Continued
532 CHAPTER 20  Alterations of Hematologic Function

DID YOU UNDERSTAND?—cont’d

7. Monocytosis occurs during the late or recuperative phase of infection when 8. The cause of lymph node enlargement and cancerous transformation in non-
macrophages (mature monocytes) phagocytose surviving microorganisms Hodgkin lymphoma is unknown. Immunosuppressed persons have a higher
and debris. incidence of non-Hodgkin lymphoma, suggesting an immune mechanism.
8. Granulocytopenia, a significant decrease in neutrophils, can be a life- 9. Generally, with non-Hodgkin lymphoma, the swelling of lymph nodes is pain-
threatening condition if sepsis occurs; it is often caused by chemothera- less, and the nodes enlarge and transform over a period of months or years.
peutic agents, severe infection, and radiation. 10. Individuals with non-Hodgkin lymphoma can survive for long periods. The
9. Infectious mononucleosis is an acute infection of B lymphocytes most com- treatment used is chemotherapy.
monly associated with the Epstein-Barr virus (EBV), a type of herpesvirus. 11. Burkitt lymphoma involves the jaw and facial bones and occurs in children
Transmission of EBV is through close personal contact, commonly via from east-central Africa and New Guinea.
saliva, thus its nickname, the kissing disease. 12. Multiple myeloma is a neoplasm of B cells (immature plasma cells) and
10. Two of the earliest manifestations of infectious mononucleosis are sore mature plasma cells. It is characterized by multiple malignant tumor masses
throat and fever caused by inflammation at the primary site of viral entry. of plasma cells scattered throughout the skeletal system and sometimes
11. Most causes of EBV infectious mononucleosis include fever lasting 7 to 10 found in soft tissue.
days, sore throat, and enlargement and tenderness of the cervical lymph nodes. 13. The exact cause of multiple myeloma is unknown, but genetic factors and
It is self-limiting and treatment consists of rest and symptomatic treatment. chronic stimulation of the mononuclear phagocyte system by bacteria, viral
12. The common pathologic feature of all forms of leukemia is an uncontrolled agents, and chemicals have been suggested.
proliferation of leukocytes, overcrowding the bone marrow and resulting in 14. The major clinical manifestations for multiple myeloma include recurrent
decreased production and function of the other blood cell lines. infections caused by suppression of the humoral immune response and
13. All leukemias are classified by the cell type involved—lymphocytic or renal disease as a result of Bence Jones proteinuria.
myelogenous—and are differentiated by onset—acute or chronic. Thus 15. Chemotherapy is the treatment of choice for multiple myeloma. Survival
there are four major types of leukemia: acute lymphocytic leukemia (ALL), is still only 2 to 3 years with chemotherapy, however. Treatment with tha-
chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), lidomide combination therapies and blood cell transplantation are showing
and chronic myelogenous leukemia (CML). promise for producing long-term remissions.
14. Although the exact cause of leukemia is unknown, it is considered a clonal
disorder. A high incidence of acute leukemias and CLL is reported in certain Alterations of Splenic Function
families, suggesting a genetic predisposition. . Splenomegaly (enlargement of the spleen) may be considered normal in cer-
1
15. The major clinical manifestation of leukemia includes fatigue caused by tain individuals, but its presence should not be ignored.
anemia, bleeding caused by thrombocytopenia, fever secondary to infec- 2. Splenomegaly results from (a) acute inflammatory or infectious processes,
tion, anorexia, and weight loss. (b) congestive disorders, (c) infiltrative processes, and (d) tumors or cysts.
16. Chemotherapy is the treatment of choice for leukemia. Acute leukemias are 3. Hypersplenism (overactivity of the spleen) results from splenomegaly.
associated with an increasing survival rate of 80% to 90%, with long-term Hypersplenism results in sequestering of the blood cells, causing increased
survival of 30% to 40%. Chronic leukemias are associated with a longer life destruction of red blood cells, which leads to the development of anemia.
expectancy than are acute leukemias.
17. Chronic leukemias progress differently than acute leukemias, advancing Alterations of Platelets and Coagulation
slowly and without warning. The presence of the Philadelphia chromosome 1. Thrombocytopenia is characterized by a platelet count below 100,000/mm3
is a diagnostic marker for CML. of blood; a count below 50,000/mm3 increases the potential for hemor-
rhage associated with minor trauma.
Alterations of Lymphoid Function 2. Thrombocytopenia exists in primary or secondary forms and is commonly
1. The number of lymphocytes is decreased (lymphocytopenia) in most acute associated with autoimmune diseases and viral infections; bacterial sepsis
infections and in some immunodeficiency syndromes. with DIC also results in thrombocytopenia.
2. Lymphocytosis occurs in viral infections (infectious mononucleosis and 3. Thrombocythemia is characterized by a platelet count more than 400,000 plate-
infectious hepatitis, in particular), leukemia, lymphomas, and some chronic lets/mm3 of blood and is symptomatic when the count exceeds 1,000,000/
infections. mm3, at which time the risk for intravascular clotting (thrombosis) is high.
3. Lymphomas are tumors of primary lymphoid tissue (thymus, bone marrow) 4. Thrombocythemia is caused by accelerated platelet production in the bone
or secondary lymphoid tissue (lymph nodes, spleen, tonsils, intestinal lym- marrow.
phoid tissue). The two major types of malignant lymphomas are Hodgkin 5. Qualitative alterations in normal platelet adherence or aggregation prevent
lymphoma and non-Hodgkin lymphoma. platelet plug formation and may result in prolonged bleeding times.
4. Distinctive abnormal chromosomes are present in multiple cells of the 6. Platelet dysfunction results from changes in the cellular contents and
lymph nodes of an individual with Hodgkin lymphoma. The abnormal cell is integrity.
called the Reed-Sternberg cell. 7. Disorders of coagulation are usually caused by defects or deficiencies of
5. A virus might be involved in the pathogenesis of Hodgkin lymphoma. Some one or more clotting factors.
familial clustering suggests an unknown genetic mechanism. 8. Coagulation is impaired when there is a deficiency of vitamin K because of
6. An enlarged, painless mass or swelling, most commonly in the neck, is an insufficient production of prothrombin and synthesis of clotting factors II,
initial sign of Hodgkin lymphoma. Local symptoms are produced by lymph- VII, IX, and X, often associated with liver diseases.
adenopathy, usually caused by pressure or obstruction. 9. Disseminated intravascular coagulation (DIC) is a complex syndrome result-
7. Treatment of Hodgkin lymphoma includes radiation therapy and chemo- ing from a variety of clinical conditions that release tissue factor, causing
therapy. A cure is possible regardless of the stage of Hodgkin lymphoma; an increase in fibrin and thrombin activity in the blood and producing aug-
however, individuals treated with chemotherapy who relapse in less than 2 mented clot formation and accelerated fibrinolysis. Sepsis is a condition
years have a poorer prognosis. that is often associated with DIC.
 CHAPTER 20  Alterations of Hematologic Function 533

DID YOU UNDERSTAND?—cont’d

10. DIC is characterized by a cycle of intravascular clotting followed by active distal to the occlusion; death can result when clots obstruct blood flow to
bleeding caused by the initial consumption of coagulation factors and the heart, brain, or lungs.
platelets and diffuse fibrinolysis. 13. Hypercoagulability is the result of deficient anticoagulation proteins. Sec-
11. Diagnosis of DIC is based on measurement in the blood of end products ondary causes are conditions that promote venous stasis.
characteristic of dysfunctional coagulation activity. Treatment is complex 14. The term Virchow triad refers to three factors that can cause thrombus
and nonstandardized and focused on removing the primary cause, restoring formation: (a) loss of integrity of the vessel wall, (b) abnormalities of blood flow,
hemostasis, and preventing further organ damage. and (c) alterations in the blood constituents.
12. Thromboembolic disease results from a fixed (thrombus) or moving
(embolus) clot that blocks flow within a vessel, denying nutrients to tissues

 KEY TERMS
•  bsolute polycythemia  506
A •  ereditary hemochromatosis (HH)  508
H •  eutropenia  509
N
• Acquired sideroblastic anemia  505 • Hereditary sideroblastic anemia  505 • Neutrophilia  509
• Agranulocytosis  509 • Heterophilic antibody  512 • NK cell neoplasm  518
• Anemia  500 • Hodgkin lymphoma (HL)  516 • Non-Hodgkin lymphoma (NHL)  518
• Anisocytosis  501 • Hypercoagulability  530 • Normocytic-normochromic anemia
• Basopenia  509 • Hypersplenism  521 (NNA)  505
• Basophilia  509 • Hypoplastic anemia  505 • Pancytopenia  513
• B cell neoplasm  518 • Hypoxemia  501 • Pernicious anemia (PA)  502
• Bence Jones protein  520 • Idiopathic thrombocytopenia purpura • Phlebotomy  505
• Blast cell  512 (ITP)  524 • Plasmin  527
• Burkitt lymphoma  519 • Impaired hemostasis  526 • Poikilocytosis  501
• Consumptive thrombohemorrhagic • Infectious mononucleosis (IM)  511 • Polycythemia  506
disorder  527 • Intrinsic factor (IF)  502 • Polycythemia vera (PV)  506
• D-dimer  529 • Iron deficiency anemia (IDA)  504 • Reed-Sternberg (RS) cell  516
• Disseminated intravascular coagulation • Koilonychia  504 • Relative polycythemia  506
(DIC)  527 • Leukemia  512 • Reversible sideroblastic anemia  505
• Embolus  530 • Leukocytosis  508 • Secondary thrombocythemia  525
• Eosinopenia  509 • Leukopenia  508 • Shift-to-the-left (leukemoid reaction)  509
• Eosinophilia  509 • Lymphoblastic lymphoma (LL)  521 • Shift-to-the-right  509
• Essential (primary) thrombocythemia • Lymphocytopenia  509 • Sideroblastic anemia (SA)  505
(ET)  525 • Lymphocytosis  509 • Splenomegaly  521
• Felty syndrome  509 • Macrocytic (megaloblastic) anemia  502 • T cell neoplasm  518
• Folate  503 • Microcytic-hypochromic anemia  504 • Thrombocythemia (thrombocytosis)  525
• Granulocytopenia  509 • Monocytopenia  509 • Thrombocytopenia  523
• Granulocytosis  509 • Monocytosis  509 • Thrombotic thrombocytopenia purpura
• Hemolysis  501 • M protein  520 (TTP)  524
• Hemosiderosis  505 • Multiple myeloma (MM)  520 • Thrombus  530
• Heparin-induced thrombocytopenia • Myelodysplastic syndrome  505 • Vasculitis  526
(HIT)  524 • Myeloproliferative disorder  514 • Virchow triad  530

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ease and iron deficiency anemia: diagnostic and therapeutic implications, Ann Hematol 84(6):347–352, 2005.
Blood 113(21):5277–5286, 2009. 9. Greenberg PL: Myelodysplastic syndromes, J Natl Compr Canc Netw
2. Muñoz M, García-Erce JA, Remacha AF: Disorders of iron metabolism. 9(1):30–56, 2011.
Part II: iron deficiency and iron overload, J Clin Pathol 2010 Dec 20:[Epub 10. Leguit RJ, van den Tweel JG: The pathology of bone marrow failure,
ahead of print.] Histopathology 57(5):655–670, 2010.
3. den Elzen WP, et al: Subnormal vitamin B12 concentrations and anaemia 11. Odumade OA, Hogquist KA, Balfour HH: Progress and problems in
in older people: a systematic review, BMC Geriatr 10:42, 2010. understanding and managing primary Epstein-Barr virus infections, Clin
4. Guidi GC, Lechi Santonastaso C: Advancements in anemias related to Microbiol Rev 24(1):193–209, 2011.
chronic conditions, Clin Chem Lab Med 48(9):1217–1226, 2010. 12. Bell AT, Fortune B, Sheeler R: Clinical inquiries: what test is the best for
5. Young NS, Calado RT, Scheinberg P: Current concepts in the pathophysi- diagnosing infectious mononucleosis? J Fam Pract 55(9):799–802, 2006.
ology and treatment of aplastic anemia, Blood 108(8):2509–2519, 2006. 13. Konopleva MY, Jordan CT: Leukemia stem cells and microenvironment:
6. Vannucchi AM, Guglielmelli P: Advances in understanding and manage- biology and therapeutic targeting, J Clin Oncol 2011 Jan 10:[Epub ahead of
ment of polycythemia vera, Curr Opin Oncol 22(6):636–641, 2010. print.]
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14. Hodgson K, et al: Chronic lymphocytic leukemia and autoimmunity: a 24. Butt A, Aronow WS, Chandy D: Heparin-induced thrombocytopenia and
systematic review, Haematologica 2011 Jan 17:[Epub ahead of print.] thrombosis, Compr Ther 36:23–27, 2010.
15. Roboz GJ, Guzman M: Acute myeloid leukemia stem cells: seek and 25. Bennett CN, de Jong JLO, Neufeld EJ: Targeted ITP strategies: do they
destroy, Exp Rev Hematol 2(6):663–672, 2009. elucidate the biology of ITP and related disorders? Pediatr Blood Cancer
16. Bomken S, et al: Understanding the cancer stem cell, Br J Cancer 47(Suppl 5):706–709, 2006.
103(4):439–445, 2010. 26. Kiss JE: Thrombotic thrombocytopenic purpura: recognition and man-
17. Monroy CM, et al: Hodgkin disease risk: role of genetic polymorphisms agement, Int J Hematol 9(1):36–45, 2010.
and gene-gene interactions in inflammation pathway genes, Mol Carcinog 27. Tsai HM: Pathophysiology of thrombotic thrombocytopenic purpura, Int
50(1):36–46, 2011. J Hematol 91(1):1–19, 2010.
18. Vereide DT, Sugden B: Lymphomas differ in their dependence on Epstein- 28. Harrison CN, et al: Guideline for investigation and management of adults
Barr virus, Blood 117(6):1977–1985, 2011. and children presenting with a thrombocytosis, Br J Haematol 149(3):
19. Zelentz AD, et al: NCCN clinical practice guidelines in oncology; non- 352–375, 2010.
Hodgkin’s lyphomas, J Natl Compr Canc Netw 8(3):288–334, 2010. 29. Bick RL: Disseminated intravascular coagulation current concepts of etiol-
20. Surveillance Epidemiology and End Results (SEER): SEER stat fact sheets: ogy, pathology, diagnosis, and treatment, Hematol Oncol Clin North Am
myeloma, Bethesda, Md, 2009, National Cancer Institute. Accessed Jan 22, 17(1):149–176, 2003.
2011. Available at http//seer.cancer.gov. (Based on Nov 2009 SEER data 30. Bockenstedt PL: Management of hereditary hypercoagulable disorders,
submission, posted to the SEER website, 2010.) Hematology Amer Soc Hematol Educ Program 2006:444–449, 2006.
21. Anguilillo DJ, Ueno M, Goto S: Basic principles of platelet biology and 31. Tripodi A, de Groot PG, Pengo V: Antiphospholipid syndrome: Labora-
clinical implications, Circ J 74(4):597–607, 2010. tory detection, mechanisms of action and treatment, J Jntern Med Feb 15.
22. Thijs T, et al: Review: platelet physiology and antiplatelet agents, Clin doi: 10.111/j. 1365–2796, 2011. 02362, 2011 [Epub ahead of print].
Chem Lab Med 2010 Nov 5:[Epub ahead of print.]
23. Handin RI: Inherited platelet disorders, Hematology Amer Soc Hematol
Educ Program 396–402, 2005.
 CHAPTER

21
Alterations of Hematologic
Function in Children
Nancy E. Kline

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Disorders of Erythrocytes, 535 Neoplastic Disorders, 546
Acquired Disorders, 536 Leukemia and Lymphoma, 546
Inherited Disorders, 539
Disorders of Coagulation and Platelets, 544
Inherited Hemorrhagic Disease, 544
Antibody-Mediated Hemorrhagic Disease, 545

Among the diseases that affect erythrocytes in children are acquired The most dramatic form of acquired congenital hemolytic anemia
disorders, such as iron deficiency anemia and hemolytic disease of the is hemolytic disease of the newborn (HDN), also termed erythroblas-
newborn, and inherited disorders, such as glucose-6-phosphate dehy- tosis fetalis. HDN is an alloimmunity (isoimmunity) disease in which
drogenase deficiency, sickle cell disease, and the thalassemias. maternal blood and fetal blood are antigenically incompatible, causing
Childhood disorders that involve the coagulation process and the mother’s immune system to produce antibodies against fetal eryth-
platelets include inherited hemorrhagic diseases, such as the hemo- rocytes. Fetal erythrocytes attacked by (i.e., bound to) maternal anti-
philias, and antibody-mediated hemorrhagic diseases, including idio- bodies are recognized as foreign or defective by the fetal mononuclear
pathic thrombocytopenic purpura. Finally, leukocyte disorders, such phagocyte system and are removed from the circulation by phagocy-
as leukemia and the lymphomas (both Hodgkin lymphoma and non- tosis, usually in the fetal spleen. (For a complete examination of HDN,
Hodgkin lymphoma), are discussed in this chapter. see the discussion that follows.) Other acquired hemolytic anemias—
some of which begin in utero—include those caused by infections or
the presence of toxic chemicals.
DISORDERS OF ERYTHROCYTES The inherited forms of hemolytic anemia result from intrinsic
Anemia is the most common blood disorder in children. Like the defects of the child’s erythrocytes, any of which can lead to eryth-
anemias of adulthood, the anemias of childhood are caused by inef- rocyte removal by the mononuclear phagocyte system. Structural
fective erythropoiesis or premature destruction of erythrocytes. The defects include abnormal cellular size or shape and abnormalities
most common cause of insufficient erythropoiesis is iron deficiency, of plasma membrane structure (spherocytosis). Intracellular defects
which may result from insufficient dietary intake or chronic loss of include enzyme deficiencies, the most common of which is glu-
iron caused by bleeding. The hemolytic anemias of childhood may cose-6-phosphate dehydrogenase (G6PD) deficiency, and defects
be divided into (1) disorders that result from premature destruction of hemoglobin synthesis, which manifest as sickle cell disease or
caused by intrinsic abnormalities of the erythrocytes and (2) disorders thalassemia, depending on which component of hemoglobin is
that result from damaging extraerythrocytic factors. The hemolytic defective. These and other causes of childhood anemia are listed in
anemias are either inherited or acquired. Table 21-1.

535
536 CHAPTER 21  Alterations of Hematologic Function in Children

TABLE 21-1 ANEMIAS OF CHILDHOOD

CAUSE ANEMIC CONDITION
Deficient Erythropoiesis or Hemoglobin Synthesis
Decreased stem cell population in marrow (congenital or acquired pure red cell aplasia) Normocytic-normochromic anemia
Decreased erythropoiesis despite normal stem cell population in marrow (infection, inflammation, cancer, chronic renal Normocytic-normochromic anemia
disease, congenital dyserythropoiesis)
Deficiency of a factor or nutrient needed for erythropoiesis
Cobalamin (vitamin B12), folate Megaloblastic anemia
Iron Microcytic-hypochromic anemia

Increased or Premature Hemolysis

Alloimmune disease (maternal-fetal Rh, ABO, or minor blood group incompatibility) Autoimmune hemolytic anemia
Autoimmune disease (idiopathic autoimmune hemolytic anemia, symptomatic systemic lupus erythematosus, lymphoma, Autoimmune hemolytic anemia
drug-induced autoimmune processes)
Inherited defects of plasma membrane structure (spherocytosis, elliptocytosis, stomatocytosis) or cellular size or both Hemolytic anemia
(pyknocytosis)
Infection (bacterial sepsis, congenital syphilis, malaria, cytomegalovirus infection, rubella, toxoplasmosis, disseminated Hemolytic anemia
herpes)
Intrinsic and inherited enzymatic defects (deficiencies) of glucose-6-phosphate dehydrogenase [G-6-PD], pyruvate kinase, Hemolytic anemia
5′-nucleotidase, glucose phosphate isomerase
Inherited defects of hemoglobin synthesis Sickle cell anemia
Thalassemia
Disseminated intravascular coagulation (see Chapter 20) Hemolytic anemia
Galactosemia Hemolytic anemia
Prolonged or recurrent respiratory or metabolic acidosis Hemolytic anemia
Blood vessel disorders (cavernous hemangiomas, large vessel thrombus, renal artery stenosis, severe coarctation of aorta) Hemolytic anemia

Acquired Disorders Other symptoms and signs include splenomegaly, widened skull
Iron Deficiency Anemia sutures, decreased physical growth and developmental delays, pica (a
Iron deficiency anemia is the most common blood disorder of infancy behavior in which nonfood substances are eaten), and altered neuro-
and childhood, with the highest incidence occurring between 6 months logic and intellectual functions, especially those involving attention
and 2 years of age. Incidence is not related to gender or race, but span, alertness, and learning ability.
socioeconomic factors are important because they affect nutrition.1
Iron deficiency anemia is common in children because they need an EVALUATION AND TREATMENT  The most definitive test for dif-
extremely high amount of iron for normal growth to occur. ferentiating iron deficiency from other microcytic states is the absence
Between 4 years of age and the onset of puberty, dietary iron defi- of iron stores in the bone marrow. However, measurements of serum
ciency is uncommon. During adolescence, however, it is relatively ferritin concentration, transferrin saturation, and free erythrocyte pro-
common, especially in menstruating females. Rapid growth, together toporphyrin level can help avoid a painful bone marrow evaluation
with the average teenager’s dietary habits, causes iron depletion. to make a diagnosis. Evaluation and treatment of iron deficiency ane-
mia in children are similar to those in adults. Dietary modification is
PATHOPHYSIOLOGY  Blood loss is a common cause of iron required to prevent recurrences of iron deficiency anemia.
­ eficiency anemia in childhood. Chronic iron deficiency anemia from
d
occult (hidden) blood loss may be caused by a gastrointestinal lesion, Hemolytic Disease of the Newborn
parasitic infestation, or hemorrhagic disease. As many as one third The most common cause of hemolytic anemia in newborns is alloim-
of infants with severe iron deficiency anemia have chronic intestinal mune disease (HDN). HDN can occur only if antigens on fetal eryth-
blood loss induced by exposure to a heat-labile protein in cow’s milk. rocytes differ from antigens on maternal erythrocytes. Maternal-fetal
Such exposure causes an inflammatory gastrointestinal reaction that incompatibility exists if mother and fetus differ in ABO blood type or
damages the mucosa and results in diffuse hemorrhage. if the fetus is Rh-positive and the mother is Rh-negative. Some minor
blood antigens also may be involved. (The antigenic properties of
CLINICAL MANIFESTATIONS  The symptoms of mild anemia—­ erythrocytes are described in Chapter 7.)
listlessness and fatigue—usually are not present or are undetectable in ABO incompatibility occurs in about 20% to 25% of all pregnan-
infants and young children, who are unable to describe these symp- cies, but only 1 in 10 cases of ABO incompatibility results in HDN.
toms. Therefore parents generally do not note any change in the child’s Rh incompatibility occurs in fewer than 10% of pregnancies and
behavior or appearance until moderate anemia has developed. General rarely causes HDN in the first incompatible fetus. Even after five or
irritability, decreased activity tolerance, weakness, and lack of interest more pregnancies, only 5% of women have babies with hemolytic dis-
in play are nonspecific indications of anemia. When hemoglobin levels ease. Usually erythrocytes from the first incompatible fetus cause the
fall below 5 g/dl, pallor, anorexia, tachycardia, and systolic murmurs mother’s immune system to produce antibodies that affect the fetuses
may occur. of subsequent incompatible pregnancies. Only one in three cases of
 CHAPTER 21  Alterations of Hematologic Function in Children 537

Maternal
circulation Maternal
circulation
Maternal
Rh-negative Maternal
erythrocyte Rh-negative
erythrocyte

A Fetal
B Rh
Rh-positive antibodies
erythrocyte
Fetal enters
Rh-positive maternal
erythrocyte circulation

Maternal
circulation
C D

D antigen
Agglutination of
fetal Rh-positive
Hemolysis
erythrocytes
leads to hemolytic
disease of
the newborn

Maternal
Rh antibodies
cross the
placenta

FIGURE 21-1  Hemolytic Disease of the Newborn (HDN). A, Before or during delivery, Rh-positive
erythrocytes from the fetus enter the blood of an Rh-negative woman through a tear in the placenta.  
B, The mother is sensitized to the Rh antigen and produces Rh antibodies. Because this usually ­happens
after delivery, there is no effect on the fetus in the first pregnancy. C, During a subsequent pregnancy
with an Rh-positive fetus, Rh-positive erythrocytes cross the placenta, enter the maternal circulation,
and (D) stimulate the mother to produce antibodies against the Rh antigen. (Modified from Seeley RR,
Stephens TD, Tate P: Anatomy and physiology, ed 3, St Louis, 1995, Mosby.)

HDN is caused by Rh incompatibility; most cases are caused by ABO which are produced on exposure to certain foods or infection by
incompatibility. gram-negative bacteria. (Anti-O antibodies do not exist because type
O erythrocytes are not antigenic.) Therefore IgG against type A or B
PATHOPHYSIOLOGY  HDN will result (1) if the mother’s blood con- erythrocytes usually is preformed in maternal blood and can enter the
tains preformed antibodies against fetal erythrocytes or produces them fetal circulation throughout the first incompatible pregnancy.
on exposure to fetal erythrocytes, (2) if sufficient amounts of antibody Anti-Rh antibodies, on the other hand, are formed only in response
(usually immunoglobulin G [IgG]) cross the placenta and enter fetal to the presence of incompatible (Rh-positive) erythrocytes in the blood
blood, and (3) if IgG binds with sufficient numbers of fetal erythrocytes of an Rh-negative mother. Sources of exposure include fetal blood that
to cause widespread antibody-mediated hemolysis or splenic removal. is mixed with the mother’s blood at the time of delivery, transfused
(Antibody-mediated cellular destruction is described in Chapter 7.) blood, and, rarely, previous sensitization of the mother by her own
Maternal antibodies may be formed against type B erythrocytes if mother’s incompatible blood (Figure 21-1).
the mother is type A or against type A erythrocytes if the mother is type The first Rh-incompatible pregnancy generally presents no diffi-
B. Usually, however, the mother is type O and the fetus is A or B. ABO culties because few fetal erythrocytes cross the placental barrier dur-
incompatibility can cause HDN even if fetal erythrocytes do not escape ing gestation. When the placenta detaches at birth, however, a large
into the maternal circulation during pregnancy. This occurs because number of fetal erythrocytes usually enter the mother’s bloodstream.
the blood of most adults already contains anti-A or anti-B antibodies, If the mother is Rh-negative and the fetus is Rh-positive, the mother
538 CHAPTER 21  Alterations of Hematologic Function in Children

Normal hemoglobin β-chain

Glutamic Glutamic
Valine Histidine Leucine Threonine Proline acid acid

Sickle cell anemia hemoglobin β-chain

Glutamic
Valine Histidine Leucine Threonine Proline Valine
A acid

5 Macrophages
phagocytose
remnants of
hemolytic sickled
cells.
Normal red blood cell Sickled red blood cell
Macrophage-sheathed
capillaries
1 Retrogade
obstruction by Splenic sinusoid
irreversibly sickled
cells is a consequence
of reduction in blood
flow that aggravates
the obstruction
because oxygen
tension decreases. 2 Preferential adhesion of
4 Hemolysis caused by
sickled cells to endothelial cell precipitation of Hb and dissociation of
surfaces increases with peripheral the red blood cell plasma membrane
resistance and causes narrowing 3 Dense trapping of from the subjacent cytoskeleton.
C of the vascular lumen.
sickled cells in splenic
sinusoids.
Sickle cell anemia is determined by the substitution of normal show a sickling deformity and hemolytic anemia in the presence or
hemoglobin (Hb A) by hemoglobin S (Hb S) caused by a point absence of normal oxygen tension. Heterozygous individuals contain a
mutation (replacement of the nucleotide triplet CTC coding mixture of Hb A and Hb S, and sickling and anemia are observed
glutamic acid at the mRNA level [GAG] by the CAC triplet [GUG] when the tension of oxygen decreases.
coding for valine) that modifies the physicochemical properties of the Irreversibly sickled red blood cells are trapped within the splenic
β-globin chain of hemoglobin. All hemoglobin is abnormal in sinusoids and are destroyed by adjacent macrophages. Hemolysis may
homozygous individuals for the mutant gene, and red blood cells also occur in the macrophage-sheathed capillaries of the red pulp.

FIGURE 21-2  Sickle Cell Hemoglobin. A, Sickle cell hemoglobin is produced by a recessive allele
of the gene encoding the beta-chain of the protein hemoglobin. It represents a single amino acid
change—from glutamic acid to valine at the sixth position of the chain. In this model of a hemoglobin
molecule, the position of the mutation can be seen near the end of the upper arm. B, Color-enhanced
electron micrograph shows normal erythrocytes and sickled blood cell. C, Brief summary of sickle cell.
(A from Raven PH, Johnson GB: Biology, ed 3, St Louis, 1992, Mosby; B copyright Dennis Kunkel
Microscopy, Inc; C from Kierszenbaum A and Tres L: Histology and cell biology: an introduction to
pathology, ed 3, St Louis, 2012, Mosby.)
 CHAPTER 21  Alterations of Hematologic Function in Children 539

produces anti-Rh antibodies. Anti-Rh antibodies persist in the blood-

stream for a long time, and if the next offspring is Rh-positive, the
mother’s anti-Rh antibodies can enter the bloodstream of the fetus and
destroy the erythrocytes. Antibodies against Rh antigen D are of the
IgG class and easily cross the placenta.
IgG-coated fetal erythrocytes usually are destroyed in the spleen. As
hemolysis proceeds, the fetus becomes anemic. Erythropoiesis acceler-
ates, particularly in the liver and spleen, and immature nucleated cells
(erythroblasts) are released into the bloodstream (hence the name eryth-
roblastosis fetalis). The degree of anemia depends on the length of time
the antibody has been in the fetal circulation, the concentration of the
antibody, and the ability of the fetus to compensate for increased hemo-
lysis. Unconjugated (indirect) bilirubin, which is formed during break-
down of hemoglobin, is transported across the placental barrier into the
maternal circulation and is excreted by the mother. Hyperbilirubine- FIGURE 21-3  Normal and Sickle-Shaped Blood Cells. Scanning
mia occurs in the neonate after birth because excretion of lipid-soluble electron micrograph of normal and sickle-shaped red blood cells.
unconjugated bilirubin through the placenta no longer is possible. The irregularly shaped cells are the sickle cells; the circular cells are
The pathophysiologic effects of HDN are more severe in Rh incom- the normal blood cells. (From Raven PH, Johnson GB: Biology, ed
patibility than in ABO incompatibility. ABO incompatibility may 3, St Louis, 1992, Mosby.)
resolve after birth without life-threatening complications. Maternal-fetal
incompatibility in which a mother with type O blood has a child with
type A or B blood usually is so mild that it does not require treatment. fetal blood sampling, amniotic fluid spectrophotometry, and ultra-
Rh incompatibility is more likely than ABO incompatibility to sound fetal assessment.
cause severe or even life-threatening anemia, death in utero, or dam- The key to treatment of HDN resulting from Rh incompatibility
age to the central nervous system. Severe anemia alone can cause death lies in prevention (immunoprophylaxis). One of the success stories
as a result of cardiovascular complications. Extensive hemolysis also of immunology has been the result obtained with Rh immune globu-
results in increased levels of unconjugated bilirubin in the neonate’s lin (RhoGAM), a preparation of antibody against Rh antigen D. If an
circulation. If bilirubin levels exceed the liver’s ability to conjugate and Rh-negative woman is given Rh immune globulin within 72 hours of
excrete bilirubin, some of it is deposited in the brain, causing cellular exposure to Rh-positive erythrocytes, she will not produce antibody
damage and eventually, if the neonate does not receive exchange trans- against the D antigen, and the next Rh-positive baby she conceives will
fusions, death. be protected.
Fetuses that do not survive anemia in utero usually are stillborn, If antigenic incompatibility of the mother’s erythrocytes is not dis-
with gross edema in the entire body, a condition called hydrops fetalis. covered in time to administer prophylactic immune globulin (Rho-
Death can occur as early as 17 weeks’ gestation and results in spontane- GAM) and a child is born with HDN, treatment consists of exchange
ous abortion. transfusions in which the neonate’s blood is replaced with new Rh-posi-
tive blood that is not contaminated with anti-Rh antibodies. Photother-
CLINICAL MANIFESTATIONS  Neonates with mild HDN may apy also is used to reduce the toxic effects of unconjugated bilirubin.
appear healthy or slightly pale, with slight enlargement of the liver or
spleen. Pronounced pallor, splenomegaly, and hepatomegaly indicate Inherited Disorders
severe anemia, which predisposes the neonate to cardiovascular failure Sickle Cell Disease
and shock. Life-threatening Rh incompatibility is rare today, largely Sickle cell disease is a group of disorders characterized by the produc-
because of the routine use of Rh immunoglobulin. tion of abnormal hemoglobin S (Hb S) within the erythrocytes. Hb
Because the maternal antibodies remain in the neonate’s circula- S is formed by a genetic mutation in which one amino acid (valine)
tory system after birth, erythrocyte destruction can continue. This replaces another (glutamic acid) (Figure 21-2). Hb S, the so-called
causes hyperbilirubinemia and icterus neonatorum (neonatal jaun- sickle hemoglobin, reacts to deoxygenation and dehydration by solidi-
dice) shortly after birth. Without replacement transfusions, in which fying and stretching the erythrocyte into an elongated sickle shape,
the child receives Rh-negative erythrocytes, the bilirubin is deposited producing hemolytic anemia (Figure 21-3).
in the brain, a condition termed kernicterus. Kernicterus produces Sickle cell disease is an inherited, autosomal recessive disorder
cerebral damage and usually causes death (icterus gravis neonato- expressed as sickle cell anemia, sickle cell–thalassemia disease, or
rum). Infants who do not die may have mental retardation, cerebral sickle cell–hemoglobin C disease, depending on mode of inheritance
palsy, or high-frequency deafness. (Table 21-2). (See Chapter 2 for a discussion of genetic inheritance of
disease.) Sickle cell anemia, a homozygous form, is the most severe.
EVALUATION AND TREATMENT  Routine evaluation of fetuses at Sickle cell–thalassemia and sickle cell–Hb C disease are heterozy-
risk for HDN (i.e., fetuses resulting from Rh- or ABO-incompatible gous forms in which the child simultaneously inherits another type of
matings) includes the Coombs test. The indirect Coombs test measures abnormal hemoglobin from one parent. Sickle cell trait, in which the
antibody in the mother’s circulation and indicates whether the fetus is child inherits Hb S from one parent and normal hemoglobin (Hb A)
at risk for HDN. The direct Coombs test measures antibody already from the other, is a heterozygous carrier state that rarely has clinical
bound to the surfaces of fetal erythrocytes and is used primarily to con- manifestations. All forms of sickle cell disease are lifelong conditions
firm the diagnosis of antibody-mediated HDN. With a prior history of and have no known cure.
fetal hemolytic disease, diagnostic tests are done to determine risk with Sickle cell disease tends to occur in persons with origins in
the current pregnancy. These tests include maternal antibody titers, equatorial countries, particularly central Africa, the Near East, the
540 CHAPTER 21  Alterations of Hematologic Function in Children

TABLE 21-2 INHERITANCE OF SICKLE CELL DISEASE

HEMOGLOBIN INHERITED HEMOGLOBIN INHERITED FORM OF SICKLE CELL DISEASE
FROM FIRST PARENT FROM SECOND PARENT IN CHILD
Hb S (an abnormal hemoglobin) Hb S Sickle cell anemia: homozygous inheritance in which child’s hemoglobin
is mostly Hb S, with remainder Hb F (fetal hemoglobin)
Hb S Defective or insufficient alpha or beta chains Sickle cell–thalassemia disease (heterozygous inheritance of Hb S and
of Hb A (alpha- or beta-thalassemia) alpha- or beta-thalassemia)
Hb S Hb C or D (both abnormal hemoglobins) Sickle cell–hemoglobin C (or D) disease (heterozygous inheritance of
hemoglobin S and either C or D)
Hb S Normal hemoglobins (mostly Hb A) Sickle cell trait, carrier state (heterozygous inheritance of Hb S and
normal hemoglobin)

Abnormal Hb S
present in
erythrocytes

Hypoxemia, decreased
pH, low temperature,
and/or decreased plasma
volume occurs

Persistent hypoxemia
Reversal of causes further reduction Sickled cells
hypoxemia in PO2 in the clog vessels
(reoxygenation, microcirculation;
rehydration) erythrocytes sickle
Sickled cells slow
blood flow, promote
Sickled erythrocytes hypoxemia, and
regain normal shape, increase sickling
resume normal
function

Decreased blood pH
decreases
hemoglobin’s affinity
for O2; PO2 drops,
increases sickling
FIGURE 21-4  Sickling of Erythrocytes.

Mediterranean area, and parts of India. In the United States, sickle cell polymerizes, forming abnormal fluid polymers. As these polymers
disease is most common in blacks, with a reported incidence ranging realign, they cause the red cell to deform into the sickle shape. Sick-
from 1:400 to 1:500 live births. In the general population, the risk of ling depends on the degree of oxygenation, pH, and dehydration of the
two black parents having a child with sickle cell anemia is 0.7%. Sickle individual. A decrease in oxygenation (hypoxemia) and pH, as well as
cell–hemoglobin C disease is less common (1 in 800 births), and sickle dehydration, increases sickling. Deoxygenation is probably the most
cell–thalassemia occurs in 1 in 1700 births. important variable in determining the occurrence of sickling.2 Sickle-
Sickle cell trait occurs in 7% to 13% of African Americans, whereas trait cells sickle at oxygen tensions of about 15 mm Hg, whereas those
its incidence among East Africans may be as high as 45%. The sickle from an individual with sickle cell disease begin to sickle at about 40
cell trait may provide protection against lethal forms of malaria, a mm Hg. Sickled erythrocytes tend to plug the blood vessels, increasing
genetic advantage to carriers who reside in endemic regions for malaria the viscosity of the blood, which slows circulation and causes vascular
(Mediterranean and African zones) but no advantage to carriers living occlusion, pain, and organ infarction. Viscosity increases the time of
in the United States. exposure to less oxygenation, promoting further sickling. Sickled cells
undergo hemolysis in the spleen or become sequestered there, causing
PATHOPHYSIOLOGY  Hemoglobin S is soluble and usually causes no blood pooling and infarction of splenic vessels. The anemia that fol-
problem when properly oxygenated. When oxygen tension decreases, lows triggers erythropoiesis in the marrow and, in extreme cases, in the
the single amino acid substitution in the beta-globin chain of Hb S liver (Figure 21-4).
 CHAPTER 21  Alterations of Hematologic Function in Children 541

CVA (stroke)
Paralysis
C Death

Retinopathy
Blindness
Hemorrhage
A Hepatomegaly
Infarction Gallstones
Pneumonia
Chest syndrome Splenomegaly
Pulmonary Splenic sequestration
hypertension Autosplenectomy
Atelectasis
Hematuria
Congestive Hyposthenuria
heart failure (dilute urine)

Abdominal
B pain

Dactylitis
(Hand-foot syndrome)
Hemolysis
Priapism

Pain
Anemia Osteomyelitis

Chronic
ulcers

FIGURE 21-5  Differences Between Effects of (A) Normal and (B) Sickled RBCs on Blood Circula-
tion and Selected Consequences in a Child. C, Tissue Effects of Sickle Cell Anemia. CVA, Cerebro-
vascular accident. (A and B adapted from Hockenberry MJ et al, editors: Wong’s nursing care of infants
and children, ed 8, St Louis, 2007, Mosby.)

Sickling usually is not permanent; most sickled erythrocytes regain young child. Because the spleen can hold as much as one fifth of
a normal shape after reoxygenation and rehydration. Irreversible sick- the body’s blood supply at one time, up to 50% mortality has been
ling is caused by irreversible plasma membrane damage caused by reported, with death being caused by cardiovascular collapse.
sickling. In persons with sickle cell anemia, in which the erythrocytes 3. Aplastic crisis. Profound anemia is caused by diminished eryth-
contain a high percentage of Hb S (75% to 95%), up to 30% of the ropoiesis despite an increased need for new erythrocytes. In sickle
erythrocytes can become irreversibly sickled. Occasionally, irreversible cell anemia, erythrocyte survival is only 10 to 20 days. Normally a
sickling occurs in sickle cell disease but not in the carrier state (sickle compensatory increase in erythropoiesis (five to eight times nor-
cell trait). Sickling also can be triggered by increased plasma osmolal- mal) replaces the cells lost through premature hemolysis. If this
ity, decreased plasma volume, and low environmental temperature. compensatory response is compromised, aplastic crisis develops in
a very short time.
CLINICAL MANIFESTATIONS  When sickling occurs, the general 4. Hyperhemolytic crisis. Although unusual, this may occur in asso-
manifestations of hemolytic anemia—pallor, fatigue, jaundice, and ciation with certain drugs or infections.
irritability—sometimes are accompanied by acute manifestations The clinical manifestations of sickle cell disease usually do not
called crises. Extensive sickling can precipitate the following four types appear until the infant is at least 6 months old, at which time the post-
of crises: natal decrease in concentrations of Hb F causes concentrations of Hb
1. Vaso-occlusive crisis (thrombotic crisis). This begins with sick- S to rise (Figure 21-5). Infection is the most common cause of death
ling in the microcirculation. As blood flow is obstructed by sickled related to sickle cell disease. Sepsis and meningitis develop in as many
cells, vasospasm occurs and a “logjam” effect blocks all blood flow as 10% of children with sickle cell anemia during the first 5 years of
through the vessel. Unless the process is reversed, thrombosis and life, with a death rate of 25%. Survival time is unpredictable, but many
infarction (death caused by lack of oxygen) of local tissue follow. individuals die in their twenties.
Vasoocclusive crisis is extremely painful and may last for days or Sickle cell–Hb C disease is usually milder than sickle cell anemia.
even weeks, with an average duration of 4 to 6 days. The frequency The main clinical problems are related to vaso-occlusive crises and are
of this type of crisis is variable and unpredictable. believed to result from higher hematocrit values and viscosity. In older
2. Sequestration crisis. Large amounts of blood become acutely children, sickle cell retinopathy, renal necrosis, and aseptic necrosis of
pooled in the liver and spleen. This type of crisis is seen only in the the femoral heads occur along with obstructive crises.
542 CHAPTER 21  Alterations of Hematologic Function in Children

1 2

Sperm Eggs Embryos

Culture dish 3

Endometrium
Amniotic cavity

5 4
Newborn
Placenta

Uterine wall

FIGURE 21-6  Prepregnancy Sickle Cell Test. This technique has potential for detection of other
inherited diseases. 1, Fertilization produces several embryos. 2, The embryos are tested for the pres-
ence of the gene. 3, The embryos without the gene are implanted. 4, Amniocentesis confirms whether
the fetus (or fetuses) has the sickle cell gene. 5, Woman has a normal child.

Sickle cell–thalassemia has the mildest clinical manifestations of all was named thalassemia, which is derived from the Greek word for
the sickle cell diseases. The normal hemoglobins, particularly Hb F, sea, because it was discovered initially in persons with origins near the
inhibit sickling. In addition, the erythrocytes tend to be small (micro- Mediterranean Sea. Beta-thalassemia, in which synthesis of the beta-
cytic) and to contain relatively little hemoglobin (hypochromic), mak- globin chain is slowed or defective, is prevalent among Greeks, Italians,
ing them less likely to occlude the microcirculation, even when in a and some Arabs and Sephardic Jews. Alpha-thalassemia, in which the
sickled state. alpha chain is affected, is most common among Chinese, Vietnamese,
Cambodians, and Laotians. Both alpha- and beta-thalassemias are
EVALUATION AND TREATMENT  The sickle cell trait does not common among blacks.
affect life expectancy or interfere with daily activities. However, on Both alpha- and beta-thalassemias are referred to as major or
rare occasions, severe hypoxia caused by shock, vigorous exercising minor, depending on how many of the genes that control alpha- or
at high altitudes, flying at high altitudes in unpressurized aircraft, or beta-chain synthesis are defective and whether the defects are inher-
undergoing anesthesia is associated with vaso-occlusive episodes in ited homozygously (thalassemia major) or heterozygously (thalasse-
persons with sickle cell trait. These cells form an ivy shape instead of mia minor). Pathophysiologic effects range from mild microcytosis to
a sickle shape. death in utero, depending on the number of defective genes and mode
The parents’ hematologic history and clinical manifestations may of inheritance. The anemic manifestation of thalassemia is microcytic-
suggest that a child has sickle cell disease, but hematologic tests are hypochromic hemolytic anemia.
necessary for diagnosis. If the sickle solubility test confirms the pres-
ence of Hb S in peripheral blood, hemoglobin electrophoresis provides PATHOPHYSIOLOGY  The fundamental defect in beta-thalassemia
information about the amount of Hb S in erythrocytes. Prenatal diag- is the uncoupling of alpha- and beta-chain synthesis. Beta-chain
nosis can be made after chorionic villus sampling as early as 8 to 10 production is depressed—moderately in the heterozygous form,
weeks’ gestation or by amniotic fluid analysis at 15 weeks’ gestation beta-thalassemia minor, and severely in the homozygous form,
(Figure 21-6). Newborn screening for sickle cell disease should be per- beta-thalassemia major (also called Cooley anemia). This results
formed according to state law. in erythrocytes having a reduced amount of hemoglobin and accu-
Treatment of sickle cell disease consists of supportive care aimed at mulations of free alpha chains. The free alpha chains are unstable
preventing consequences of anemia and avoiding crises. Genetic coun- and easily precipitate in the cell. Most erythroblasts that contain pre-
seling and psychologic support are important for the child and family. cipitates are destroyed by mononuclear phagocytes in the marrow,
Hydroxyurea is an antimetabolite that inhibits deoxyribonucleic resulting in ineffective erythropoiesis and anemia. Some of the pre-
acid (DNA) synthesis and causes an increase in the synthesis of hemo- cipitate-carrying cells do mature and enter the bloodstream, but they
globin F. It is used in the treatment of children with severe sickle cell are destroyed prematurely in the spleen, resulting in mild hemolytic
disease to increase hemoglobin level and reduce the incidence of vaso- anemia.
occlusive crises and hospitalization. It is well tolerated, with the most There are four forms of alpha-thalassemia: (1) alpha trait (the car-
common side effect being myelosuppression.3 rier state), in which a single alpha-chain–forming gene is defective;
(2) alpha-thalassemia minor, in which two genes are defective;
Thalassemias (3) hemoglobin H disease, in which three genes are defective; and
The alpha- and beta-thalassemias are inherited autosomal recessive (4) alpha-thalassemia major, a fatal condition in which all four alpha-
disorders that cause an impaired rate of synthesis of one of the two forming genes are defective. Death is inevitable because alpha chains
chains—alpha or beta—of adult hemoglobin (Hb A). The disorder are absent and oxygen cannot be released to the tissues.
 CHAPTER 21  Alterations of Hematologic Function in Children 543

FIGURE 21-7  Young Girl with Beta-Thalassemia Demonstrating

Mild Frontal Bossing (Prominence) of the Right Forehead and Mild
Maxillary Prominence. (From Hockenberry MJ et al, editors: Wong’s
nursing care of infants and children, ed 8, St Louis, 2007, Mosby.)

CLINICAL MANIFESTATIONS  Beta-thalassemia occurs more com-

monly than does alpha-thalassemia. Occasionally, synthesis of gamma
or delta polypeptide chains is defective, resulting in gamma- or delta-
thalassemia. (Hemoglobin chains are described in Chapter 19.)
Beta-thalassemia minor causes mild to moderate microcytic-­ FIGURE 21-8  Child with Beta-Thalassemia Major Who Has
hypochromic anemia, mild splenomegaly, bronze coloring of the skin, Severe Splenomegaly. (From Jorde LB et  al: Medical genetics,
and hyperplasia of the bone marrow. The degree of reticulocytosis ed 3, updated, St Louis, 2006, Mosby.)
depends on the severity of the anemia and results in skeletal changes
(Figure 21-7). Hemolysis of immature (and therefore fragile) erythro- analyzed, and a DNA genetic map can be constructed and evaluated for
cytes may cause a slight elevation in serum iron and indirect bilirubin the abnormalities characteristic of hydrops fetalis.
levels. Persons with beta-thalassemia minor are usually asymptomatic. Both alpha- and beta-thalassemia major are life-threatening. Children
Persons with beta-thalassemia major may become quite ill. Ane- with thalassemia major generally are weak, fail to thrive, show poor devel-
mia is severe and results in a significant cardiovascular burden with opment, and experience cardiovascular compromise with high-output
high-output congestive heart failure. In the past, death resulted from failure secondary to anemia. Untreated, they will die by 5 to 6 years of age.
cardiac failure. Today, blood transfusions can increase life span by 1
to 2 decades, and death usually is caused by hemochromatosis (from EVALUATION AND TREATMENT  Evaluation of thalassemia is based
transfusions). Liver enlargement occurs as a result of progressive on familial disease history, clinical manifestations, and blood tests.
hemosiderosis, whereas enlargement of the spleen is caused by extra- Peripheral blood smears that show microcytosis and hemoglobin elec-
medullary hemopoiesis and increased destruction of red blood cells trophoresis that demonstrates diminished amounts of alpha or beta
(Figure 21-8). Growth and maturation are retarded, and a characteris- chains are used to make the diagnosis. Analysis of fetal DNA from
tic chipmunk deformity develops on the face, caused by expansion of withdrawn amniotic fluid is used as a screening test to detect hydrops
bones to accommodate hyperplastic marrow (see Figure 21-7). fetalis (alpha-thalassemia major). Newborn screening for thalassemia
Persons who inherit the mildest form of alpha-thalassemia (the should be done according to state law.
alpha trait) usually are symptom free or have mild microcytosis. Alpha- Persons who are silent carriers or have thalassemia minor generally
thalassemia minor has clinical manifestations that are virtually identi- have few if any symptoms and require no specific treatment. Therapies to
cal to those of beta-thalassemia minor: mild microcytic-­hypochromic support and prolong life are necessary, however, for thalassemia major.
reticulocytosis, bone marrow hyperplasia, increased serum iron con- There is no cure for either condition. For both symptom-free carriers
centrations, and moderate splenomegaly. and those with the disease, prenatal diagnosis and genetic counseling
Signs and symptoms of alpha-thalassemia major are similar to may be the most important therapeutic measures that can be offered.
those of beta-thalassemia major, but milder. Moderate microcytic-
hypochromic anemia, enlargement of the liver and spleen, and bone
marrow hyperplasia are evident.
4 QUICK CHECK 21-1
1. Why do clinical manifestations of sickle cell disease not appear until the
Alpha-thalassemia major causes hydrops fetalis and fulminant infant is at least 6 months old?
intrauterine congestive heart failure. In addition to edema and mas- 2. Why is Rh incompatibility rare today?
sive ascites, the fetus has a grossly enlarged heart and liver. Diagnosis 3. Why do children with thalassemia major develop cardiovascular
usually is made postmortem. Prenatal screening for this disorder can complications?
be performed by use of chorionic villus sampling. These cells can be
544 CHAPTER 21  Alterations of Hematologic Function in Children

DISORDERS OF COAGULATION AND PLATELETS Point mutations, in which a single base in the DNA is mutated to
another base, represent a second type of mutation that causes hemo-
Inherited Hemorrhagic Disease philia. When a point mutation becomes a de novo stop codon (non-
Hemophilias sense mutation), translation of the protein ceases and a shortened
Awareness of a serious bleeding disorder in males was documented version of the protein is synthesized. Usually the protein is destroyed
nearly 2000 years ago in the Babylonian Talmud, which exempted intracellularly and never reaches the plasma. This type of defect is asso-
from the rite of circumcision those boys having male relatives prone ciated with severe hemophilia—that is, with coagulant activity levels
to excessive bleeding. In 1803 the first description of this disorder below 1%. Point mutations in which one amino acid is substituted
appeared in the medical literature, where it was noted to be X-linked for another can cause phenotypes of varying severity. The mutation
in nature and associated with joint bleeding and crippling. of an important amino acid can destroy protein function, activation,
Table 21-3 lists the coagulation factors that are associated with or folding; inhibit intracellular processing; or cause protein clearance.
clinical bleeding. Until 1952 the term hemophilia was reserved for Unlike deletion mutations, point mutations at the same site have been
deficiency of factor VIII (antihemophilic factor). Since that time, two recorded in different families with hemophilia.
additional coagulation proteins, factor IX (plasma thromboplastin Not all coagulation disorders are discussed in this chapter because
component [PTC]) and factor XI (plasma thromboplastin antecedent some are extremely rare (e.g., congenital dysfibrinogenemias), whereas
[PTA]), have been identified and their deficiency has been associated others have no clinical significance (e.g., Hageman factor deficiency,
with similar clinical manifestations. Congenital deficiencies of these a condition in which profound laboratory deficiency of factor XII has
three plasma clotting factors—VIII, IX, and XI—account for 90% to absolutely no clinical effects on the child).
95% of the hemorrhagic bleeding disorders collectively called hemo-
philia. Table 21-3 lists coagulation factors and associated disorders, CLINICAL MANIFESTATIONS  Children with severe hemophilia
and the major types of hemophilia are summarized in Table 21-4. start to bleed at different ages. There is no transfer of maternal clot-
ting factor to the fetus, yet many boys with hemophilia are circumcised
PATHOPHYSIOLOGY  Two types of defects dominate the hereditary without excessive bleeding. Normal hemostasis is achieved in these
defects of hemophilia to date: gene deletions and point mutations infants because clotting is activated through the extrinsic coagulation
(base pair substitutions). Both types of genetic defects are associated cascade.
with severe hemophilia A, in which no factor VIII circulates in the During the first year, spontaneous bleeding often is minimal, but
blood. Numerous gene mutations and deletions have been identified hematoma formation may result from injections and from firm hold-
at the molecular level in factor VII and IX deficiency. The molecular ing (e.g., under the arms). Easy bruising, hemarthrosis (bleeding into
defect that leads to hemophilia is identical among members of a given joints), or both occur with ambulation. By age 3 to 4 years, 90% of chil-
family; however, the deletion mutation has been unique in each family dren with hemophilia have shown episodes of persistent bleeding from
studied.4 relatively minor traumatic lacerations (e.g., to the lip or tongue). This
usually is the first clinical manifestation of hemophilia. Hemorrhage
into the elbows, knees, and ankles causes pain, limits joint movement,
TABLE 21-3 THE COAGULATION
FACTORS AND ASSOCIATED
DISORDERS TABLE 21-4 THE HEMOPHILIAS
CLOTTING TYPE DESCRIPTION
FACTORS SYNONYM DISORDER Hemophilia A Caused by factor VIII deficiency; most common
I Fibrinogen Congenital deficiency (afibrino- (classic hemophilia) of hemophilias; inherited as X-linked recessive
genemia) and dysfunction disorder; factor VIII gene has been mapped
(dysfibrinogenemia) to distal arm of X chromosome and clones;
II Prothrombin Congenital deficiency or affects males and is transmitted by females;
dysfunction 1:5000–10,000 male births; occurs with varying
V Labile factor, Congenital deficiency (parahe- degrees of severity
proaccelerin mophilia) Hemophilia B Caused by factor IX deficiency; transmitted as
VII Stable factor or Congenital deficiency ­(Christmas disease) X-linked recessive trait; clinically indistinguish-
­proconvertin able from factor VIII deficiency, however, less
VIII Antihemophilic factor Congenital deficiency is hemo- severe than hemophilia A (IX gene also has
(AHF) philia A (classic hemophilia) been cloned); 1:30,000 male births; occurs with
IX Christmas factor Congenital deficiency is ­varying degrees of severity
hemophilia B Hemophilia C Caused by factor XI deficiency; inherited as
X Stuart-Prower factor Congenital deficiency autosomal recessive disease; occurs equally
XI Plasma thromboplastin Congenital deficiency, in males and females; bleeding is usually less
antecedent sometimes referred to as severe than with A or B
hemophilia C von Willebrand Also caused by factor VIII deficiency; results from
XII Hageman factor Congenital deficiency is not disease inherited autosomal dominant trait encoded by
associated with clinical a gene on chromosome 12; has variable ­clinical
symptoms manifestations and hematologic findings; infusion
XIII Fibrin-stabilizing factor Congenital deficiency of plasma causes factor VIII activity to increase
 CHAPTER 21  Alterations of Hematologic Function in Children 545

by mononuclear phagocytes in the spleen and other lymphoid tissues

TABLE 21-5 LABORATORY TESTS
at a rate that exceeds the ability of the bone marrow to produce them.
OF COAGULATION
TEST SIGNIFICANCE PATHOPHYSIOLOGY  In approximately 70% of cases of ITP, there
Thrombin time Measures fibrinogen level; ­usually is an antecedent viral disease (e.g., cytomegalovirus [CMV], Epstein-
­elevated first because without Barr virus [EBV], parvovirus, or respiratory tract infection) that pre-
­fibrinogen, blood cannot clot cedes the eruption of petechiae or purpura by 1 to 3 weeks. High levels
Prothrombin time (PT) Decrease indicates a deficiency of of IgG have been found bound to platelets and may represent immune
factors II, V, VII, or X; also used to complexes on the platelet surface (see Health Alert: Vaccine-Associated
monitor warfarin sodium (Couma- ITP in Early Childhood).
din) therapy
Activated partial thromboplastin Assesses for factors XII, XI, IX, and HEALTH ALERT
time (PTT or APTT) VIII; also used to monitor heparin
Vaccine-Associated ITP in Early Childhood
therapy
PT or APTT mixing study Differentiates between factor defi- Over the last several years, there has been growing concern that childhood
ciency and factor antibody activity vaccinations are associated with an increased incidence of ITP. A retrospec-
Specific factor assay Measures specific factors; XIII, XII, tive study in 2010 was performed to examine the relationship between vac-
XI, X, IX, VIII, VII, V, II, fibrinogen cination and ITP in 20 children younger than age 3 years. Of these 20 children,
(factor I) 12 developed ITP following vaccination: 5 after hepatitis B virus vaccine at 1
month of age, 4 after the first dose of diphtheria-tetanus-acellular pertussis
(DTaP) vaccine at 2 to 3 months of age, 2 after the first dose of measles-
mumps-rubella (MMR) vaccine at 16 months of age, and 1 after the first dose
and predisposes the child to degenerative joint changes. Spontaneous of varicella vaccine at 14 months of age. Although this is a small sample, vac-
hematuria and epistaxis are troublesome but minor complications. cination may be a risk factor for ITP in infancy and early childhood.
Recurrent bleeding, both spontaneous and after minor trauma, is a
lifelong problem. Many affected persons experience phases or cycles of Data from Hsieh Y, Lin L: Thrombocytopenic purpura following vac-
spontaneous bleeding episodes. Mechanisms that cause this phenom- cination in early childhood: experience of a medical center in the past 2
enon are unknown. Intracranial hemorrhage and bleeding into the tis- decades, J Chin Med Assoc 73(12):634–637, 2010.
sues of the neck or abdomen constitute life-threatening emergencies.
CLINICAL MANIFESTATIONS  Bruising and a generalized petechial
EVALUATION AND TREATMENT  Although laboratory tests are of rash often occur with acute onset. Asymmetric bruising is typical and
primary value in the evaluation of hemorrhagic disorders, the history is found most often on the legs and trunk. Hemorrhagic bullae of the
and physical assessment also are important. The phases of coagulation gums, lips, and other mucous membranes may be prominent, and epi-
can be individually assessed by simple, reliable tests (Table 21-5). staxis (nose bleeding) may be severe and difficult to control. Other-
The majority of children with hemophilia A (factor VIII deficiency) wise, the child appears well. The acute phase lasts 1 to 2 weeks, but
are treated with recombinant factor VIII, and children with hemo- thrombocytopenia often persists. Although the incidence is less than
philia B (factor IX deficiency) are treated with recombinant factor IX. 1%, intracranial hemorrhage is the most serious complication of ITP.
Plasma-derived factor is available and less expensive but carries with it In some cases, the onset is more gradual, and clinical manifestations
the risk of viral infection (e.g., human immunodeficiency virus [HIV], consist of moderate bruising and a few petechiae.
hepatitis).5
The prognosis for children with hemophilia is promising. Pro- EVALUATION AND TREATMENT  Laboratory examination reveals
grams of comprehensive care and home treatment have improved the a low platelet count, and the few platelets observed on a smear are
quality of life for those with hemophilia and enhanced their general large, reflecting increased bone marrow production. The Ivy bleeding
physical capabilities. time is prolonged. Bone marrow aspiration shows normal or increased
numbers of megakaryocytes and normal levels of erythrocytes and
Antibody-Mediated Hemorrhagic Disease granulocytes.
The antibody-mediated hemorrhagic diseases are a group of disorders Even without treatment, the prognosis for children with ITP is
caused by the immune response. Antibody-mediated destruction of excellent: 75% recover completely within 3 months. After the initial
platelets or antibody-mediated inflammatory reactions to allergens acute phase, spontaneous clinical manifestations subside. By 6 months
damage blood vessels and cause seepage into tissues. The thrombo- after onset, 80% of affected children have regained normal platelet
cytopenic purpuras may be intrinsic or idiopathic, or they may be counts.6
transient phenomena transmitted from mother to fetus. The inflam-
matory, or “allergic,” purpuras, although rare, occur in response to
allergens in the blood. All of these disorders first appear during infancy
or childhood.
4 QUICK CHECK 21-2
1. List the major disorders of coagulation and platelets found in children.
2. How do gene deletions differ from point mutations?
Idiopathic Thrombocytopenic Purpura
3. Why are persons with hemophilia at risk for developing degenerative joint
Acute idiopathic thrombocytopenic purpura (ITP; autoimmune changes?
[primary] thrombocytopenic purpura) is the most common disorder 4. What is the major abnormality in idiopathic thrombocytopenic purpura
of platelet consumption. Antiplatelet antibodies bind to the plasma (ITP)?
membranes of platelets, causing platelet sequestration and destruction
546 CHAPTER 21  Alterations of Hematologic Function in Children

There is no evidence that radon gas exposure causes cancer in chil-

TABLE 21-6 MAJOR CLASSIFICATIONS
dren. Likewise, electromagnetic field (EMF) exposure has not been
OF LEUKEMIA demonstrated to be a causative factor in acute leukemias.7 In addition,
MAJOR TYPES ORIGINS no evidence suggests a chemical or drug association.8
Lympho Leukemia involving lymphoid tissue and lymphatic The multiple causation concept is useful when results of epidemi-
system (e.g., lymphatic vessels, lymph nodes, ologic studies are interpreted. For example, laboratory and epidemio-
spleen, thymus) logic studies may indicate that exposure to a certain chemical can cause
Myelo Leukemias of bone marrow (myeloid) origin leukemia, but not all children exposed to that chemical will develop
Blastic and acute Leukemias involving immature cells leukemia. Additional studies are needed to determine what other fac-
Cytic and chronic Leukemias involving mature cells tors must interact with chemical exposure to cause the disease.
Leukemic clusters that represent a greater number of leukemia
cases occurring in a particular geographic location have raised specula-
tion about environmental factors and infectious patterns of transmis-
NEOPLASTIC DISORDERS sion. Careful follow-up, however, has failed to document the abnormal
clustering. Explanations for this phenomenon therefore are statistical
Leukemia and Lymphoma artifact and coincidence.
Leukemia, cancer of the blood-forming tissues, is the most common Viruses clearly have been known to cause leukemia in a number of
malignancy of childhood, representing approximately 33% of all child- animals, including cats, fowl, and mice. Scientists have linked retrovi-
hood cancers. Childhood lymphoma, or cancer of the lymphoid sys- ruses with other types of cancer, but retroviruses have not been linked
tem (primarily lymph nodes), is the third most common malignant with childhood leukemia.
neoplasm of children in the United States, representing approximately
11% of all childhood cancers. (See Chapter 20 for a discussion of leuke- CLINICAL MANIFESTATIONS  The onset of leukemia may be abrupt
mia in adults.) Table 21-6 defines the major classifications of leukemia. or insidious, but the most common symptoms reflect the consequence
of bone marrow failure: decreased levels of both red blood cells and
Leukemia platelets and changes in white blood cells. Pallor, fatigue, petechiae,
Approximately 80% to 85% of leukemias in children are acute lym- purpura, bleeding, and fever generally are present. Approximately 45%
phoblastic leukemia (ALL). The remaining 15% to 20% are acute of children have a hemoglobin level below 7 g/dl. If acute blood loss
nonlymphocytic leukemias (ANLLs) (which include myeloblastic, occurs, characteristic symptoms of tachycardia, air hunger, restless-
promyelocytic, monocytic, and myelomonoblastic) and erythroleu- ness, and thirst may be present. Epistaxis often occurs in children with
kemia, the rare red blood cell leukemia. Because the vast majority of severe thrombocytopenia.
ANLL cases involve the myeloblastic cell, many experts refer to the Fever is usually present as a result of (1) infection associated with
disease as acute myelogenous leukemia (AML). Both a juvenile form the decrease in functional neutrophils and (2) hypermetabolism asso-
and an adult form of chronic myelocytic leukemia (CML) develop in ciated with the ongoing rapid growth and destruction of leukemic
children but are uncommon and account for only 2% of all leukemias cells. White blood cell counts greater than 200,000/mm3 can cause leu-
in childhood. Chronic lymphocytic leukemia (CLL) is virtually nonex- kostasis, an intravascular clumping of cells that results in infarction
istent in children. and hemorrhage, usually in the brain and lung.
ALL is the most common malignancy in children, representing Renal failure as a result of hyperuremia (high uric acid levels) can
nearly one third of all pediatric cancers. The annual incidence of ALL be associated with ALL, particularly at diagnosis or during active treat-
is about 30 cases per million people, with a peak incidence in children ment. Extramedullary invasion with leukemic cells can occur in nearly
2 to 5 years of age, and affects almost twice as many white children all body tissue. The central nervous system (CNS) is a common site of
as nonwhite children (4.2:100,000 versus 2.4:100,000, respectively). infiltration of extramedullary leukemias, although fewer than 10% of
Childhood ALL also is more common in boys than in girls (1.3:1.0). children with ALL have CNS involvement at diagnosis. CNS infiltra-
tion manifests later in the course of the disease. The most common
PATHOGENESIS  Investigations into the causes of childhood leuke- symptoms of CNS involvement relate to increased intracranial pres-
mia have focused on genetic susceptibility, environmental factors, and sure, causing early morning headaches, nausea, vomiting, irritability,
viral infections. Observations of a familial tendency and links with a and lethargy.
number of inherited disorders have implicated genetic factors in the Gonadal involvement can occur and leukemic infiltration into
origin of leukemia. bones and joints is common. Reports of bone or joint pain actually
Inherited diseases that predispose a child to leukemia (both ALL lead to the diagnosis of leukemia in some children. In most children,
and AML) include Down syndrome, Fanconi anemia, Bloom syn- bone pain is characterized as migratory, vague, and without areas of
drome, and ataxia-telangiectasia. Leukemia also has been associated swelling or inflammation. If joint pain is the primary symptom and
with known genetic diseases, such as congenital agammaglobulin- some swelling is associated with the pain, however, misdiagnoses of
emia. AML is attributable to prior chemotherapy, especially alkylating rheumatoid arthritis and rheumatic fever have occurred.
agents. AML can develop from preexisting myeloproliferative dis- Other organs reported to be sites of leukemic invasion include the
orders that also are preleukemia syndromes. When these disorders kidneys, heart, lungs, thymus, eyes, skin, and gastrointestinal tract.
­progress to ANLL, an insidious pattern of leukemic dysfunction usu- Children with leukemia usually have shown symptoms for only 1 week
ally is revealed. before diagnosis.
Many environmental factors (e.g., exposure to ionizing radiation
and electromagnetic fields, parental use of alcohol and tobacco) have EVALUATION AND TREATMENT  Although blood test results can
been investigated as potential risk factors, but none has been defini- raise the clinician’s suspicion of leukemia, a bone marrow aspiration
tively shown to cause lymphoblastic leukemia in children. is required to establish the diagnosis. The blast cell is the hallmark of
 CHAPTER 21  Alterations of Hematologic Function in Children 547

FIGURE 21-9  Monoblasts From Acute Monoblastic Leukemia.

Monoblasts in a marrow smear from an individual with acute mono-
blastic leukemia. The monoblasts are larger than myeloblasts and
usually have abundant cytoplasm, often with delicate scattered
azurophilic granules (an element that stains well with blue aniline
dyes). (From Damjanov I, Linder J, editors: Anderson’s pathology,
ed 10, St Louis, 1996, Mosby.)

acute leukemia (Figure 21-9). This relatively undifferentiated cell is

characterized by diffusely distributed nuclear chromatin, with one or
more nucleoli and basophilic cytoplasm. Healthy children have fewer
than 5% blast cells in the bone marrow and none in the peripheral
blood. In ALL, the bone marrow often is replaced by 80% to 100% B
blast cells, with a reduction in normal developing red blood cells and FIGURE 21-10  Lymphomas. A, Large cell lymphoma. The tumor
granulocytes. Occasionally, the marrow appears hypocellular, making contains prominent areas of sclerosis (arrow). B, Burkitt lymphoma.
the diagnosis difficult to differentiate from aplastic anemia. When this A starry sky pattern is seen at low magnification. (From Damjanov I,
occurs, bone marrow biopsy or biopsy of extramedullary sites is neces- Linder J: Pathology: a color atlas, St Louis, 2000, Mosby.)
sary to confirm the diagnosis.
Combination chemotherapy, with or without radiation therapy to
localized sites, such as the CNS, is the treatment of choice for acute Lymphomas
leukemia. In ALL, identification of various risk groups has led to the Non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma constitute
development of different intensities of drug protocols. Thus treatment approximately 11% of all cases of childhood cancer. Approximately
is tailored specifically for a particular risk group. The 5-year rela- 750 cases of lymphoma occur in children between birth and 14 years
tive survival rate for ALL is about 80% (see Health Alert: Dasatinib: of age in the United States each year.9 NHL occurs more often than
A Promising Agent to Treat Refractory Chronic Myeloid Leukemia). Hodgkin lymphoma (4.5% versus 3.5% of all pediatric malignancies).
Either group of diseases is rare before the age of 5 years, and the rela-
tive incidence increases throughout childhood. Boys are more likely
HEALTH ALERT to be diagnosed with a malignant lymphoma than are girls. At par-
Dasatinib: A Promising Agent to Treat Refractory ticular risk are children with inherited or acquired immunodeficiency
Chronic Myeloid Leukemia syndromes, who have increased rates of lymphoreticular cancers that
range between 100 and 10,000 times the rate of normal children.
Dasatinib is in a class of medications called protein-tyrosine kinase inhibitors;
Non-Hodgkin lymphoma. Generally, most classification systems
these medications block the action of an abnormal protein that signals cancer
divide NHL into two categories—nodular or diffuse—on the basis of
cells to multiply. Dasatinib has been demonstrated to treat chronic myeloid
cellular pattern. Whereas half of all adults with NHL have a nodular
leukemia (CML) in adults whose disease has not responded to other medica-
form of the disease, children rarely demonstrate this pattern. Nodular
tions, including imatinib (Gleevec), or in those who cannot take these medica-
disease represents a less aggressive form of lymphoma. Almost without
tions because of severe side effects. A phase I study recently conducted in
exception, childhood NHL becomes evident as a diffuse disease and
children with refractory CML demonstrated that this drug is well tolerated
can be further subdivided into three groups: (1) large cell (histiocytic),
in children. Further phase II studies are needed to determine the efficacy of
(2) lymphoblastic, and (3) small noncleaved cell (Burkitt or non-
this oral medication that may hold promise as an additional line of therapy
Burkitt lymphoma) (Figure 21-10). Large cell NHL often involves
for children.
chromosomal translocations. Disease sites commonly involve extra-
Data from Aplenc R et al: Pediatric phase I trial and pharmacokinetic nodal sites, such as brain, lung, bone, and skin. Lymphoblastic NHL
study of dasatinib: a report from the Children’s Oncology Group Phase also shows chromosomal translocations, particularly chromosomes
I Consortium, J Clin Oncol, 2011 Jan 24. (Epub ahead of print.) 7 and 14. Disease sites commonly include the mediastinum and
548 CHAPTER 21  Alterations of Hematologic Function in Children

peripheral lymph nodes. Small noncleaved cell NHL involves translo-

cations of chromosomes 8 and 14. Children with small noncleaved cell
NHL commonly have intra-abdominal disease at diagnosis.
As in ALL, immunophenotyping is an important part of the clas-
sification of childhood NHL. Almost 45% of cases of the disease in
children originate from T cells; an equal number originate from B cells.
The remaining group, which represents less than 10% of childhood
NHLs, is classified as non-T, non-B.

PATHOGENESIS  Viral etiology is suggested, with the strongest

correlation between the Epstein-Barr virus and African Burkitt lym-
phoma. The relationship outside Africa is weak, however, even though
the tumor is histopathologically and clinically indistinguishable.
Chronic immunostimulation also has been suggested as a factor in
the development of lymphomas, because these diseases are seen more
often when chronic persistent antigenic stimulation occurs from infec-
tion, such as that caused by malaria or intestinal parasites. Genetic FIGURE 21-11  Diagnostic Reed-Sternberg Cell. A large multinu-
cleated or multilobated cell with (arrow) inclusion body–like nucle-
susceptibility also may play a role in the process of malignant transfor-
oli surrounded by a halo of clear nucleoplasm. (From Damjanov I,
mation. There is increased evidence of NHL in children with congeni- Linder J: Pathology: a color atlas, St Louis, 2000, Mosby.)
tal immunodeficiency syndromes, such as Wiskott-Aldrich syndrome,
ataxia-telangiectasia, and Bloom syndrome. Children with acquired
immunodeficiency syndrome (AIDS) have an increased risk of devel- Children with advanced small noncleaved cell lymphoma of the
oping NHL. However, the incidence of AIDS-related malignancies abdomen have the poorest prognosis. Although remission occurs in
has declined dramatically with the use of highly active antiretroviral more than 90% of these children, most experience subsequent relapses.
therapy in the developed world.10 Even in the presence of advanced lymphoblastic lymphoma, however,
60% to 80% of children can be cured. Overall, children with localized
CLINICAL MANIFESTATIONS  NHL has been found to arise from disease have a 90% survival rate and those with advanced disease have
any lymphoid tissue. Signs and symptoms therefore are specific for the a 60% to 70% survival rate.9
site involved. Because childhood NHL is a rapidly progressive disease,
symptoms generally are present only a few weeks before diagnosis is Hodgkin Lymphoma
made. Rapidly enlarging lymphoid tissue and painless lymphade- Although the etiologic agent for Hodgkin lymphoma, a lymphoma,
nopathy are common with abdominal sites of involvement, usually has not been identified in children, an infectious mode of transmis-
representing a gastrointestinal origin for the disease. Symptoms often sion, particularly focused on viruses, has been implicated. Many per-
include abdominal pain and vomiting, but a palpable mass is not sons with Hodgkin lymphoma have high Epstein-Barr virus titers. At
always present. Most children with abdominal symptoms have diffuse, this time, however, the evidence is not sufficient to link an Epstein-
small noncleaved cell NHL (Burkitt or non-Burkitt) of B cell origin. Barr virus infection to Hodgkin lymphoma.
If the tumor recurs, it appears again in the abdomen before distant Genetic susceptibility has been suggested, because observations
metastasis. show that siblings have a sevenfold increase in risk, particularly siblings
The other common site of childhood NHL is the chest region. An of the same gender. In general, Hodgkin lymphoma is more common
anterior mediastinal mass, with or without pleural effusion, often is in males—in childhood, 60% of all cases occur in males.
present. If the mass is large enough, respiratory compromise, tracheal Hodgkin lymphoma is rare in childhood. It occurs only infre-
compression, and superior vena cava syndrome may arise, which quently in children younger than 2 years, and few cases are observed
constitute a medical emergency. Children with anterior mediastinal before the age of 5 years. A gradual rise in incidence occurs through
involvement often are male adolescents and usually have diffuse lym- the age of 11 years, with a marked increase through adolescence that
phoblastic lymphoma of T cell origin. This often evolves into extensive continues into the 30 to 39 year age group. The annual incidence of
bone marrow involvement and is considered to be an overt leukemic Hodgkin lymphoma in the United States is 4:1,000,000 in children
phase, therefore referred to as leukemic transformation. CNS involve- younger than 15 years. Histologically, the tumor consists of neoplastic
ment and testicular infiltration often occur. Reed-Sternberg cells that are typically found surrounded by small lym-
CNS involvement is common. A relatively small number (10% to phocytes, macrophages, neutrophils, and plasma cells (Figure 21-11).
20%) of children with NHL have lymphoid tissue involvement of the Painless adenopathy in the lower cervical chain, with or without
head and neck (Waldeyer ring, nasopharynx, sinuses). Signs and symp- fever, is the most common symptom in children. Other lymph nodes
toms include tonsillitis, sinusitis, and a painless nasopharynx mass. In and organs also may be involved (Figure 21-12). Mediastinal involve-
African Burkitt lymphoma, involvement of facial bones, particularly ment can cause pressure on the trachea or bronchi, leading to airway
the jaw, is common. obstruction. Extranodal primary sites in Hodgkin lymphoma are rare.
Initial symptoms consist of anorexia, malaise, and lassitude. Inter-
EVALUATION AND TREATMENT  Diagnosis is made by biopsy of mittent fever is present in 30% of children, and weight loss also may
disease sites, usually the involved lymph nodes, tonsils, bone marrow, accompany these symptoms. Hodgkin lymphoma has a well-defined
spleen, liver, bowel, or skin. Most children with NHL are cured of the staging system that considers the extent and location of disease and the
disease. Optimal treatment is still being developed, but combination presence of fever, weight loss, or night sweats at diagnosis.
chemotherapy, with or without radiation therapy for prevention of Treatment for Hodgkin lymphoma includes chemotherapy and
CNS involvement, is being used successfully. radiation therapy. For many years, the standard chemotherapy was a
 CHAPTER 21  Alterations of Hematologic Function in Children 549

regimen of mechlorethamine, Oncovin (vincristine), procarbazine, and

prednisone (MOPP) given for 6 to 12 cycles. Although hematologic
toxicities and associated infections were minimal with MOPP therapy,
sterility was reported in male children. Currently, chemotherapy-only
Waldeyer trials have been based on alternative regimens of MOPP/ABVD (Adri-
ring amycin [doxorubicin], bleomycin, vinblastine, dacarbazine) or COPP
Cervical (cyclophosphamide, vincristine [Oncovin], procarbazine, prednisone).
Supraclavicular Although long-term follow-up data are not available, it is hoped that
gonadal toxicity will be minimized.11
The survival rate for children with Hodgkin lymphoma is high.
Mediastinal Most children are seen initially with limited disease and have a 90%
Axillary
survival rate. Even children who are first seen with advanced disease
Spleen have a 70% to 90% survival rate.
Liver

Para-aortic
and mesenteric
4 QUICK CHECK 21-3
1. List the childhood leukemias in order of rate of incidence.
2. Why do children with leukemia experience bone or joint pain?
Iliac 3. What are the common types of non-Hodgkin lymphoma (NHL) in children?

FIGURE 21-12  Main Areas of Lymphadenopathy and Organ

Involvement in Hodgkin Lymphoma. (From Hockenberry MJ
et al, editors: Wong’s nursing care of infants and children, ed 8, St
Louis, 2007, Mosby.)

DID YOU UNDERSTAND?

Disorders of Erythrocytes 2. The antibody-mediated hemorrhagic diseases are a group of disorders
1. Iron deficiency anemia is the most common blood disorder of infancy and caused by the immune response. Antibody-mediated destruction of platelets
childhood; the highest incidence occurs between 6 months and 2 years of or antibody-mediated inflammatory reactions to allergens damage blood ves-
age. sels and cause seepage into tissues.
2. Hemolytic disease of the newborn (HDN) results from incompatibility 3. ITP, the most common of the childhood thrombocytopenic purpuras, is a dis-
between the maternal and the fetal blood, which may involve differ- order of platelet consumption in which antiplatelet antibodies bind to the
ences in Rh factors or blood type (ABO). Maternal antibodies enter the plasma membranes of platelets. This results in platelet sequestration and
fetal circulation and cause hemolysis of fetal erythrocytes. Because the destruction by mononuclear phagocytes at a rate that exceeds the ability of
immature liver is unable to conjugate and excrete the excess bilirubin that the bone marrow to produce them.
results from the hemolysis, icterus neonatorum, kernicterus, or both can
develop. Kernicterus, which also may develop from other causes, results Neoplastic Disorders
in increased breakdown of red blood cells or decreased liver output of 1. The childhood leukemias include, in order of their rate of incidence, acute lym-
enzymes. phoblastic, acute myeloblastic, and the very rare chronic myelocytic leukemia.
3. Infections of the newborn, often acquired by the mother and transmitted to 2. Although the cause of childhood leukemia is not known for certain, it is prob-
the infant, may result in hemolytic anemia. ably the result of multiple interactions between hereditary or genetic predis-
4. Sickle cell disease is a genetically determined defect of hemoglobin synthe- position and environmental influences.
sis inherited by an autosomal recessive transmission; it causes a change in 3. Acute lymphoblastic leukemia is a potentially curable disease, with about
the shape of a red blood cell that results in decreased oxygen or hydration. It 80% of cases cured.
is most common among Africans and those of Mediterranean descent. 4. The lymphomas of childhood are Hodgkin lymphoma and non-Hodgkin
5. The thalassemias are a heterogeneous group of hereditary hypochromic lymphoma.
anemias of varying severity. Basic genetic defects include abnormalities of 5. The origin of non-Hodgkin lymphoma is unknown. Factors that have been
messenger-RNA processing or deletion of genetic materials, resulting in a implicated include defective host immunity, exposure to a viral agent, chronic
decrease in the chains for hemoglobin. immunostimulation, and genetic predisposition.
6. Non-Hodgkin lymphoma has a favorable prognosis, with a 60% to 80% rate
Disorders of Coagulation and Platelets of cure.
1. Hemophilia is a condition characterized by impairment of the coagulation of 7. Hodgkin lymphoma is thought to be caused by a still unidentified etiologic
blood and a subsequent tendency to bleed. The classic disease is hereditary agent.
and limited to males, being transmitted through the female to the second 8. Hodgkin lymphoma in children is a readily curable disease with a 90% sur-
generation. Many similar conditions attributable to the absence of various vival rate in children with limited disease and a 70% to 90% survival rate in
clotting factors are now recognized. those with advanced disease.
550 CHAPTER 21  Alterations of Hematologic Function in Children

 KEY TERMS
•  lpha trait  542
A • H emolytic anemia  535 •  ernicterus  539
K
• Alpha-thalassemia major  542 • Hemolytic disease of the newborn (HDN) • Multiple causation concept  546
• Alpha-thalassemia minor  542 (erythroblastosis fetalis)  535 • Non-Hodgkin lymphoma (NHL)  547
• Aplastic crisis  541 • Hodgkin lymphoma  548 • Sequestration crisis  541
• Beta-thalassemia major (Cooley • Hydrops fetalis  539 • Sickle cell anemia  539
anemia)  542 • Hyperbilirubinemia  539 • Sickle cell disease  539
• Beta-thalassemia minor  542 • Hyperhemolytic crisis  541 • Sickle cell trait  539
• Blast cell  546 • Icterus gravis neonatorum  539 • Sickle cell–Hb C disease  539
• Erythroblastosis fetalis  535 • Icterus neonatorum (neonatal • Sickle cell–thalassemia  539
• Glucose-6-phosphate dehydrogenase jaundice)  539 • Thalassemia  542
(G6PD) deficiency  535 • Idiopathic thrombocytopenic purpura • Vaso-occlusive crisis
• Hemoglobin H disease  542 (ITP; autoimmune [primary] thrombocy- (thrombotic crisis)  541
• Hemoglobin S (Hb S)  539 topenic purpura)  545

REFERENCES 7. Buka I, Kotsntrng S, Osomio Vargas AR: Trends in childhood cancer

incidence: review of environmental linkages, Pediatr Clin North Am
1. Schneider JM, et al: Anemia, iron deficiency, and iron deficiency anemia 54(1):177–203, 2007.
in 12-36-mo-old children from low-income families, Am J Clin Nutr 8. Davies SM, Ross JA: Childhood cancer etiology: recent reports, Med Pedi-
82(6):1269–1275, 2005. atr Oncol 40:35–38, 2003.
2. Kyung P: Sickle cell disease and other hemoglobinopathies, Int Anesthesiol 9. U.S. Cancer Statistics Working Group: United States cancer statistics:
Clin 42(3):77–93, 2004. 1999–2005, incidence and mortality web-based report, Atlanta, 2010, U.S.
3. Stallworth J, Jerrell J, Tripathi A: Cost-effectiveness of hydroxyurea in Department of Health and Human Services, Centers for Disease Control
reducing the frequency of pain episodes and hospitalization in pediatric and Prevention, and National Cancer Institute. Available at www.cdc.gov/
sickle cell disease, Am J Hematol 85(10):795–797, 2010. uscs.
4. Mariani G, Bernardi F: Factor II deficiency, Semin Thromb Hemost 10. Mbulaiteye SM, et al: Spectrum of cancer among HIV-infected persons
35(4):400–406, 2009. in Africa: the Uganda AIDS-Cancer Registry Match Study, Int J Cancer
5. Bergman G: Progress in the treatment of bleeding disorders, Thromb Res 118(4):985–990, 2006.
127(suppl 1):S3–S5, 2011. 11. Metzger M, et al: Hodgkin lymphoma. In Pizzo PA, Poplack DG, editors:
6. Gupta V, Tilak V, Bhatia BD: Immune thrombocytopenic purpura, Indian Principles and practice of pediatric oncology, ed 6, Philadelphia, 2011, Lip-
J Pediatr 75(7):723–728, 2008. pincott, pp 638–662.
 CHAPTER

22
Structure and Function of the
Cardiovascular and Lymphatic Systems
Valentina L. Brashers and Kathryn L. McCance

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
The Circulatory System, 551 The Systemic Circulation, 567
The Heart, 551 Structure of Blood Vessels, 567
Structures That Direct Circulation Through the Heart, 552 Factors Affecting Blood Flow, 570
Structures That Support Cardiac Metabolism: Regulation of Blood Pressure, 573
The Coronary Vessels, 556 Regulation of the Coronary Circulation, 578
Structures That Control Heart Action, 557 The Lymphatic System, 579
Factors Affecting Cardiac Output, 563

The function of the circulatory system is to deliver oxygen, nutrients, two systems are serially connected; thus the output of one becomes the
and other substances to all the body’s cells and to remove the waste input of the other.
products of cellular metabolism. Delivery and removal are achieved Arteries carry blood flow from the heart to all parts of the body,
by a complex array of tubing (the blood vessels) connected to a pump where they branch into increasingly smaller vessels and ultimately
(the heart). The heart pumps blood continuously through the blood become a fine meshwork of capillaries. Capillaries allow the closest
vessels with cooperation from other systems, particularly the nervous contact and exchange between the blood and the interstitial space, or
and endocrine systems, which are intrinsic regulators of the heart and interstitium—the environment in which the cells live. Veins channel
blood vessels. Nutrients and oxygen are supplied by the digestive and blood flow from capillaries in all parts of the body back to the heart.
respiratory systems. Gaseous wastes of cellular metabolism are exhaled The plasma passes through the walls of the capillaries into the intersti-
by the lungs and other wastes are removed by the kidneys. Of criti- tial space. This fluid is eventually returned to the cardiovascular system
cal importance to cardiovascular function is the vascular endothelium. by vessels of the lymphatic system.
As a multifunctional organ, its health is essential to normal vascular
physiology, and its dysfunction is a critical factor in the development
THE HEART
of vascular disease.
The adult heart weighs less than 1 pound (2.2 kg) and is about the
size of a fist. It lies obliquely (diagonally) in the mediastinum, an area
THE CIRCULATORY SYSTEM above the diaphragm and between the lungs. Heart structures can be
The heart pumps blood through two separate circulatory systems: one described with respect to three general categories of function:
to the lungs and one to all other parts of the body. Structures on the 1. Structural support of heart tissues and circulation of pulmonary and
right side of the heart, or right heart, pump blood through the lungs. systemic blood through the heart. This includes the heart wall and
This system is termed the pulmonary circulation. The left side of the fibrous skeleton, which enclose and support the heart and divide it
heart, or left heart, sends blood throughout the systemic circulation, into four chambers; the valves that direct flow through the cham-
which supplies all of the body except the lungs (Figure 22-1). These bers; and the great vessels that conduct blood to and from the heart.

551
552 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems

HEART HEART
Right atrium Left atrium

Right AV valve Left AV valve

Right ventricle Left ventricle

Pulmonary Aortic
SL valve SL valve
LUNGS
Vena Pulmonary Pulmonary
Arteries Aorta
cava artery veins

Arterioles

Veins of Arteries of
each organ Capillaries each organ

Venules

Venules of Arterioles of
each organ Veins each organ

Capillaries of each organ

FIGURE 22-1  Diagram Showing Serially Connected Pulmonary and Systemic Circulatory Sys-
tems and How to Trace the Flow of Blood. Right heart chambers propel unoxygenated blood through
the pulmonary circulation, and the left heart propels oxygenated blood through the systemic circulation.
(From Patton KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)

2. Maintenance of heart cells. This comprises vessels of the coronary

circulation—the arteries and veins that serve the metabolic needs
of all the heart cells—and the lymphatic vessels of the heart.
3. Stimulation and control of heart action. Among these structures are
the nerves and specialized muscle cells that direct the rhythmic
contraction and relaxation of the heart muscles, propelling blood Pericardial space
throughout the pulmonary and systemic circulatory systems. Parietal layer
Fibrous Visceral layer Serous
pericardium (epicardium) pericardium
Structures That Direct Circulation Through the Heart Myocardium
The Heart Wall Endocardium
The heart wall has three layers: the pericardium, myocardium, and Coronary
endocardium (Figure 22-2). The pericardium is a double-walled vessels
membranous sac that encloses the heart and (1) prevents displace- Fatty
ment of the heart during gravitational acceleration or decelera- connective
tissue
tion, (2) serves as a physical barrier that protects the heart against Superficial Deep
infection and inflammation from the lungs and pleural space, and
(3) ­contains pain receptors and mechanoreceptors to elicit reflex
changes in blood pressure and heart rate. The two layers of the peri-
cardium are the parietal and the visceral pericardia (see Figure 22-2).
These are separated by a fluid-containing space called the pericardial
Trabeculae carneae
cavity. The pericardial fluid (10 to 30 ml) is secreted by cells of the
mesothelium and lubricates the membranes that line the pericardial FIGURE 22-2  Wall of the Heart. This section of the heart wall shows
the fibrous pericardium, the parietal and visceral layers of the serous
cavity, enabling them to slide over one another with a minimum
pericardium (with the pericardial space between them), the myocar-
amount of friction as the heart beats. The amount and character of dium, and the endocardium. Note the fatty connective tissue between
the pericardial fluid are altered if the pericardium is inflamed (see the visceral layer of the serous pericardium (epicardium) and the myo-
Chapter 23). cardium. Note also that the endocardium covers beamlike projec-
The thickest layer of the heart wall, the myocardium, is composed tions of myocardial muscle tissue called trabeculae. (From Patton KT,
of cardiac muscle and is anchored to the heart’s fibrous skeleton. The Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)
 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems 553

myocardial cells provide the contractile force needed for blood to flow layer and constitute much of the bulk of the heart. The ventricles are
through the heart and into the pulmonary and systemic circulations. formed by a continuum of muscle fibers originating from the fibrous
The internal lining of the myocardium, the endocardium, comprises skeleton at the base of the heart.
connective tissue and squamous cells (see Figure 22-2). This lining is The myocardial thickness of each cardiac chamber depends on the
continuous with the endothelium that lines all the arteries, veins, and amount of pressure or resistance it must overcome to eject blood. The
capillaries of the body, creating a continuous, closed circulatory system. two atria have the thinnest walls because they are low-pressure cham-
bers that serve as storage units and conduits for blood that is emptied
Chambers of the Heart into the ventricles. Normally, there is little resistance to flow from the
The heart has four chambers: the left atrium, the right atrium, the atria to the ventricles. The ventricular myocardium, on the other hand,
right ventricle, and the left ventricle. (Blood flow through these cham- must be strong enough to pump against pressures in the pulmonary or
bers is illustrated in Figure 22-3.) The atria are smaller than the ven- systemic vessels. The mean pulmonary artery pressure is only 15 mm
tricles and have thinner walls. The ventricles have a thicker myocardial Hg, whereas the mean systemic arterial pressure is about 92 mm Hg.
For this reason, the left ventricle’s myocardium is several times thicker
Pulmonary trunk Aortic arch than that of the right ventricle.
Right pulmonary Left pulmonary The right ventricle is shaped like a crescent, or triangle, enabling
artery artery a bellows-like action that efficiently ejects large volumes of blood
TO LUNG through a very small valve into the low-pressure pulmonary system.
TO LUNG
The left ventricle is larger than the right ventricle and is bullet shaped,
FROM LUNG Left atrium helping it to eject blood through a relatively large valve opening into
Branches of left the high-pressure systemic circulation.
Superior vena pulmonary vein
cava (from The septal membrane separates the right and left sides of the heart
head and arms) FROM LUNG and prevents blood from crossing over. The atria are separated by the
Pulmonary Aortic semilunar interatrial septum, and the ventricles by the interventricular septum.
semilunar valve Indentations of the endocardium form valves that separate the atria from
valve Mitral valve the ventricles and the ventricles from the aorta and pulmonary arteries.
Right atrium Left
Tricuspid ventricle Fibrous Skeleton of the Heart
valve Interventricular Four rings of dense fibrous connective tissue provide a firm anchor-
Chordae septum
tendineae age for the attachments of the atrial and ventricular musculature, as
Myocardium well as the valvular tissue (Figure 22-4). The fibrous rings are adjacent
Right ventricle (heart muscle) and form a central, fibrous supporting structure collectively termed
Inferior vena cava Papillary the annuli fibrosi cordis.
(from trunk and legs) Descending muscle
aorta Valves of the Heart
FIGURE 22-3  Structures That Direct Blood Flow Through the One-way blood flow through the heart is ensured by the four heart
Heart. Arrows indicate path of blood flow through chambers, valves. During ventricular relaxation, the two atrioventricular valves
valves, and major vessels. open and blood flows from the atria to the relaxed ventricles. As the

Left AV Pulmonary SL valve Right AV

(mitral) valve (tricuspid)
Aortic SL valve valve

Skeleton of heart
Left AV
(mitral) valve

Right AV
(tricuspid)
valve

A B
FIGURE 22-4  Structure of the Heart Valves. A, The heart valves in this drawing are depicted as viewed
from above (looking down into the heart). Note that the semilunar (SL) valves are closed and the atrio-
ventricular (AV) valves are open, as when the atria are contracting. View B is similar to view A except
that the semilunar valves are open and the atrioventricular valves are closed, as when the ventricles
are contracting. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)
554 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems

ventricles contract, increasing ventricular pressure causes these valves The Great Vessels
to close and prevent backflow into the atria. The semilunar valves of Blood moves in and out of the heart through several large vessels (see
the heart open when intraventricular pressure exceeds aortic and pul- Figure 22-3). The right heart receives venous blood from the systemic
monary pressures, and blood flows out of the ventricles and into the circulation through the superior and inferior venae cavae, which
pulmonary and systemic circulations. After ventricular contraction enter the right atrium. Blood leaves the right ventricle and enters the
and ejection, intraventricular pressure falls and the pulmonic and aor- pulmonary circulation through the pulmonary artery. This artery
tic semilunar valves close, preventing backflow into the right and left divides into right and left branches to transport unoxygenated blood
ventricles, respectively. The coordinated actions of the heart valves are from the right heart to the right and left lungs. The pulmonary arteries
shown in Figures 22-3 and 22-4. branch further into the pulmonary capillary bed, where oxygen and
The atrioventricular (tricuspid and mitral) valve openings are carbon dioxide exchange occurs.
guarded by flaps of tissue called leaflets or cusps, which are attached The four pulmonary veins, two from the right lung and two from
to the papillary muscles by the chordae tendineae cordis (see Figure the left lung, carry oxygenated blood from the lungs to the left side of
22-3). The papillary muscles are extensions of the myocardium that the heart. The oxygenated blood moves through the left atrium and
pull the cusps together and downward at the onset of ventricular con- ventricle and out into the aorta, which delivers it to systemic vessels
traction, thus preventing their backward expulsion into the atria. that supply the body.
The right atrioventricular valve is called the tricuspid valve because
it has three cusps. The left atrioventricular valve is a bicuspid (two- Blood Flow During the Cardiac Cycle
cusp) valve called the mitral valve. The tricuspid and mitral valves The pumping action of the heart consists of contraction and relaxation
function as a unit because the atrium, fibrous rings, valvular tissue, of the myocardial layer of the heart wall. Each ventricular contraction
chordae tendineae, papillary muscles, and ventricular walls are con- and the relaxation that follows it constitute one cardiac cycle. (Blood
nected. Collectively, these six structures are known as the mitral and flow through the heart during a single cardiac cycle is illustrated in Fig-
tricuspid complex. Damage to any one of the six components of this ure 22-5.) During relaxation, termed diastole, blood fills the ventricles.
complex can alter function significantly. The ventricle fills rapidly in early diastole and again in late diastole
Blood leaves the right ventricle through the pulmonic semilunar when the atrium contracts. The ventricular contraction that follows,
valve, and it leaves the left ventricle through the aortic semilunar valve termed systole, propels the blood out of the ventricles and into the
(see Figures 22-3 and 22-4). Both the pulmonic and aortic semilunar circulation. Contraction of the left ventricle is slightly earlier than con-
valves have three cup-shaped cusps that arise from the fibrous skeleton. traction of the right ventricle.

Diastole Systole

Semilunar
valves
open

L. atrium
L. atrium

R. R. atrium L. ventricle
L. ventricle
atrium

R.
ve
R. nt
ve ric
Semilunar nt le
valves closed ric
le Atrioventricular
valves closed

Atrioventricular
valves open
A B
FIGURE 22-5  Blood Flow Through the Heart During a Single Cardiac Cycle. A, During diastole,
blood flows into atria, atrioventricular valves are pushed open, and blood begins to fill ventricles. Atrial
systole squeezes any blood remaining in atria out into ventricles. B, During ventricular systole, ven-
tricles contract, pushing blood out through semilunar valves into pulmonary artery (right ventricle) and
aorta (left ventricle). (Modified from Patton KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis,
2010, Mosby.)
 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems 555

The phases of the cardiac cycle can be identified on initiation of

TABLE 22-1 NORMAL INTRACARDIAC
ventricular myocardial contraction (Figures 22-6 and 22-7). Expulsion
of blood from the ventricles marks the end of one cardiac cycle.
PRESSURES
MEAN (MM HG) RANGE (MM HG)
Normal Intracardiac Pressures Right atrium 4 0-8
Normal intracardiac pressures are shown in Table 22-1. Right ventricle
Systolic 24 15-28
End-diastolic 4 0-8
Left atrium 7 4-12

Reduced ejection

Rapid ventricular
Left ventricle

filling—diastasis
Rapid ejection

Isovolumetric
Isovolumetric

Systolic 130 90-140

Atrial systole

contraction

ventricular
relaxation
End-diastolic 7 4-12

Reduced
120 filling
Aortic valve
closes Aortic
Aortic pressure
100 valve
opens 4 QUICK CHECK 22-1
80 1. Why are the two separate circulatory systems said to be “serially
Left ventricular connected”?
Pressure
(mmHg)

pressure
60 2. Why does the thickness of the myocardium vary dramatically in the differ-
ent heart chambers?
40 Mitral 3. Trace blood flow through the heart during a single cardiac cycle.
valve Mitral
closes valve
20 opens

5 Left atrial
pressure
Aortic blood flow

4 1
Atrial
(L/min)

3
5 systole
2 2
Passive Isovolumetric
1 ventricular ventricular
0
filling
contraction

38
Ventricular volume

32
(ml)

26
Cardiac
20 cycle
1 2
sounds
Heart

4 3

a
c v
Venous
pulse

4
Isovolumetric 3
ventricular Ejection
R relaxation
Electrocardiogram

T P
P

Q
S Ventricular
systole
FIGURE 22-7  The Phases of the Cardiac Cycle. 1, Atrial systole.
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 2, Isovolumetric ventricular contraction. Ventricular volume remains
Time (sec) constant as pressure increases rapidly. 3, Ejection. 4, Isovolumetric
FIGURE 22-6  Composite Chart of Heart Function. This chart is a ventricular relaxation. Both sets of valves are closed, and the ven-
composite of several diagrams of heart function (cardiac pumping tricles are relaxing. 5, Passive ventricular filling. The atrioventricular
cycle, blood pressure, blood flow, volume, heart sounds, venous (AV) valves are forced open, and the blood rushes into the relaxing
pulse, and electrocardiogram [ECG]), all adjusted to the same ventricles. (From Patton KT, Thibodeau GA: Anatomy & physiology,
timescale. ed 7, St Louis, 2010, Mosby.)
556 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems

Structures That Support Cardiac Metabolism: Coronary Arteries

The Coronary Vessels The right coronary artery and the left coronary artery (see Figure
The blood within the heart chambers does not supply oxygen and other 22-8) traverse the epicardium, myocardium, and endocardium and
nutrients to the cells of the heart. Like all other organs, including the branch to become arterioles and then capillaries. Their main branches
lungs, heart structures are nourished by vessels of the systemic circu- are outlined in Box 22-1.
lation. The branch of the systemic circulation that supplies the heart
is termed the coronary circulation and consists of coronary arteries, Collateral Arteries
which receive blood through openings in the aorta called the coronary The collateral arteries are actually connections, or anastomoses,
ostia, and the cardiac veins, which empty into the right atrium through between two branches of the same or the opposite coronary artery.1
the opening of a large vein called the coronary sinus (Figure 22-8). The epicardium contains more collateral vessels than the endocardium.
(Regulation of the coronary circulation, which is similar to regulation of New collateral vessels are formed through the process of angiogen-
flow through systemic and pulmonary vessels, is described elsewhere.) esis, which is stimulated by hypoxia and vascular endothelial growth

Superior Aorta
vena cava Pulmonary Superior
trunk vena cava
Aorta Left
Aortic coronary Pulmonary
semilunar artery trunk
valve Left
Left Right
atrium
Right atrium atrium
atrium Circumflex Coronary
artery sinus
Right Middle
Anterior
coronary cardiac vein
interventricular
artery Great
artery Great
cardiac
cardiac vein
Right Left vein
marginal ventricle Left
Small ventricle
artery cardiac
Right Posterior Right
vein
ventricle interventricular ventricle
artery
A B

Aorta

Superior vena cava Pulmonary trunk

Left pulmonary arteries

Right pulmonary arteries
Left pulmonary veins
Right pulmonary veins
Left atrium
Right atrium Left coronary artery

Right coronary artery

Anterior interventricular artery

Right ventricle Left ventricle

Inferior vena cava

C
FIGURE 22-8  Coronary Circulation. A, Arteries. B, Veins. Both A and B are anterior views of the
heart. Vessels near the anterior surface are more darkly colored than vessels of the posterior surface
seen through the heart. C, View of the anterior (sternocostal) surface. (A and B modified from Patton
KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby; C from Seeley RR, Stephens
TD, Tate P: Anatomy and physiology, ed 3, St Louis, 1995, Mosby.)
 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems 557

potentials are described in Chapters 1 and 4.) The muscle fibers of the
BOX 22-1 MAIN BRANCHES
myocardium are uniquely joined so that action potentials pass from
OF THE CORONARY ARTERIES cell to cell rapidly and efficiently.
Left coronary artery. Arises from single ostium behind left cusp of aortic The myocardium also contains its own conduction system—­
semilunar valve; ranges from a few millimeters to a few centimeters long; specialized cells that enable it to generate and transmit action poten-
passes between left arterial appendage and pulmonary artery and gener- tials without stimulation from the nervous system (Figure 22-9). These
ally divides into two branches: the left anterior descending artery and the cells are concentrated at certain sites in the myocardium called nodes.
circumflex artery; other branches are distributed diagonally across the free The cardiac cycle is stimulated by these nodes of specialized cells.
wall of the left ventricle. Although the heart is innervated by the autonomic nervous system
Left anterior descending artery (or anterior interventricular artery). Delivers (both sympathetic and parasympathetic fibers), neural impulses are
blood to portions of left and right ventricles and much of interventricular not needed to maintain the cardiac cycle. Thus the heart will beat in
septum; travels down the anterior surface of the interventricular septum the absence of any innervation.
toward apex of the heart. Heart action is also influenced by substances delivered to the myo-
Circumflex artery. Travels in a groove (coronary sulcus) that separates left cardium in coronary blood. Nutrients and oxygen are needed for cellu-
atrium from left ventricle and extends to left border of heart; supplies blood lar survival and normal function, whereas hormones and biochemicals
to left atrium and lateral wall of left ventricle; often branches to posterior affect the strength and duration of myocardial contraction and the
surfaces of left atrium and left ventricle. degree and duration of myocardial relaxation. Normal or appropriate
Right coronary artery. Originates from an ostium behind the right aortic cusp, function depends on the availability of these substances, which is why
travels from behind the pulmonary artery, and extends around the right coronary artery disease can seriously disrupt heart function.
heart to the heart’s posterior surface, where it branches to atrium and
ventricle; three major branches are conus (supplies blood to upper right The Conduction System
ventricle), right marginal branch (supplies right ventricle to the apex), and Normally, electrical impulses arise in the sinoatrial node (SA node,
posterior descending branch (lies in posterior interventricular sulcus and sinus node), which is often called the pacemaker of the heart. The
supplies smaller branches to both ventricles). SA node is located at the junction of the right atrium and superior
vena cava, just superior to the tricuspid valve. The SA node is heavily
innervated by both sympathetic and parasympathetic nerve fibers.4 In
factors. The collateral circulation is responsible for supplying blood the resting adult the SA node generates about 75 action potentials per
and oxygen to the myocardium that has become ischemic following minute. Each one travels rapidly from cell to cell and through special
gradual narrowing of one or more major coronary arteries (coronary pathways in the atrial myocardium, causing both atria to contract.
artery disease). Unfortunately, diabetes, which predisposes to coronary There are three pathways in the atria called the anterior, middle, and
artery disease, also impedes collateral formation because of increased posterior internodal pathways. These pathways consist of ordinary
production of antiangiogenic factors, such as endostatin and angio- myocardial cells and specialized conducting fibers. The anterior
statin. An increased understanding of the process of angiogenesis has interatrial myocardial band, or Bachmann bundle, conducts the
led to the use of angiogenic factors in the treatment of coronary artery impulse from the SA node to the left atrium. The posterior internodal
disease that is not responsive to more conventional therapies.2 pathway connects the right and left atria and the SA node and AV
node for conduction from the SA node to the atrioventricular node
Coronary Capillaries (AV node).4,5
The heart has an extensive capillary network. Blood travels from the The AV node is well situated for mediating conduction between
arteries to the arterioles and then into the capillaries, where exchange of the atria and ventricles. It is located in the right atrial wall superior to
oxygen and other nutrients takes place. At rest, the heart extracts 70% the tricuspid valve and anterior to the ostium of the coronary sinus.
to 80% of the oxygen delivered to it and coronary blood flow is directly Behind it are numerous autonomic parasympathetic ganglia. These
correlated with myocardial oxygen consumption.3 Any alteration of ganglia serve as receptors for the vagus nerve and cause slowing of
the cardiac muscles dramatically affects blood flow in the capillaries. impulse conduction through the AV node.
Conducting fibers from the AV node converge to form the bundle
Coronary Veins and Lymphatic Vessels of His (atrioventricular bundle), within the posterior border of the
After passing through the extensive capillary network, blood from the interventricular septum. The bundle of His then gives rise to the right
coronary arteries drains into the cardiac veins, which travel alongside and left bundle branches. The right bundle branch (RBB) is thin and
the arteries. Most of the venous drainage of the heart occurs through travels without much branching to the right ventricular apex. Because
veins in the visceral pericardium. The veins then feed into the great car- of its thinness and relative lack of branches, the RBB is susceptible to
diac vein (see Figure 22-8) and coronary sinus on the posterior surface interruption by damage to the endocardium. The left bundle branch
of the heart, between the atria and ventricles, in the coronary sulcus. (LBB) arises perpendicularly from the bundle of His and, in some
The myocardium has an extensive system of lymphatic vessels. hearts, divides into two branches, or fascicles. The left anterior bundle
With cardiac contraction, the lymphatic vessels drain fluid to lymph branch (LABB) passes the left anterior papillary muscle and the base
nodes in the anterior mediastinum that eventually empty into the of the left ventricle and crosses the aortic outflow tract. Damage to
superior vena cava. The lymphatics are important for protecting the the aortic valve or the left ventricle can interrupt this branch. The left
myocardium against infection and injury. posterior bundle branch (LPBB) travels posteriorly, crossing the left
ventricular inflow tract to the base of the left posterior papillary mus-
Structures That Control Heart Action cle. This branch spreads diffusely through the posterior inferior left
The continuous, rhythmic repetition of the cardiac cycle (systole ventricular wall. Blood flow through this portion of the left ventricle is
and diastole) depends on the transmission of electrical impulses, relatively nonturbulent, so the LBB is somewhat protected from injury
termed cardiac action potentials, through the myocardium. (Action caused by wear and tear.
558 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems

Aorta

Superior
vena cava Pulmonary
artery

Pulmonary Pulmonary
veins veins
Sinoatrial
(SA) node
(pacemaker) Mitral
Atrioventricular (bicuspid)
(AV) node valve
Right Purkinje fibers
atrium
Left
Tricuspid
ventricle
valve
Right Right and left
ventricle Inferior branches of AV bundle
vena cava (bundle of His)
FIGURE 22-9  Conduction System of Heart. Specialized cardiac muscle cells in the wall of the heart
rapidly conduct an electrical impulse throughout the myocardium. The signal is initiated by the sinoatrial
(SA) node (pacemaker) and spreads to the rest of the atrial myocardium and to the atrioventricular (AV)
node. The AV node then initiates a signal that is conducted through the ventricular myocardium by way
of the atrioventricular bundle (of His) and Purkinje fibers. (Modified from Patton KT, Thibodeau GA:
Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)

The Purkinje fibers are the terminal branches of the RBB and LBB.
TABLE 22-2 INTERCELLULAR AND
They extend from the ventricular apexes to the fibrous rings and pen-
etrate the heart wall to the outer myocardium. The first areas of the
EXTRACELLULAR ION
ventricles to be excited are portions of the interventricular septum. CONCENTRATIONS
The septum is activated from both the RBB and the LBB. The extensive IN THE MYOCARDIUM
network of Purkinje fibers promotes the rapid spread of the impulse
INTRACELLULAR EXTRACELLULAR
to the ventricular apices. The basal and posterior portions of the ven-
CONCENTRATION CONCENTRATION
tricles are the last to be activated.
(mM) (mM)

4 QUICK CHECK 22-2

Sodium (Na+)
Potassium (K+)
15
150
145
4
1. Outline the conduction system of the heart.
Chloride (Cl−) 5 120
2. What happens ionically during depolarization and during repolarization?
Calcium (Ca++) 10−7 2
3. Why are the left and right coronary vessels considered the major coronary
vessels? mM, Micromolar (millimoles per kilogram).

Propagation of cardiac action potentials. Electrical activation of membrane potential (in millivolts) and the decreased negative charge
the muscle cells, termed depolarization, is caused by the movement caused by depolarization is the cardiac action potential. Table 22-2
of electrically charged solutes (ions) across cardiac cell membranes. summarizes the intracellular and extracellular ionic concentrations
Deactivation, called repolarization, occurs the same way. (Movement of cardiac muscle. Hence, drugs that alter ion movement (e.g., cal-
of ions across cell membranes is described in Chapter 1; electrical acti- cium) have profound effects on the action potential and can alter
vation of muscle cells is described in Chapter 36.) heart rate. The various phases of the cardiac action potential are
When ions move into and out of the cell, an electrical (voltage) related to changes in the permeability of the cell membrane, primarily
difference across the cell membrane, called the membrane potential, to sodium and potassium changes. Threshold is the point at which
is created. The resting membrane potential of myocardial cells is the cell membrane’s selective permeability to sodium and potassium
between −80 and −90 millivolts (mV), whereas that of the SA node is temporarily disrupted, leading to depolarization. If the resting
is between −50 and −60 mV and that of the AV node is between −60 membrane potential becomes more negative because of a decrease
and −70 mV.4 During depolarization, the inside of the cell becomes in extracellular potassium concentration (hypokalemia), it is termed
less negatively charged. In cardiac cells, the difference between resting hyperpolarization.
 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems 559

A refractory period, during which no new cardiac action potential ventricular myocardial cells. The QRS complex represents the sum
can be initiated by a stimulus, follows depolarization. This effective of all ventricular muscle cell depolarizations. The configuration and
or absolute refractory period corresponds to the time needed for the amplitude of the QRS complex vary considerably among individuals.
reopening of channels that permit sodium and calcium influx. A rela- The duration is normally between 0.06 and 0.10 second. During the
tive refractory period occurs near the end of repolarization, following ST interval, the entire ventricular myocardium is depolarized. The QT
the effective refractory period. During this time, the membrane can be interval is sometimes called the “electrical systole” of the ventricles. It
depolarized again but only by a greater-than-normal stimulus. Abnor- lasts about 0.4 second but varies inversely with the heart rate. The T
mal refractory periods as a result of disease can cause abnormal heart wave represents ventricular repolarization.
rhythms or dysrhythmias (see Chapter 23). Automaticity. Automaticity, or the property of generating spon-
The normal electrocardiogram. The normal electrocardiogram taneous depolarization to threshold, enables the SA and AV nodes to
is recorded from electrical activity transmitted by skin electrodes and generate cardiac action potentials without any stimulus. Cells capable
reflects the sum of all the cardiac action potentials (Figure 22-10). The of spontaneous depolarization are called automatic cells. Those of the
P wave represents atrial depolarization. The PR interval is a measure cardiac conduction system can stimulate the heart to beat even when
of time from the onset of atrial activation to the onset of ventricular it is removed from the body. Spontaneous depolarization is possible
activation (normally 0.12 to 0.20 second). The PR interval represents in automatic cells because the membrane potential does not “rest”
the time necessary for electrical activity to travel from the sinus node during return to the resting membrane potential. Instead, it slowly
through the atrium, AV node, and His-Purkinje system to activate creeps toward threshold during the diastolic phase of the cardiac cycle.

R R

ECG deflections ECG intervals

S-T
P segment T
T
P
Voltage

Voltage

Atrial Q S Ventricular
depolarization repolarization P-R interval Q-R-S
Ventricular 0.12-0.20 sec under 0.10 sec
depolarization
(and atrial Q-T interval
repolarization) under 0.38

Time Time
A B
SA node

LA
RA
AV node

Depolarization

Repolarization
RV LV

P ST T U LBB
QRS RBB
P QRS
PR QT
C
FIGURE 22-10  Electrocardiogram (ECG) and Cardiac Electrical Activity. A, Normal ECG. Depolar-
ization and repolarization. B, ECG intervals among P, QRS, and T waves. C, Schematic representation
of ECG and its relationship to cardiac electrical activity. AV, Atrioventricular; LA, left atrium; LBB, left
bundle branch; LV, left ventricle; RA, right atrium; RBB, right bundle branch; RV, right ventricle. (A and
B from Patton KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)
560 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems

Because threshold is approached during diastole, return to the resting

membrane potential in automatic cells is called diastolic depolariza- Cardiovascular control centers in the brain
tion. The electrical impulse normally begins in the SA node because its
cells depolarize more rapidly than other automatic cells.
Rhythmicity. Rhythmicity is the regular generation of an action
potential by the heart’s conduction system. The SA node sets the pace Hypothalamus
because normally it has the fastest rate. The SA node depolarizes spon-
taneously 60 to 100 times per minute. If the SA node is damaged, the
AV node will become the heart’s pacemaker at a rate of about 40 to
60 spontaneous depolarizations per minute. Eventually, however, con- Medullary “Centers”
duction cells in the atria usually take over from the AV node. Purkinje
fibers are capable of spontaneous depolarization but at a rate of only
Symp Vagal
30 to 40 beats/min.4 

4 QUICK CHECK 22-3

Receptor
1. What are the pathways of conduction through the heart?
2. What does each of the electrocardiogram waves (P, Q, R, S, T) represent? afferents

3. Define automaticity and rhythmicity.

Cardiac Innervation
Although the heart’s nodes and conduction system generate cardiac
action potentials independently, the autonomic nervous system influ- 
ences the rate of impulse generation (firing), depolarization, and repo-
larization of the myocardium and the strength of atrial and ventricular
contraction. Autonomic neural transmission produces changes in the 
heart and circulatory system faster than metabolic or humoral agents.
Speed is important, for example, in stimulating the heart to increase
its pumping action during times of stress or fear—the so-called fight- Blood vessels Heart
or-flight response. Although increased delivery of oxygen, glucose, FIGURE 22-11  Autonomic Innervation of Cardiovascular Sys-
hormones, and other blood-borne factors sustains increased cardiac tem. Inhibition (−); activation (+).
activity, the rapid initiation of increased activity depends on the sym-
pathetic and parasympathetic fibers of the autonomic nervous system. Because the myofibrils in both cardiac and skeletal fibers consist of
Sympathetic and parasympathetic nerves. Sympathetic and para- alternating light and dark bands of protein, the fibers appear striped,
sympathetic nerve fibers innervate all parts of the atria and ventricles or striated. The dark and light bands of the myofibrils are called sarco-
and the SA and AV nodes. The sympathetic and parasympathetic nerves meres and are normally between 1.6 and 2.2 μm long (Figure 22-12).
affect the speed of the cardiac cycle (heart rate, or beats per minute) Length determines the limits of myocardial stretch at the end of dias-
and the diameter of the coronary vessels (Figure 22-11). Sympathetic tole and subsequently the force of contraction during systole.
nervous activity enhances myocardial performance. Stimulation of the Differences between cardiac and skeletal muscle reflect heart func-
SA node by the sympathetic nervous system rapidly increases heart tion. Cardiac cells are arranged in branching networks throughout
rate. Furthermore, neurally released norepinephrine or circulating cat- the myocardium, whereas skeletal muscle cells tend to be arranged
echolamines interact with β-adrenergic receptors on the cardiac cell in parallel units throughout the length of the muscle. Cardiac fibers
membranes. The overall effect is an increased influx of Ca++, which have only one nucleus, whereas skeletal muscle cells have many nuclei.
increases the contractile strength of the heart and increases the speed Other differences enable cardiac fibers to:
of electrical impulses through the heart muscle and the nodes. Finally, 1. Transmit action potentials quickly from cell to cell. Electrical impulses
increased sympathetic discharge dilates the coronary vessels.4 are transmitted rapidly from cardiac fiber to cardiac fiber because
The parasympathetic nervous system affects the heart through the network of fibers is connected at intercalated disks, which are
the vagus nerve, which releases acetylcholine. Acetylcholine causes thickened portions of the sarcolemma. The intercalated disks con-
decreased heart rate and slows conduction through the AV node. Ace- tain two junctions: desmosomes, which attach one cell to another;
tylcholine also causes coronary vasodilation.4 and gap junctions, which allow the electrical impulse to spread
from cell to cell (see Chapter 1). Together, these junctions provide
Myocardial Cells a low-resistance pathway for impulse propagation.
The cells of cardiac muscle (the myocardium) are composed of long, 2. Maintain high levels of energy synthesis. Unlike skeletal muscle, the
narrow fibers that contain bundles of longitudinally arranged myofi- heart cannot rest and is in constant need of energy compounds
brils; a nucleus (cardiac muscle) or many nuclei (skeletal muscle); mito- such as adenosine triphosphate (ATP). Therefore the cytoplasm
chondria; an internal membrane system (the sarcoplasmic reticulum); surrounding the bundles of myofibrils in each cardiac muscle cell
cytoplasm (sarcoplasm); and a plasma membrane (the sarcolemma), contains a superabundance of mitochondria (25% of the cellular
which encloses the cell. Cardiac and skeletal muscle cells also have an volume). Cardiac muscle cells have more mitochondria than do
“external” membrane system made up of transverse tubules (T tubules) skeletal muscle cells to provide the necessary respiratory enzymes
formed by invaginations of the sarcolemma. The sarcoplasmic reticu- for aerobic metabolism and supply quantities of ATP sufficient for
lum forms a network of channels that surrounds the muscle fiber. the constant action of the myocardium.
 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems 561

Nucleus

T tubule
Sarcoplasmic Diad
reticulum

Intercalated I band
disks
Z line

Sarcomere

M line
Sarcolemma Mitochondrion

Myofibril

FIGURE 22-12  Cardiac Muscle Fiber. Unlike other types of muscle fibers, cardiac muscle fiber is typi-
cally branched and forms junctions, called intercalated disks, with adjacent cardiac muscle fibers. Like
skeletal muscle fibers, cardiac muscle fibers contain sarcoplasmic reticula and T tubules—although
these structures are not as highly organized as in skeletal muscle fibers. (From Patton KT, Thibodeau
GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)

3. Gain access to more ions, particularly sodium and potassium, in the the center of each I band. The area from one dark Z line to an adjacent
extracellular environment. Cardiac fibers contain more T tubules Z line is the sarcomere. In the center of the sarcomere is the H zone, a
than do skeletal muscle fibers. This gives each myofibril in the somewhat less dense region. A thin, dark M line travels through the cen-
myocardium ready access to molecules needed for the continu- ter of the H zone. A single tropomyosin molecule (a relaxing protein)
ous transmission of action potentials, which involves transport of lies alongside seven actin molecules. Troponin, another relaxing pro-
sodium and potassium through the walls of the T tubules. Because tein, associates with the tropomyosin molecule, forming the troponin-
the T tubule system is continuous with the extracellular space and tropomyosin complex (see Figure 22-14). The troponin complex itself
the interstitial fluid, it facilitates the rapid transmission of the elec- has three components. Troponin T aids in the binding of the troponin
trical impulses from the surface of the sarcolemma to the myofi- complex to actin and tropomyosin; troponin I inhibits the ATPase of
brils inside the fiber. This activates all the myofibrils of one fiber actomyosin; and troponin C contains binding sites for the calcium ions
simultaneously. The sarcoplasmic reticulum is located around the involved in contraction. These troponin molecules are released into the
myofibrils. When an action potential is transmitted through the T bloodstream during myocardial infarction or injury, where they can be
tubules, it induces the sarcoplasmic reticulum to release its stored measured.
calcium, which activates the contractile proteins actin and myosin. Myocardial metabolism. Cardiac muscle, like other muscle tissue,
Actin, myosin, and the troponin-tropomyosin complex. The thick fil- depends on the constant production of ATP for energy. ATP is pro-
aments of myosin constitute the central dark band called the anisotro- duced within the mitochondria mainly from glucose, fatty acids, and
pic, or A, band (see Figure 22-12). The myosin molecule resembles a golf lactate. If the myocardium is inadequately perfused because of coro-
club with two large bulbous heads protruding from one end of a straight nary artery disease, anaerobic metabolism becomes an essential source
shaft (Figure 22-13, A). The bilobed heads contain an actin-binding site of energy (see Chapter 1). The energy produced by metabolic processes
and a site of ATPase activity. A thick filament contains about 200 myo- is used for muscle contraction and relaxation, electrical excitation,
sin molecules bundled together with the heads of the molecules (called membrane transport, and synthesis of large molecules. Normally, the
cross-bridges) facing outward (Figure 22-14, C). The actin molecules are amount of ATP produced supplies sufficient energy to pump blood
part of the thin filaments (Figure 22-14, A). The light bands are called throughout the system.
isotropic, or I, bands (see Figure 22-12). The thin filaments of actin Cardiac work is often expressed in terms of myocardial oxygen
appear light and extend from the Z line, a dense fibrous line that crosses consumption (MVO  2), which correlates closely with total cardiac
562 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems

Myosin head
Membrane

A Sarcoplasmic
reticulum T tubule
Myosin molecule
Ca

Actin Ca
B

Myosin
head
Myosin microfilament
Myosin Sarcomere
A
Actin molecules Ca binds Troponin
to troponin Actin
Tropomyosin molecule

Actin microfilament

C Myosin
Myosin
binding site
FIGURE 22-13  Structure of Myosin. A, Each myosin molecule is a microfilament
Myosin
coil of two chains wrapped around one another. At the end of each B
chain is a globular region, much like a golf club, called the head. B,
ATP
Myosin molecules usually are combined into filaments, which are binding site Ca
stalks of myosin from which the heads protrude. C, Actin microfila-
ment. (From Raven PH, Johnson GB: Understanding biology, ed 3,
Dubuque, Iowa, 1995, Brown.)
Cross-bridge

energy requirements. MV̇O2 is determined by the following three

major factors: (1) amount of wall stress during systole, which can be C
estimated by measuring the systolic blood pressure; (2) duration of sys- FIGURE 22-14  Myofilaments and Mechanisms of Muscle Con-
tolic wall tension, which is measured indirectly by the heart rate; and traction. A, Thin and thick myofilaments. In resting muscle, cal-
(3) contractile state of the myocardium, for which no clinical measure- cium ions are stored in the sarcoplasmic reticulum. When an action
ment exists. MV̇O2 can increase several-fold with exercise and decrease potential reaches the muscle cell, the T tubules carry the action
moderately under conditions such as hypotension and hypothermia. potential deep into the sarcoplasm. The action potential causes the
The oxygen supply to the myocardium is delivered exclusively by sarcoplasmic reticulum to release the store of calcium ions. B, In
resting muscle the myosin binding sites are covered by troponin
the coronary arteries. Approximately 70% to 75% of the oxygen from
and tropomyosin. The calcium ions released into the sarcoplasm
the coronary arteries is used immediately by cardiac muscle, leaving as a result of action potential bind to the troponin. C, This binding
little oxygen in reserve. The oxygen content of the blood cannot be causes the tropomyosin and troponin to move out of the way of
increased under normal atmospheric conditions nor can the amount the myosin binding sites, leaving the myosin heads free to bind to
of O2 extracted from the blood be appreciably increased from the rest- the actin microfilament. ATP, Adenosine triphosphate. (From Raven
ing level. Any increased energy needs can be met only by increasing PH, Johnson GB: Understanding biology, ed 3, Dubuque, Iowa,
coronary blood flow. When oxygen content decreases, the local con- 1995, Brown.)
centration of metabolic factors increases. One of these, adenosine,
dilates coronary arterioles, increasing coronary blood flow.
Calcium and excitation-contraction coupling. Excitation-­
Myocardial Contraction and Relaxation contraction coupling is the process by which an action potential in
Myocardial contractility is a change in developed tension at a given the plasma membrane of the muscle fiber triggers the cycle, leading to
resting fiber length. In functional terms, contractility is the ability cross-bridge activity and contraction. Activation of this cycle depends
of the heart muscle to shorten. On a molecular basis, thin filaments on the availability of calcium.
of actin slide over thick filaments of myosin, according to the cross- Calcium is stored in the tubule system and the sarcoplasmic reticulum.
bridge theory of muscle contraction.4 Anatomically, contraction It enters the myocardial cell from the interstitial fluid after electrical exci-
occurs when the sarcomere shortens, so adjacent Z lines move closer tation, which increases membrane permeability to calcium. Two types
together (see Figures 22-12 and 22-15). The A band width, including of calcium channels (L-type, T-type) are identified in cardiac tissues.4,6
thick myosin filaments, is unchanged, with the movement coming The L-type, or long-lasting, channels predominate and are the channels
from the long sets of filaments. The degree of shortening depends on blocked by calcium channel–blocking drugs (verapamil, nifedipine, dil-
how much the thin filaments overlap the thick filaments. tiazem).6 The T-type, or transient, channels are much less abundant in
 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems 563

Ca

ADP ADP

A B 
Pi C Pi D

FIGURE 22-15  Cross-Bridge Theory of Muscle Contraction. A, Each myosin cross-bridge in the thick
filament moves into a resting position after an adenosine triphosphate (ATP) molecule binds and trans-
fers its energy. B, Calcium ions released from the sarcoplasmic reticulum bind to troponin in the thin
filament, allowing tropomyosin to shift from its position blocking the active sites of actin molecules.
C, Each myosin cross-bridge then binds to an active site on a thin filament, displacing the remnants of
ATP hydrolysis—adenosine diphosphate (ADP) and inorganic phosphate (Pi). D, The release of stored
energy from step A provides the force needed for each cross-bridge to move back to its original posi-
tion, pulling actin along with it. Each cross-bridge will remain bound to actin until another ATP molecule
binds to it and pulls it back into its resting position, A. (From Patton KT, Thibodeau GA: Anatomy &
physiology, ed 7, St Louis, 2010, Mosby.)

the heart. T-type channels are not blocked by currently available calcium The ventricle does not eject all the blood it contains, and the amount
channel–blocking drugs; therefore T-type channel blockers are being ejected per beat is called the ejection fraction. The ejection fraction can
developed.7 Calcium entering the cell triggers the release of calcium from be estimated by echocardiography and is the stroke volume divided by
the storage sites, particularly the sarcoplasmic reticulum. Calcium then the end-diastolic volume. The end-diastolic volume of the normal ven-
diffuses toward the myofibrils and binds with troponin. tricle is about 70 to 80 ml/m2, and the stroke volume is about 40 to 60
The calcium-troponin complex interaction facilitates the contrac- ml/beat; thus the normal ejection fraction of the resting heart is about
tion process. In the resting state, troponin I is bound to actin and the 60% to 75%. The ejection fraction is increased by factors that increase
tropomyosin molecule covers the sites where the myosin heads bind contractility (e.g., sympathetic nervous system activity). A decrease in
to actin. Therefore interaction between actin and myosin is prevented. ejection fraction is a hallmark of ventricular failure. The effects of aging
Calcium binding to troponin inhibits troponin C (which enhances tro- on cardiovascular function are summarized in Table 22-3.
ponin I–actin binding) and causes tropomyosin to be displaced, conse- The factors that determine cardiac output are (1) preload, (2) after-
quently uncovering the binding sites on the myosin heads. Myosin and load, (3) myocardial contractility, and (4) heart rate. Preload, after-
actin can now form cross-bridges, and ATP can be dephosphorylated load, and contractility affect stroke volume.
to adenosine diphosphate (ADP). Under these circumstances, sliding
of the thick and thin filaments can occur, and the muscle contracts. Preload
Myocardial relaxation. Adequate relaxation is just as vital to Preload is the volume and associated pressure generated in the ven-
optimal cardiac function as contraction; and calcium, troponin, and tricle at the end of diastole (ventricular end-diastolic volume [VEDV]
tropomyosin also facilitate relaxation. After contraction, free calcium and pressure [VEDP]). Preload is determined by two primary factors:
ions are actively pumped out of the cell back into the interstitial fluid (1) the amount of venous return entering the ventricle during diastole,
or reaccumulated in the sarcoplasmic reticulum and stored. Tropo- and (2) the blood left in the ventricle after systole (end-systolic vol-
nin releases its bound calcium. The tropomyosin complex blocks the ume). Venous return is dependent on blood volume and flow through
active sites on the actin molecule, preventing cross-bridges with the the venous system and the atrioventricular valves. End-systolic volume
myosin heads. A decreased ability by the myocardium to relax leads to is dependent on the strength of ventricular contraction and the resis-
increased diastolic filling pressures and eventually heart failure.8 tance to ventricular emptying.
The Laplace law describes the relationship by which the amount of
4 QUICK CHECK 22-4 tension generated in the wall of the ventricle (or any chamber or ves-
sel) to produce a given intraventricular pressure depends on the size
1. What features distinguish myocardial cells from skeletal cells?
2. Describe the interactions of actin, myosin, and the troponin-tropomyosin (radius and wall thickness) of the ventricle. Ventricular end-diastolic
complex in controlling heart function. volume, which determines the size of the ventricle and the stretch of
3. Define excitation-contraction coupling. the cardiac muscle fibers, therefore affects the tension (or force) for
contraction. The Frank-Starling law of the heart describes the length-
tension relationship of VEDV (preload) to myocardial contractility (as
Factors Affecting Cardiac Output measured by stroke volume). Muscle fibers have an optimal resting
Cardiac performance can be quantified by measuring the cardiac out- length from which to generate the maximum amount of contractile
put. Cardiac output is the volume of blood flowing through either the strength. Within a physiologic range of muscle stretching, increased
systemic or the pulmonary circuit per minute and is expressed in liters preload increases stroke volume (and therefore cardiac output and
per minute (L/min). To determine cardiac output, heart rate (beats stroke work) (Figure 22-16, curve B). Excessive ventricular filling
per minute) is multiplied by stroke volume (liters per beat). Normal and preload (increased VEDV) stretches the heart muscle beyond
cardiac output is about 5 L/min for a resting adult. optimal length and stroke volume begins to fall. Factors that increase
564 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems

TABLE 22-3 CARDIOVASCULAR FUNCTION IN ELDERLY PERSONS

DETERMINANT RESTING CARDIAC PERFORMANCE EXERCISE CARDIAC PERFORMANCE
Cardiac output Unchanged or slightly decreased in women only Declines because of a decrease in heart rate and stroke volume
Heart rate Slight decrease Increases less than in younger people, possibly because of decreased
cardiovascular response to catecholamines; overall slight decrease
Stroke volume Slight increase Slight increase
Ejection fraction Unchanged Increases less from rest to exercise in younger people
Afterload Increased Uncertain
End-diastolic volume Unchanged Smaller for women
End-systolic volume Unchanged Lesser increase
Contraction Increased because of prolonged relaxation Decreases with vigorous exercise*
Cardiac dilation No change Increases at end-diastole and end-systole
V̇O2 max Not applicable Declines because of a decline in skeletal muscle mass

Data from Gerstenblith G, Lakatta EG: Aging and the cardiovascular system. In Willerson JT, Cohn JN, editors: Cardiovascular medicine, New York,
1995, Churchill Livingstone; Kaye D, Esler M: Sympathetic neuronal regulation of the heart in aging and heart failure, Cardiovasc Res 66(2):256–
264, 2005; Kenny RA, Ceifer CM: Aging and geriatric heart disease. In Crawford MH, DiMarco JP, editors: Cardiology, London, 2001, Mosby.
*As measured by end-systolic volume/systolic blood pressure (ESV/SBP), an index of contractility.

contractility cause the heart to operate on a higher length-tension to contract more effectively, whereas high aortic pressures (increased
curve (Figure 22-16, curve A). Factors that decrease contractility (Fig- afterload) slow contraction and cause higher workloads against which
ure 22-16, curve C) cause the heart to operate at a lower length-tension the heart must function so it can eject less blood. Increased aortic pres-
curve. Figure 22-17 illustrates the relationship between VEDV and sure is usually the result of increased peripheral vascular resistance
stroke volume, cardiac output, and stroke work. (PVR), also called total peripheral resistance (TPR). In individuals
Increases in preload (VEDV) not only cause a decline in stroke with hypertension, increased PVR means that afterload is chronically
volume, but also result in increases in VEDP. These changes can lead elevated, resulting in increased ventricular workload and hypertrophy
to heart failure (see Chapter 23). Increased VEDP causes pressures to of the myocardium. In some individuals, changes in afterload are the
“back up” into the pulmonary or systemic venous circulation, where result of aortic valvular disease (see Figure 22-17).
they force plasma out through vessel walls, causing fluid to accumulate
in lung tissues (pulmonary edema; see Chapter 26) or in the peripheral Myocardial Contractility
tissues (peripheral edema). Stroke volume, or the volume of blood ejected per beat during systole,
also depends on the force of contraction, which depends on myocardial
Afterload contractility or the degree of myocardial fiber shortening. Three major
Left ventricular afterload is the resistance to ejection of blood from the factors determine the force of contraction (see Figure 22-17):
left ventricle. It is the load the muscle must move after it starts to contract. 1. Changes in the stretching of the ventricular myocardium caused by
Aortic systolic pressure is a good index of afterload. Pressure in the ven- changes in VEDV (preload). As discussed previously, increased
tricle must exceed aortic pressure before blood can be pumped out dur- blood flow from the veins into the heart distends the ventricle by
ing systole. Low aortic pressures (decreased afterload) enable the heart increasing preload, which increases the stroke volume and, subse-
quently, cardiac output, up to a certain point. However, an exces-
sive increase in preload leads to decreased stroke volume.
2. Alterations in the inotropic stimuli of the ventricles. Chemicals affect-
200
ing contractility are called inotropic agents. The most important
volume or stroke work or
Cardiac output or stroke

systolic muscle tension

A Increased positive inotropic agents are epinephrine and norepinephrine

released from the sympathetic nervous system. Other positive ino-
B Normal
contractility tropes include thyroid hormone and dopamine. The most impor-
100 C tant negative inotropic agent is acetylcholine released from the
Decreased vagus nerve. Many drugs have positive or negative inotropic prop-
erties that can have profound effects on cardiac function.
3. Adequacy of myocardial oxygen supply. Myocardial contractility also
is affected by oxygen and carbon dioxide levels (tensions) in the
0
coronary blood. With severe hypoxemia (arterial oxygen saturation
Ventricular end-diastolic volume (ml)
less than 50%), contractility is decreased. With less severe hypox-
FIGURE 22-16  Frank-Starling Law of the Heart. Relationship emia (saturation more than 50%), contractility is stimulated. Mod-
between length and tension in heart. End-diastolic volume deter-
erate degrees of hypoxemia may increase contractility by enhancing
mines end-diastolic length of ventricular muscle fibers and is pro-
portional to tension generated during systole, as well as to cardiac
the myocardial response to circulating catecholamines.1
output, stroke volume, and stroke work. A change in myocardial con- Preload, afterload, and contractility all interact with one another to
tractility causes the heart to perform on a different length-­tension determine stroke volume and cardiac output. Changes in any one of
curve. A, Increased contractility; B, normal contractility; C, heart these factors can result in deleterious effects on the others, resulting in
failure or decreased contractility. (See text for further explanation.) heart failure (see Chapter 23).
 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems 565

Cardiac output


Stroke volume Heart rate

Preload Afterload Contractility Central nervous FIGURE 22-17  Factors Affecting Cardiac Per-
system formance. Cardiac output, which is the amount
of blood (in liters) ejected by the heart per min-
Autonomic
End nervous system ute, depends on heart rate (beats per minute) and
diastolic- stroke volume (milliliters of blood ejected during
End- volume Neural ventricular systole).
Aortic reflexes
systolic
pressure
volume
Sympathetic Atrial
stimulation receptors
Total peri-
Venous
pheral Hormones
return
resistance Myocardial
oxygen supply

Heart Rate If blood pressure is decreased, the baroreceptor reflex accelerates

As described previously, the activity of the SA node is the primary heart rate and causes vessels to constrict. These responses raise blood
determinant of the heart rate. The average heart rate in healthy adults is pressure back toward normal. This reflex is critical to maintaining
about 70 beats/min. This diminishes by 10 to 20 beats/min during sleep adequate tissue perfusion. When blood pressure is increased, the pres-
and can accelerate to more than 100 beats/min during muscular activity soreceptors increase their rate of discharge, sending neural impulses
or emotional excitement. In well-conditioned athletes at rest, the heart over the glossopharyngeal nerve (ninth cranial nerve) and through the
rate is normally about 50 to 60 beats/min. In highly trained or elite ath- vagus nerve to the cardiovascular control centers in the medulla. These
letes, the resting heart rate can be below 50 beats/min; these athletes reflexes increase parasympathetic activity and decrease sympathetic
also have a greater stroke volume and lower peripheral resistance in activity, causing blood vessels to dilate and heart rate to decrease (see
active muscles than they had before training. The control of heart rate Figure 22-18). The role of baroreceptors in influencing blood pressure
includes activity of the central nervous system, autonomic nervous sys- is discussed in more detail later in this chapter.
tem, neural reflexes, atrial receptors, and hormones (see Figure 22-17). Atrial receptors. Receptors that influence heart rate exist in both
Cardiovascular control centers in the brain. The cardiovascular atria (Figure 22-18).1,4 They are located in the right atrium at its junc-
control center is in the brain stem in the medulla, with secondary areas tions with the venae cava and in the left atrium at its junctions with the
in the hypothalamus, cerebral cortex, and thalamus along with complex pulmonary veins. Distention of the atria causes stimulation of these
networks of excitatory or inhibitory interneurons (connecting neurons) atrial receptors (for example, when intravascular volume is increased
throughout the brain. The hypothalamic centers regulate cardiovascular by intravenous infusions). This causes activation of the Bainbridge
responses to changes in temperature; the cerebral cortex centers adjust reflex, which increases heart rate (see Figure 22-18). The magnitude of
cardiac reaction to a variety of emotional states; and the medullary con- the change in heart rate depends on the relative contributions of this
trol center regulates heart rate and blood pressure (see Figure 22-11). reflex with baroreceptor activity.10
The nerve fibers from the cardiovascular control center synapse Stimulation of these atrial receptors also increases urine volume,
with autonomic neurons that influence the rate of firing of the SA node. presumably because of a neurally mediated reduction in antidiuretic
As previously discussed, increased heart rate occurs with sympathetic hormone. In addition, atrial natriuretic peptide (ANP) and brain
(adrenergic) stimulation. Thus the interneurons that cause sympa- natriuretic peptide (BNP) are released from atrial tissue in response to
thetic neuronal excitation are collectively called the cardioexcitatory the increases in blood volume. ANP and BNP have powerful diuretic
center.9 When the parasympathetic nerves to the heart are stimulated and natriuretic (salt excretion) properties, resulting in decreased blood
(primarily via the vagus nerve), heart rate slows and the sympathetic volume and pressure.4,11
nerves to the heart, arterioles, and veins are inhibited. Because para- Hormones and biochemicals. Hormones and biochemicals affect
sympathetic excitation and simultaneous sympathetic inhibition gen- the arteries, arterioles, venules, capillaries, and contractility of the
erally depress cardiac function, these interneurons are often referred myocardium. Norepinephrine increases heart rate, enhances myo-
to as the cardioinhibitory center. At rest, the heart rate in healthy cardial contractility, and constricts blood vessels. Epinephrine dilates
individuals is primarily under the control of parasympathetic stimu- vessels of the liver and skeletal muscle and also causes an increase in
lation. Administration of drugs that block parasympathetic function myocardial contractility. Some adrenocortical hormones, such as
(anticholinergic) or physical interruption of the vagus nerve causes hydrocortisone, potentiate the effects of these catecholamines.
significant tachycardia (abnormally fast heart rate) because this inhibi- Thyroid hormones enhance sympathetic activity, promoting
tory parasympathetic influence is lost. increased cardiac output. A decrease in growth hormone, as well as in
Neural reflexes. The baroreceptor reflex facilitates both blood thyroid and adrenal hormones, results in bradycardia (heart rate below
pressure changes and heart rate changes. It is mediated by tissue pres- 60 beats/min), reduced cardiac output, and low blood pressure. (See
sure receptors (pressoreceptors) in the aortic arch and carotid arteries. other hormones in the Regulation of Blood Pressure section.)
566 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems

Increased Stimulate
Intravenous Bainbridge
right atrial atrial 
infusion reflex
pressure receptors
Heart
rate
Increased Increased
Baroreceptor
cardiac arterial 
reflex
output pressure
FIGURE 22-18  Heart Rate and Intravenous Infusions. Intravenous infusions of blood or electrolyte
solutions tend to increase heart rate through the Bainbridge reflex and to decrease heart rate through
the baroreceptor reflex. The actual change in heart rate induced by such infusions is the result of these
two opposing effects. (From Berne RM, Levy MN: Cardiovascular physiology, ed 8, St Louis, 2001,
Mosby.)

Occipital
Facial
Internal carotid
External carotid
Right common carotid Left common carotid
Left subclavian
Brachiocephalic Arch of aorta
Lateral thoracic
Right coronary Pulmonary
Left coronary
Axillary
Aorta
Brachial Celiac

Splenic
Superior mesenteric
Renal
Abdominal aorta Inferior mesenteric
Common iliac Radial
Internal iliac Ulnar
FIGURE 22-19  Circulatory System. A, Principal (hypogastric) Palmar arch:
arteries of body. Deep
External Superficial
iliac
Digital

Deep medial
circum ex femoral
Deep femoral
Femoral

Popliteal

Anterior tibial

Peroneal

Posterior tibial

Arcuate
Dorsal pedis
Dorsal
metatarsal
A
 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems 567

4 QUICK CHECK 22-5

arterioles, which branch further into the smallest vessels, the capil-
laries, where nutrient exchange between the blood and tissues occurs.
1. Why is the Frank-Starling law of the heart important to the understanding
Blood from the capillaries then enters tiny venules that join to form
of heart failure?
the larger veins, which return venous blood to the right heart. Periph-
2. Discuss the baroreceptor reflex and explain how it facilitates blood pres-
eral vascular system is an imprecise term used to describe the part
sure and heart rate changes.
of the systemic circulation that supplies the skin and the extremities,
3. Summarize the cardiovascular changes with aging.
particularly the legs and feet.

Structure of Blood Vessels

THE SYSTEMIC CIRCULATION
Blood vessel walls are composed of three layers: (1) the tunica intima
The arteries and veins of the systemic circulation are illustrated in (innermost, or intimal, layer), (2) the tunica media (middle, or medial,
Figure 22-19. Blood from the left side of the heart flows through the layer), and (3) the tunica externa or adventitia (outermost, or exter-
aorta and into the systemic arteries. The arteries branch into small nal, layer). These structures are illustrated in Figure 22-20. Blood vessel

Inferior sagittal sinus

Superior sagittal sinus
Straight sinus
Angular Transverse sinus
Cervical plexus
Facial External jugular
Internal jugular
Right brachiocephalic Left brachiocephalic
Right subclavian Left subclavian
Superior vena cava Cephalic
Right pulmonary Axillary
Great cardiac
Small cardiac
Inferior vena cava Basilic
Hepatic Median basilic
Hepatic portal Splenic
Median Inferior mesenteric
cubital
Superior Common iliac
mesenteric Internal iliac
Gastroepiploic FIGURE 22-19, cont’d B, Principal veins of
Common iliac body. (From ­Patton KT, Thibodeau GA: Anatomy
& physiology, ed 7, St Louis, 2010, Mosby.)
External iliac Digital

Femoral
Femoral

Great saphenous

Small saphenous Popliteal

Fibular (peroneal)

Anterior tibial
Posterior tibial

Digital
Dorsal
B venous
arch
568 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems

Tunica intima
Endothelium Tunica intima
Basement Endothelium
membrane Basement membrane
Tunica media Tunica media
Smooth muscle Smooth muscle
Tunica externa Tunica externa
Fibrous connective Fibrous connective
tissue tissue
Nervi vasorum Nervi vasorum
Vasa vasorum Vasa vasorum
Collagen fibers Collagen fibers

Large vein Elastic artery

Tunica intima
Valve Endothelium
Tunica intima Basement membrane
Internal elastic
Endothelium
membrane
Basement
membrane Tunica media
Smooth muscle
Tunica media
Smooth muscle Tunica externa
Tunica externa Fibrous connective
tissue
Fibrous connective Internal elastic
tissue membrane

Medium-sized vein Muscular artery

Tunica intima Valve Tunica intima

Endothelium Endothelium
Basement membrane Basement membrane
Tunica media Tunica media
Smooth muscle Smooth muscle
Endothelium
Tunica externa Basement Tunica externa
Fibrous connective tissue membrane Fibrous connective tissue

Venule Arteriole
Capillary
FIGURE 22-20  Structure of the Blood Vessels. The tunica externa of the veins are color-coded blue
and the arteries red. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010,
Mosby.)

Capillary
Arteriole

Precapillary
sphincters B
A
FIGURE 22-21  Capillary Wall. A, Capillaries have a wall composed of only a single layer of flattened
cells, whereas the walls of the larger vessels also have smooth muscle. B, Capillary with red blood cells
in single file (× 500). (A from Patton KT, Thibodeau GA: Anatomy & physiology, ed 7, St Louis, 2010,
Mosby; B, Copyright Ed Reschke.)
 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems 569

walls vary in thickness depending on the thickness or absence of one or The capillaries branch from the metarterioles, meeting at a ring of
more of these three layers. Cells of the larger vessels are nourished by smooth muscle called the precapillary sphincter. As the sphincters
the vasa vasorum, small vessels located in the tunica externa. contract and relax, they regulate blood flow through the capillaries.
Appropriately stimulated, the precapillary sphincters help to maintain
Arterial Vessels arterial pressure and regulate selective flow to vascular beds.
Arterial walls are composed of elastic connective tissue, fibrous con- The capillary walls are very thin, making possible the rapid exchange
nective tissue, and smooth muscle. Elastic arteries have a thick tunica of substrates, metabolites, and special products (e.g., hormones)
media with more elastic fibers than smooth muscle fibers. Examples between the blood and the interstitial fluid, from which they are taken
include the aorta and its major branches and the pulmonary trunk. up by the cells. A single endothelial cell may form the entire vessel wall
Elasticity allows the vessel to stretch as blood is ejected from the heart if the capillary has no tunica media or tunica externa. In some capillar-
during systole. During diastole, elasticity promotes recoil of the arter- ies, the endothelial cells contain oval windows or pores termed fenes-
ies, maintaining blood pressure within the vessels. trations, which are generally covered by a thin diaphragm.
Muscular arteries are medium- and small-sized arteries and Substances pass between the capillary lumen and the interstitial
are farther from the heart than the elastic arteries. They contain fluid (1) through junctions between endothelial cells, (2) through fen-
more muscle fibers than the elastic arteries because they need less estrations in endothelial cells, (3) in vesicles moved by active transport
stretch and recoil. The muscular arteries distribute blood to arteri- across the endothelial cell membrane, or (4) by diffusion through the
oles throughout the body and help control blood flow because their endothelial cell membrane. A single capillary may be only 0.5 to 1 mm
smooth muscle can be stimulated to contract or relax. Contraction in length and 0.01 mm in diameter, but the capillaries are so numerous
narrows the vessel lumen (the internal cavity of the vessel), which that their total surface area may be more than 600 m2, or larger than
diminishes flow through the vessel (vasoconstriction). When the 100 football fields.
smooth muscle layer relaxes, more blood flows through the vessel
lumen (vasodilation). Endothelium
An artery becomes an arteriole where the diameter of its lumen All tissues depend on a blood supply and the blood supply depends
narrows to less than 0.5 mm. The arterioles are composed almost on endothelial cells, which form the lining, or endothelium, of the
exclusively of smooth muscle and regulate the flow of blood into the blood vessel (Figure 22-23). Endothelial cells are really quite remark-
capillaries by vasoconstriction, which retards the flow of blood into the able in that they can adjust their number and arrangement to accom-
capillaries, and vasodilation, which permits blood to enter the capil- modate local requirements. They are a life-support tissue extending
laries freely (Figure 22-21). The thick smooth muscle layer of the arte- and remodeling the network of blood vessels to enable tissue growth,
rioles is a major determinant of the resistance blood encounters as it motion, and repair. Vascular endothelial cells produce a number of
flows through the systemic circulation. essential chemicals including vasodilators, vasoconstrictors, antico-
The capillary network is composed of connective channels, or thor- agulants, and growth factors. The endothelium performs these vital
oughfares, called metarterioles, and “true” capillaries (Figure 22-22). functions through synthesis and release of vasoactive chemicals.

Precapillary Preferential channel

sphincters (metarteriole) Arteriole

Metarteriole

Capillary

Capillary
Venule

FIGURE 22-22  Capillary Network. Blood enters network as arterial blood and exits as venous blood.
570 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems

TABLE 22-4 FUNCTIONS OF THE

ENDOTHELIUM
Endothelium
FUNCTION ACTIONS INVOLVED
Filtration and permeability Facilitates transport of large molecules via
Basal lamina vesicular transport movement through
intercellular junctions
Facilitates transport of small molecules via
Elastic lamina
movement of vesicles, through opening of
tight junctions, and across cytoplasm
Smooth muscle Vasomotion Stimulates vascular relaxation through
production of nitric oxide, prostacyclin, and
Adventitia other vasodilators
(connective tissue) Stimulates vascular constriction through
production of endothelin and angiotensin II
FIGURE 22-23  Endothelium. Practically imperceptible, the endo- Clotting Stimulates clotting by inducing platelet
thelial cells arrange themselves as a fine lining that has numerous adhesion via production of von Willebrand
life-support functions (see Table 22-4).
factor, platelet-activating factor, and
others
Table 22-4 and Figures 22-24 and 22-25 summarize some of the more Prevents clotting through production of en-
important endothelial functions. Dysfunction of the endothelium has dogenous anticoagulants such as heparin
been implicated in virtually every type of vascular disorder, including sulfate
atherosclerosis and hypertension (see Chapter 23).4,12 Promotes fibrinolysis via production of tissue
plasminogen activating factor (t-PH) and
Veins plasminogen activator inhibitor (PAI-A)
Compared with arteries, veins are thin walled and fibrous and have Inflammation Expresses adhesion molecules that allow
a larger diameter (see Figure 22-20). Veins also are more numerous for monocyte and polymorphonucleocyte
than arteries. The smallest venules closest to the capillaries have an margination and diapedesis
inner lining composed of the endothelium of the tunica intima and Expresses receptors for oxidized lipoproteins,
surrounded by fibrous tissue. The largest venules are surrounded by allowing them to enter vascular intima
a few smooth muscle fibers constituting a thin tunica media. In veins,
the tunica externa has less elastic tissue than in arteries, so veins do From Hansson GK, Nilsson J: Pathogenesis of atherosclerosis. In
not recoil after distention as quickly as do arteries. Like arteries, veins Crawford MH, DiMarco JP, editors: Cardiology, ed 2, London, 2004,
Mosby.
receive nourishment from the tiny vasa vasorum.
Some veins, most commonly in the lower limbs, contain valves to
regulate the one-way flow of blood toward the heart (Figure 22-26). through an organ result from changes in the vascular resistance within
These valves are folds of the tunica intima and resemble the semilu- the organ. Resistance in a vessel is inversely related to blood flow—that
nar valves of the heart. When a person stands up, contraction of the is, increased resistance leads to decreased blood flow. Poiseuille law
skeletal muscles of the legs compresses the deep veins of the legs and shows the relationship among blood flow, pressure, and resistance:
assists the flow of blood toward the heart. This important mechanism δP
Q=
of venous return is called the muscle pump (Figure 22-27). R
where Q = blood flow, P = pressure difference (P1 − P2), and R =
Factors Affecting Blood Flow resistance. Resistance to flow cannot be measured directly, but it can
Blood flow is the amount of fluid moved per unit of time and is usu- be calculated if the pressure difference and flow volumes are known.
ally expressed as liters per minute (L/min) or milliliters per minute Resistance to blood flow in a single vessel is determined by the radius
(ml/min), or as cubic centimeters per second (cm3/sec). Flow is reg- and length of the blood vessel and by the blood viscosity.
ulated by the same physical properties that govern the movement of The most important factor determining resistance in a single ves-
simple fluids in a closed, rigid system—that is, pressure, resistance, sel is the radius or diameter of the vessel’s lumen (Figure 22-28, A).
velocity, turbulent versus laminar flow, and compliance. Small changes in the lumen’s radius or diameter lead to large changes
in vascular resistance. Another important factor is the length of the
Pressure and Resistance vessel. Resistance to flow is generally greater in longer tubes because
Pressure in a liquid system is the force exerted on the liquid per unit resistance increases with length. Blood flow varies inversely with the
area and is expressed as dynes per square centimeter (dynes/cm2), viscosity of the fluid. Thick fluids move more slowly and experience
millimeters of mercury (mm Hg), or units of pressure (torr). Blood greater resistance to flow than thin fluids. For example, blood that con-
flow depends partly on the difference between pressures in the arterial tains a high percentage of red cells is more viscous. This relationship is
and venous vessels supplying the organ. Fluid moves from the arterial expressed as the hematocrit—the ratio of the volume of red blood cells
“side” of the capillaries, a region of greater pressure, to the venous side, to the volume of whole blood. A high hematocrit level reduces flow
a region of lesser pressure. through the blood vessels, particularly the microcirculation (arteri-
Resistance is the opposition to force. In the cardiovascular sys- oles, capillaries, venules).
tem, most opposition to blood flow is provided by the diameter and Resistance to flow through a system of vessels, or total resistance,
length of the blood vessels themselves. Therefore changes in blood flow depends not only on characteristics of individual vessels but also on
CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems 571

Thromboxane A 2
Angiotensin I Angiotensin II
Platelets
Blood
vessel

Endothelium

ACE

Smooth muscle Serotonin

CONSTRICTION Endothelin

Adventitia Nerve Norepinephrine

FIGURE 22-24  Endothelium Regulation of Vasomotion (Constriction and Dilation) and Platelet
Aggregation by Release of a Variety of Constricting and Dilating Substances. Constricting fac-
tors include arachidonic acid and metabolites, such as thromboxane A2 (which aspirin inhibits), and a
potent amino acid peptide called endothelin. The endothelium also converts angiotensin I into angioten-
sin II by the membrane-bound angiotensin-converting enzyme that also metabolizes the endogenous
endothelium-dependent vasodilator, bradykinin. (Modified from Stern S: Silent myocardial ischemia,
St Louis, 1998, Mosby.)

Blood Shear stress Norepinephrine

vessel Platelets Acetylcholine
Thrombin
5-HT, ADP Bradykinin
ATP Substance P NOS
Endothelium Angiotensin II
Vasopressin
Nitric oxide PGI 2

Nitric oxide

Adventitia

Smooth muscle RELAXATION

FIGURE 22-25  Factors Causing Endothelium-Dependent Vasodilation. A variety of exogenous
pharmacologic substances, platelet-derived factors, and shear stress can promote release of nitric
oxide by stimulating nitric oxide synthase (NOS). Prostacyclin (PGI2) causes relaxation of vascular
smooth muscle cells by a cyclic adenosine monophosphate (cAMP)-dependent mechanism, and both
nitric oxide and PGI2 inhibit platelet aggregation. ADP, Adenosine diphosphate; ATP, adenosine triphos-
phate; 5-HT, serotonin. (Modified from Stern S: Silent myocardial ischemia, St Louis, 1998, Mosby.)
572 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems

whether the vessels are arranged in series or in parallel and on the total
cross-sectional area of the system. Vessels arranged in series will gen-
erally provide less resistance than vessels arranged in parallel. Blood
flowing through the distributing arteries, beginning with branches off
the aorta and ending at arterioles in the capillary bed, encounters more
resistance than blood flowing through the capillary bed itself, where
flow is distributed among many short, tiny branches arranged in paral-
lel (see Figure 22-28, B). The total cross-sectional area of the arteriolar
system is greater than that of the arterial system, yet the greater num-
ber of arterioles arranged in parallel leads to great resistance to flow Muscles
contracted
Valves
open

Blood reservoir

Muscles
relaxed

Valves closed
FIGURE 22-26  Valves of Vein. Pooled blood is moved toward heart
as valves are forced open by pressure from volume of blood down-
stream. (From Patton KT, Thibodeau GA: Anatomy & ­physiology,
FIGURE 22-27  Muscle Pump.
ed 7, St Louis, 2010, Mosby.)

d=1
1 ml/min Capillaries
Arterioles Venules
Pressure = 100 mm Hg

Arteries Veins
d=2 1 min
16 ml/min Aorta Vena cava
Total
cross-
d=3 sectional
1 min
area
256 ml/min

Velocity
of blood
flow
(cm/sec)
1 min
A B
FIGURE 22-28  Lumen Diameter, Blood Flow, and Resistance. A, Effect of lumen diameter (d) on
flow through vessel. B, Blood flows with great speed in the large arteries. However, branching of arte-
rial vessels increases the total cross-sectional area of the arterioles and capillaries, reducing the flow
rate. When capillaries merge into venules and venules merge into veins, the total cross-sectional area
decreases, causing the flow rate to increase. (B from Patton KT, Thibodeau GA: Anatomy & physiology,
ed 7, St Louis, 2010, Mosby.)
 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems 573

in the arteriolar system. In contrast, the capillary system has a larger Vascular Compliance
number of vessels arranged in parallel than the arteriolar system, and Vascular compliance is the increase in volume a vessel can accommo-
the total cross-sectional area is much greater; thus there is lower resis- date for a given increase in pressure. Compliance depends on the ratio
tance overall through the capillary system. This, plus the slow velocity of elastic fibers to muscle fibers in the vessel wall. The elastic arteries
of flow in each capillary, promotes optimal capillary-tissue exchange. are more compliant than the muscular arteries. The veins are more
compliant than either type of artery, and they can serve as storage areas
Velocity for the circulatory system.
Blood velocity is the distance blood travels in a unit of time, usually Compliance determines a vessel’s response to pressure changes. For
centimeters per second (cm/sec). It is directly related to blood flow example, a large volume of blood can be accommodated by the venous
(amount of blood moved per unit of time) and inversely related to system with only a small increase in pressure. In the less compliant
the cross-sectional area of the vessel in which the blood is flowing. As arterial system, where smaller volumes and higher pressures are nor-
blood moves from the aorta to the capillaries, the total cross-sectional mal, even small changes in the volume of blood can cause significant
area of the vessels increases and the velocity of flow decreases. changes in pressure within the arterial vessels.
Stiffness is the opposite of compliance. Several conditions and dis-
Laminar Versus Turbulent Flow orders can cause stiffness, with the most common being arteriosclero-
Normally, blood flow through the vessels is laminar (laminar flow), sis (see Chapter 23).
meaning that concentric layers of molecules move “straight ahead.”
Each concentric layer flows at a different velocity (Figure 22-29). The
cohesive attraction between the fluid and the vessel wall prevents the 4 QUICK CHECK 22-6
molecules of blood that are in contact with the wall from moving. 1. What is the function of the arterioles?
The next thin layer of blood is able to slide slowly past the stationary 2. Identify the functions of the endothelium.
layer and so on until, at the center, the blood velocity is greatest. Large 3. Why does the total cross-sectional area in the capillary system lower the
­vessels have room for a large center layer; therefore they have less resis- resistance to flow?
tance to flow and greater flow and velocity than smaller vessels.
Where flow is obstructed, the vessel turns, or blood flows over
rough surfaces, the flow becomes turbulent (turbulent flow), with
whorls or eddy currents that produce noise, causing a murmur to be Regulation of Blood Pressure
heard on auscultation. Resistance increases with turbulence. Arterial Pressure
Arterial blood pressure is determined by the cardiac output times the
peripheral resistance (see Figure 22-30). The systolic blood pressure
is the arterial blood pressure during ventricular contraction or systole.
Vessel wall The diastolic blood pressure is the arterial blood pressure during ven-
tricular filling or diastole. The mean arterial pressure (MAP), which
is the average pressure in the arteries throughout the cardiac cycle,
Blood flow
depends on the elastic properties of the arterial walls and the mean vol-
ume of blood in the arterial system. MAP can be approximated from
the measured values of the systolic (Ps) and diastolic (Pd) pressures as
follows:
1
MAP = Pd + (Ps − Pd )
3
where Ps − Pd is the pulse pressure.
Arterial pressure is constantly regulated to maintain tissue perfu-
sion, or blood supply to the capillary beds, during a wide range of phys-
A iologic conditions, such as changes in body position, muscular activity,
and circulating blood volume. The major factors and ­relationships that
regulate arterial blood pressure are summarized in Figure 22-30.

Vessel
Effects of Cardiac Output
wall The cardiac output (minute volume) of the heart can be changed
by alterations in heart rate, stroke volume (volume of blood ejected
during each ventricular contraction), or both. An increase in cardiac
Constriction
output without a decrease in peripheral resistance will cause both arte-
rial volume and arterial pressure to increase. The higher arterial pres-
B Blood flow sure increases blood flow through the arterioles. On the other hand, a
decrease in the cardiac output causes an immediate drop in the mean
FIGURE 22-29  Laminar and Turbulent Blood Flow. A, Laminar
arterial blood pressure and arteriolar flow.
flow. Fluid flows in long, smooth-walled tubes as if it is composed
of a large number of concentric layers. B, Turbulent flow. Turbulent
Effects of Total Peripheral Resistance
flow is caused by numerous small currents flowing crosswise or
oblique to the long axis of the vessel, resulting in flowing whorls Total resistance in the systemic circulation, sometimes called total
and eddy currents. (From Seeley RR, Stephens TD, Tate P: Anat- peripheral resistance, is determined by changes in the diameter of the
omy and physiology, ed 3, St Louis, 1995, Mosby.) arterioles. Arteriolar constriction increases mean arterial pressure by
574 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems

Blood pressure  Cardiac output (CO)  Peripheral resistance (PR)

Hypertension  Increased CO and/or Increased PR

(Heart rate  stroke volume)

Preload Blood viscosity

Contractility Vessel diameter

Hematocrit
Venous (arteriolar)
Fluid volume
constriction

Sympathetic
nervous activity

Constrictor Dilator
(alpha) (beta, only
to skeletal
muscle
arterioles)

Local regulation Humoral regulation

Ionic factors
(O2, K, CO2, H) Vasodilators Vasoconstrictors
Autoregulation Prostaglandins Angiotensin
Kinins Epinephrine
Endothelial- Ca
derived factors Endothelial-
(nitric oxide) derived factors

FIGURE 22-30  Factors Regulating Blood Pressure.

preventing the free flow of blood into the capillaries. Dilation has the Effect of Hormones
opposite effect. Reflex control of total cardiac output and peripheral Antidiuretic hormone. Antidiuretic hormone (ADH) is released by
resistance includes (1) sympathetic stimulation of heart, arterioles, the posterior pituitary and causes reabsorption of water by the kidney.
and veins; and (2) parasympathetic stimulation of the heart (Figure With reabsorption, the blood plasma volume will increase, increasing
22-31). The autonomic nervous system is monitored by the cardio- blood pressure. Antidiuretic hormone, also known as arginine vaso-
vascular control center in the brain. Vasoconstriction is regulated by pressin, is also a potent vasoconstrictor, thus increasing peripheral
an area of the brain stem that maintains a constant (tonic) output of resistance (Figure 22-32, and see Chapters 4 and 17).
norepinephrine from sympathetic fibers in the peripheral arterioles. Renin-angiotensin system. Renin is an enzyme synthesized and
This tonic activity is essential for maintenance of blood pressure. secreted by the juxtaglomerular cells of the kidney. It also has been
Information about pressure and resistance is sensed by neural recep- found in the adrenal cortex, salivary gland, brain, pituitary gland,
tors (baroreceptors, chemoreceptors) in arterial walls and delivered to arterial smooth muscle cells in the vascular endothelium, and myo-
the medullary centers. cardium. Renin is an essential factor that interacts with many other
Baroreceptors. As discussed previously, baroreceptors are stretch systems to control vascular tone and renal sodium excretion.13 The
receptors located in the aorta and in the carotid sinus (see Figure primary factor that stimulates renin release is a drop in renal perfu-
22-31, A). They respond to changes in smooth muscle fiber length by sion as detected by the juxtaglomerular cells. Other factors that stimu-
altering their rate of discharge and supply sensory information to the late renin release include a decrease in the amount of sodium chloride
cardioinhibitory center in the brain stem. When activated, these baro- delivered to the kidney, β-adrenergic stimuli, and low potassium con-
receptors decrease cardiac output (heart rate and stroke volume) and centrations in plasma. Once in the circulation, renin splits off a poly-
peripheral resistance, and thus lower blood pressure. (Postural changes peptide from angiotensinogen to generate angiotensin I (Ang I). This
and the baroreceptor reflex are discussed in Chapter 23.) is converted by an enzyme, angiotensin-converting enzyme (ACE), to
Arterial chemoreceptors. Specialized areas within the aortic and angiotensin II (Ang II), a powerful vasoconstrictor that stimulates the
carotid arteries are sensitive to concentrations of oxygen, carbon diox- secretion of aldosterone from the adrenal gland (see Figures 22-33, A,
ide, and hydrogen ions (pH) in the blood (see Figure 22-31, B). These and 17-18). This kidney-based renin-angiotensin system serves as an
chemoreceptors are most important for the control of respiration but important regulatory loop. For example, decreases in blood pressure
also transmit impulses to the medullary cardiovascular centers that or renal blood flow (as might occur after hemorrhage or dehydration)
regulate blood pressure. If arterial oxygen concentration or pH falls, a stimulate secretion of renin. This causes the formation of Ang I, which
reflexive increase in blood pressure occurs, whereas an increase in car- is then converted to Ang II. Ang II causes vasoconstriction and aldo-
bon dioxide concentration causes a slight increase in blood pressure. sterone secretion. The resultant increase in TPR and sodium retention
The major chemoreceptive reflex is the result of alterations in arterial restores blood pressure. Overall, the renin-angiotensin system is acti-
oxygen concentration, with only minor effects resulting from altered vated after volume depletion or hypotension, and is suppressed after
pH or carbon dioxide levels. volume repletion.
 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems 575

Glossopharyngeal nerve (CN IX) Carotid sinus

baroreceptors

Vagus nerve (CN X)

Aortic
baroreceptors

Vagus nerve (parasympathetic)

Cardiac control center and Cardiac nerve

vasomotor center
in medulla
Sympathetic nerve
fibers

Smooth muscle in
blood vessel walls
Sympathetic chain

Carotid
bodies
O2, CO2, Peripheral
Decrease Aortic
pH ( H) chemo-
parasympathetic bodies
impulses receptors

Vagus nerve
CO2, O2 (parasympathetic)
pH ( H)
Medullary
chemoreceptors
Cardiac nerve
Increase Cardiac control center
sympathetic impulses
Vasomotor center
Sympathetic nerve
fibers

Smooth muscle in
blood vessel walls

Sympathetic
B chain

FIGURE 22-31  Baroreceptors and Chemoreceptor Reflex Control of Blood Pressure. A, Barore-
ceptor reflexes. B, Vasomotor chemoreflexes. (Modified from Patton KT, Thibodeau GA: Anatomy &
physiology, ed 7, St Louis, 2010, Mosby.)
576 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems

receptors are a main target in preventive and reparative strategies in

cardiovascular diseases. Aldosterone also has direct deleterious effects
on cardiovascular tissues.20
The role of AT2 receptors remains controversial. AT2 stimulation
results in NO-mediated vasodilation in many vascular beds and it is
Posterior suggested that this receptor plays a modulating and protective role
pituitary when AT1 is activated.21 However, other investigators suggest that AT2
receptor stimulation may actually contribute to cardiovascular remod-
eling.22 Numerous studies are under way to further elucidate the role
of these important vascular receptors. In addition, a second form of
ACE, called ACE2, helps to degrade Ang II into Ang 1-7, which bal-
ances the effects of Ang II on the vasculature23 (see Health Alert: Mul-
tiple Effects of the Renin-Angiotensin-Aldosterone System).
Natriuretic peptides. Another mechanism that can change blood
ADH
(Vasoconstriction) plasma volume and, therefore, blood pressure involves the natriuretic
peptides (NPs) (see Figure 22-32). The natriuretic peptides include
atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP),
Adrenal C-type natriuretic peptide (CNP), and urodilatin. These peptides
cortex help regulate sodium excretion (natriuresis), diuresis, vasodilation,
Angiotensin II and antagonism of the renin-angiotensin system. Atrial natriuretic
NPs
­peptide (ANP) is a hormone secreted from cells in the right atrium
(ACE) when right atrial blood pressure increases. ANP increases urine
Aldosterone Angiotensin I sodium loss, leading to the formation of a large volume of dilute urine
that decreases blood volume and blood pressure.24 Brain natriuretic
Renin peptide (BNP) is secreted from cardiac cells and also increases sodium
loss from the kidney. It is used both as a marker and as a treatment
Angiotensinogen for acute heart failure.25,26 C-type natriuretic peptide (CNP) is found
Kidney throughout the vascular endothelium and in cardiac, renal, skeletal,
and reproductive tissues. It has been found to promote vasodilation,
Fluid and Na loss from ANP (urine)
increase cardiac contractility, and inhibit smooth muscle prolifera-
FIGURE 22-32  Three Mechanisms That Influence Total Plasma
tion and vascular remodeling.27 Urodilatin is made in the kidneys and
Volume. The antidiuretic hormone (ADH) mechanism and renin-
promotes natriuresis and is being explored for the treatment of heart
angiotensin and aldosterone mechanisms tend to increase water
retention and thus increase total plasma volume. The natriuretic failure.28
peptides antagonize these mechanisms by promoting water loss Adrenomedullin. Adrenomedullin (ADM) is present in cardio-
and sodium loss, thus promoting a decrease in total plasma volume. vascular, pulmonary, renal, gastrointestinal, cerebral, and endocrine
ACE, Angiotensin-converting enzyme; ANP, atrial natriuretic pep- tissues. ADM is secreted by the adrenal medulla and from endothe-
tide; NPs, natriuretic peptides. (Modified from Patton KT, Thibodeau lial and smooth muscle cells and mediates vasodilation and sodium
GA: Anatomy & physiology, ed 7, St Louis, 2010, Mosby.) excretion. Thus ADM plays an important role in fluid and electrolyte
balance and cardiorenal regulation. ADM also plays an important role
in vascular protection by decreasing oxidative stress, limiting endo-
Ang II has two primary receptors, AT1 and AT2 (Figure 22-34). thelial injury, causing vasodilation, and promoting angiogenesis.29,30
Both subtypes, AT1 and AT2, are expressed in human hearts. AT1 also Other functions of ADM include neurotransmission, vascular growth,
is found on vascular smooth muscle and endothelial cells, nerve end- hormone secretion regulation, down-regulation of the proinflamma-
ings, conduction tissues, adrenal cortex, liver, kidney, and brain. AT2 tory cytokines, and modulation of anticoagulant properties.31 There-
has been found in fetal mesenchymal tissue, adrenal medulla, uterus fore changes in ADM levels have been correlated with several diseases
and ovarian follicles, renal tubules, and vasculature. A third type of including cardiovascular and renal sepsis, cancer, and diabetes31 (see
Ang II receptor, AT4, has been described although its effects are still Health Alert: Adrenomedullin).
being evaluated.14 The majority of Ang II actions occur through the Insulin. Insulin has direct vascular actions that contribute to both
AT1 receptor, including vasoconstriction, stimulation of aldoste- vascular protection and vascular injury.32,33 The vascular protection
rone release, myocyte hypertrophy, fibroblast proliferation, collagen and injury properties are summarized in Box 22-2. Insulin resistance
synthesis, smooth muscle cell growth, endothelial adhesion mol- and diabetes have a profound effect on cardiovascular disorders,
ecule expression, and catecholamine synthesis.15 There also exists including hypertension and atherosclerotic disease (see Chapter 23).
a tissue-based renin-angiotensin system that can be independently Adipokines. Adipocytes synthesize and release several hormones
regulated from the circulation. The tissue renin-angiotensin system that influence blood pressure, including adiponectin, leptin, and resis-
is activated in response to tissue injury.16 Through stimulation of the tin.34,35 Leptin and resistin levels are increased in obesity and are asso-
AT1 receptor and through the tissue renin-angiotensin system, Ang ciated with increased blood pressure and hypertension. Adiponectin
II is involved in maladaptive alterations, such as ventricular and vas- is a protective factor for the cardiovascular system that is found in
cular remodeling, atherosclerosis, alterations in renal function, and reduced levels in patients with obesity-related hypertension. Increasing
heart failure17-19 (see Figure 22-33, B, and Chapter 23). Therefore evidence suggests that aberrant production and release of these factors
treatments such as angiotensin-converting enzyme (ACE) inhibitors from adipocytes may contribute not only to hypertension but also to
and angiotensin receptor blockers (ARBs) that inhibit mostly AT1 atherosclerosis and heart failure (see Chapter 23).
 Heart

Bradykinin Brain
Adrenal

ACE Kidney
destroys
Bradykinin

Lungs

ACE

Angiotensinogen Angiotensin I Angiotensin II Efferent

arteriole

()
Renin
Angiotensin III

Liver Ang II

Receptor

Kidney
Angiotensin IV

A B
FIGURE 22-33  Angiotensins and the Organs Affected. A, The shaded blue area is the classic path-
way of biosynthesis that generates the renin and angiotensin I. Angiotensinogen is synthesized in the
liver and is released into the blood where it is cleaved to form angiotensin I by renin secreted by cells in
the kidneys. Angiotensin-converting enzyme (ACE) in the lungs catalyzes the formation of angiotensin
II from angiotensin I and destroys the potent vasodilator bradykinin. Further cleavage generates the
angiotensins III and IV. The reddish shading shows the organs affected by angiotensin II, including brain,
heart, adrenals, kidney, and the kidney’s efferent arterioles. The dashed arrow (left) shows the inhibition
of renin by angiotensin II. B, Summary of angiotensin II effects on blood vessel structure and function
leading to atherosclerosis. (Adapted from Goodfriend TL et al: N Engl J Med 334:2649–2654, 1996.)

HEALTH ALERT
Multiple Effects of the Renin-Angiotensin-Aldosterone System
Exciting research is uncovering additional roles of the renin-angiotensin-aldoste- 3. A new angiotensin receptor (AT4) has been described that is concentrated
rone system (RAA) in cardiovascular and systemic conditions: in the brain and may be involved in cerebral processing, cerebroprotection,
1. The RAA has profound effects on glucose metabolism, endothelial cell func- local blood flow, stress, anxiety, and depression.
tion, and renal disease, which has led to new uses for drugs that block angio- 4. A new type of angiotensin-converting enzyme (ACE2) has been identified that
tensin receptors, especially in individuals with diabetes and kidney disease. decreases Ang II levels and may offer an entirely new approach to combating
2. Activation of angiotensin 1 receptor (AT1) promotes systemic inflammation hypertension.
and mediates inflammatory myocyte hypertrophy, fibroblast proliferation, col- 5. Vaccines for Ang II and its receptors are being developed that might provide
lagen synthesis, smooth muscle cell growth, endothelial adhesion molecule a more targeted and potent blockade of the RAA.
expression, and catecholamine synthesis. Thus there is likely an important 6. Aldosterone has a number of deleterious effects, including myocardial necro-
role for the RAA in many diseases including atherosclerosis, heart failure, sis and fibrosis, vascular stiffening and injury, reduced fibrinolysis, endothe-
and shock. lial dysfunction, catecholamine release, and promotion of dysrhythmias.

Data from Bader M: Tissue renin-angiotensin-aldosterone systems: targets for pharmacological therapy, Annu Rev Pharmacol Toxicol 50:439–465,
2010; Benigni A, Cassis P, Remuzzi G: Angiotensin II revisited: new roles in inflammation, immunology and aging, EMBO Mol Med 2(7):247–257,
2010; Briet M, Schiffrin EL: Aldosterone: effects on the kidney and cardiovascular system, Nat Rev Nephrol 6(5):261–273, 2010; Vanderheyden
PM: From angiotensin IV binding site to AT4 receptor, Mol Cell Endocrinol 302(2):159–166, 2009; Zhong J et al: Angiotensin-converting enzyme 2
suppresses pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction, Circulation 122(7):717–728, 18 p following 728, 2010.
578 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems

Angiotensin I HEALTH ALERT

Bradykinin Adrenomedullin
ACE inhibitors ACE ADM is a vasodilator secreted by the adrenal medulla and by endothelial
Inactive bradykinin cells. It also increases sodium excretion and antagonizes the effects of aldo-
(fragments) sterone and angiotensin II on tissues. Thus ADM agonists are being evaluated
as potential treatments for hypertension, kidney disease, and heart failure.
AT1 Angiotensin II
More recently, the role of adrenomedullin in improving ion channel function
antagonist
and angiogenesis (growth of new blood vessels) has been explored as a poten-
drugs
tial mechanism to reduce ischemic and reperfusion injury to the myocardium.
Other areas for which adrenomedullin may present new therapeutic options
include pulmonary hypertension, postmenopausal hot flashes, pregnancy-
induced hypertension, hepatic cirrhosis, and bone disorders.
AT1
AT2 Data from Alonso-Martínez JL et al: Hemodynamic effects of chronic
smoking in liver cirrhosis: a role for adrenomedullin, Eur J Gastro-
enterol Hepatol 22(5):513–518, 2010; Kim S et al: Adrenomedullin
Signaling pathways protects against hypoxia/reoxygenation-induced cell death by suppres-
sion of reactive oxygen species via thiol redox systems, FEBS Lett
584(1):213–218, 2010; Kita T, Tokashiki M, Kitamura K: Aldosterone
Influence genes ? antisecretagogue and antihypertensive actions of adrenomedullin in
patients with primary aldosteronism, Hypertens Res 33(4):374–379,
2010; Nishida H et al: New aspects for the treatment of cardiac dis-
• Vascular diseases eases based on the diversity of functional controls on cardiac muscles:
mitochondrial ion channels and cardioprotection, J Pharmacol Sci
• Cardiac diseases
109(3):341–347, 2009; Shah K et al: Attenuation of renal ischemia and
• Renal diseases reperfusion injury by human adrenomedullin and its binding protein,  
FIGURE 22-34  Angiotensins and Their Receptors, AT1 and AT2. J Surg Res 163(1):110–117, 2010; Takahashi K et al: The renin-
Blocking the angiotensin-converting enzyme (ACE) with ACE inhibi- angiotensin system, adrenomedullins and urotensin II in the kidney:
tors decreases the amount of angiotensin II. Blocking the receptor possible renoprotection via the kidney peptide systems, Peptides
AT1 with drugs (AT1 antagonists) blocks the attachment of angio- 30(8):1575–1585, 2009.
tensin II to the cell, preventing the cellular effects and decreasing
the vascular, cardiac, and renal effects.

Venous Pressure between pressure in the aorta and pressure in the coronary vessels of
The main determinants of venous blood pressure are (1) the volume of the right atrium. Aortic pressure is the driving pressure that perfuses
fluid within the veins and (2) the compliance (distensibility) of the ves- vessels of the myocardium. Vasodilation and vasoconstriction nor-
sel walls. The venous system accommodates approximately 60% of the mally maintain coronary blood flow despite stresses imposed by the
total blood volume at any given moment, with venous pressure averag- constant contraction and relaxation of the heart muscle and despite
ing less than 10 mm Hg. The arteries accommodate about 15% of the shifts (within a physiologic range) of coronary perfusion pressure.
total blood volume, with an average arterial pressure (blood pressure) Several anatomic factors influence coronary blood flow. The aor-
of about 100 mm Hg. tic valve cusps obstruct coronary blood flow by pushing against the
The sympathetic nervous system controls venous compliance. openings of the coronary arteries during systole. Also during systole,
The walls of the veins are highly innervated by sympathetic fibers the coronary arteries are compressed by ventricular contraction. The
that, when stimulated, cause venous smooth muscle to contract and resulting systolic compressive effect is particularly evident in the sub-
increase muscle tone. This stiffens the wall of the vein, which reduces endocardial layers of the left ventricular wall and can greatly increase
distensibility and increases venous blood pressure, forcing more blood resistance to coronary blood flow. Therefore most coronary blood flow
through the veins and into the right heart. in the left ventricle occurs during diastole. During the period of systolic
Two other mechanisms that increase venous pressure and venous compression, when flow is slowed or stopped, oxygen is supplied by
return to the heart are (1) the skeletal muscle pump and (2) the respi- myoglobin, a protein present in heart muscle that binds oxygen during
ratory pump. During skeletal muscle contraction, the veins within the diastole and then releases it when blood levels of oxygen drop during
muscles are partially compressed, causing decreased venous capacity systole.
and increased return to the heart (see Figure 22-27). The respiratory
pump acts during inspiration, when the veins of the abdomen are Autoregulation
partially compressed by the downward movement of the diaphragm. Autoregulation (automatic self-regulation) enables individual ves-
Increased abdominal pressure moves blood toward the heart. sels to regulate blood flow by altering their own arteriolar resistances.
Autoregulation in the coronary circulation maintains constant blood
Regulation of the Coronary Circulation flow at perfusion pressures (mean arterial pressure) between 60 and
Flow of blood in the coronary circulation is directly proportional 180 mm Hg, provided that other influencing factors are held constant.
to the perfusion pressure and inversely proportional to the vascular Thus autoregulation ensures constant coronary blood flow despite
resistance of the bed. Coronary perfusion pressure is the difference shifts in the perfusion pressure within the stated range.
 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems 579

BOX 22-2 VASCULAR PROTECTION AND INJURY PROPERTIES OF INSULIN

Protection Injury
Insulin has numerous protective actions on blood vessels: Hyperinsulinemia has some deleterious effects on blood vessels:
1. Increases endothelial cell production of nitric oxide 1. Increases growth of vascular smooth muscle cells (VSMCs)
a Nitric oxide (NO) (in vitro) inhibits growth of vascular smooth muscle cells a Increases activity of insulin-like growth factor-1
b NO decreases the inflammatory reaction by inhibiting the expression of b Increases angiotensin II–mediated vascular remodeling
adhesion molecules, inhibiting the activity of proinflammatory cytokines 2. Increases the effect of platelet-derived growth factor
(e.g., tumor necrosis factor-alpha [TNF-α], monocyte chemoattractant 3. Increases sympathetic nervous system activity and thus contributes to
protein-1 [MCP-1]). Thus NO decreases the binding of monocytes/macro- increased blood pressure
phages to the vessel wall Insulin resistance is likely more important to the development of hypertension
2. Enhances acetylcholine-mediated vasodilation and the atherogenesis process than hyperinsulinemia:
3. Reduces platelet adherence and thus decreases thrombus formation 1. Reduces NO production and increases vasoconstrictors such as angiotensin
a Increased NO also inhibits the thrombotic process by preventing plate- II and catecholamines
let adhesion and enhancing the effect of prostacyclin to inhibit platelet 2. Promotes inflammation with increased production of toxic oxygen free radi-
aggregation cals and other inflammatory mediators
b Insulin increases the endogenous anticoagulant plasminogen activator 3. Increases clot formation
inhibitor 4. Contributes to endothelial damage
4. Is anti-inflammatory 5. Contributes to deleterious lipid changes
a Reduces toxic oxygen free radical production
b Decreases levels of C-reactive protein

Data from Bloomgarden ZT: Inflammation, atherosclerosis, and aspects of insulin action, Diabetes Care 28(9):2312–2319, 2005; Duckles SP, Miller
VM: Hormonal modulation of endothelial NO production, Pflugers Arch 459(6):841–851, 2010; Kuritzky L, Nelson SE: Beneficial effects of insulin
on endothelial function, inflammation, and atherogenesis and their implications, J Fam Pract 54(6):S7–S9, 2005; Richards OC, Raines SM, Attie
AD: The role of blood vessels, endothelial cells, and vascular pericytes in insulin secretion and peripheral insulin action, Endocr Rev 31(3):343–363,
2010; Sowers JR, Frohlich ED: Insulin and insulin resistance: impact on blood pressure and cardiovascular disease, Med Clin North Am 88(1):
63–82, 2004.

The mechanism of autoregulation is not known, but two explana- Autonomic Regulation
tions have been proposed. The myogenic hypothesis proposes that Although the coronary vessels themselves contain sympathetic (α- and
autoregulation originates in vascular smooth muscle, presumably that β-adrenergic) and parasympathetic neural receptors, coronary blood
of the arterioles, as a response to changes in arterial perfusion pres- flow is regulated locally through metabolic autoregulation. Metabolic
sure. Increased coronary perfusion pressure increases the pressure autoregulation overrides neurogenic influences.4
against the vessel wall and the stretch increases the vessel’s radius,
resulting in an increase in wall tension. Initially, coronary blood flow
increases with the abrupt distention of the blood vessels. The stretch-
4 QUICK CHECK 22-7
1. Why is capillary flow increased with increased mean arterial pressure?
ing eventually stimulates contraction of the smooth muscles, which 2. Why is angiotensin significant in blood flow?
increases vascular resistance. The return of more normal flow follows 3. Identify the factors regulating blood pressure.
constriction of the arterioles. Because stretching of vascular smooth 4. Define natriuretic peptides and adrenomedullin.
muscle increases intracellular Ca++ concentration, it is proposed that
an increase in transmural pressure activates membrane calcium chan-
nels.1 This mechanism also works in the opposite direction—that is,
vasodilation is stimulated by decreased arterial pressure.
THE LYMPHATIC SYSTEM
The metabolic hypothesis of autoregulation proposes that auto- The lymphatic system is a special vascular system that picks up excess
regulation of coronary vessels originates in the myocardium. The tissue fluid and returns it to the bloodstream (Figure 22-35). Nor-
stimulus is an increase in the metabolic needs of the myocardium mally, fluid is forced out of the blood at the arterial end of the capillary
(e.g., because of strenuous exercise). With an increased myocardial bed and is reabsorbed into the bloodstream at the venous end. How-
oxygen requirement, myocardial cells release substances that pro- ever, capillary outflow exceeds venous reabsorption by about 3 L/day,
mote vasodilation. The best known of these substances is adenosine, so some fluid lags behind in the interstitium. To maintain sufficient
a potent vasodilator released in response to a decrease in myocardial blood volume in the cardiovascular system, this fluid must eventually
oxygenation. Low coronary blood flow, hypoxemia, or increased met- rejoin the bloodstream; this is the function of the lymphatic system.
abolic activity of the heart can all increase the heart muscle’s need for The components of the lymphatic system are the lymphatic ves-
oxygen.1,35 An increased concentration of adenosine in the interstitial sels and the lymph nodes (Figure 22-36). (Lymph nodes and lymphoid
fluid decreases the resistance of the coronary arterioles and increases tissues are described in Chapters 5 and 7.) In this pumpless system,
blood flow. Perfusion strongly correlates with the amount of adenos- a series of valves ensures one-way flow of the excess interstitial fluid
ine released.35 When coronary perfusion pressure is increased, the (now called lymph) toward the heart. The lymphatic capillaries are
increased flow washes out the vasodilatory substances. As the dila- closed at the ends, as shown in Figure 22-37.
tors are removed, vasoconstriction occurs and returns flow toward Lymph consists primarily of water and small amounts of dissolved
normal. proteins, mostly albumin that are too large to be reabsorbed into the
580 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems

Arteriole Blood Venule

(from heart) capillary (from heart)
Tonsils

Entrance of
Cervical thoracic duct into
lymph subclavian vein
node

Right Thymus
lymphatic gland
duct
Axillary
Tissue lymph
cells Peyer node
patches in
intestinal Thoracic
wall duct

Spleen
Red
bone
marrow
Interstitial Lymphatic
fluid capillary
Lymph fluid
(to veins)
FIGURE 22-35  Role of the Lymphatic System in Fluid Balance.
Fluid from plasma flowing through the capillaries moves into intersti- Inguinal
tial spaces. Although much of this interstitial fluid is either absorbed lymph
by tissue cells or reabsorbed by capillaries, some of the fluid tends node
to accumulate in the interstitial spaces. As this fluid builds up, it
tends to drain into lymphatic vessels that eventually return the fluid
to the venous blood. (From Patton KT, Thibodeau GA: Anatomy &
physiology, ed 7, St Louis, 2010, Mosby.)

less permeable blood capillaries. Once within the lymphatic system,

lymph travels through larger vessels called lymphatic venules and FIGURE 22-36  Principle Organs of the Lymphatic System. The
lymphatic veins. The lymphatic vessels run alongside the arteries and inset shows the areas drained by the right lymphatic duct (green)
veins and eventually drain into one of two large ducts in the thorax— and the thoracic duct (blue). (From Patton KT, Thibodeau GA: Anat-
the right lymphatic duct and the thoracic duct. The right lymphatic omy & physiology, ed 7, St Louis, 2010, Mosby.)
duct drains lymph from the right arm and the right side of the head
and thorax, whereas the larger thoracic duct receives lymph from the
rest of the body (see Figure 22-36). The right lymphatic duct and the
thoracic duct drain lymph into the right and left subclavian veins, vessels (see Figure 22-36). Lymph enters the node through several
respectively. afferent lymphatic vessels, filters through the sinuses in the node,
The lymphatic veins are thin walled like the veins of the cardio- and leaves by way of efferent lymphatic vessels. Lymph flows slowly
vascular system. In the larger lymphatic veins, endothelial flaps form through the node, which facilitates the phagocytosis of foreign sub-
valves similar to those in the circulatory veins (see Figure 22-26). stances within the node and prevents them from reentering the blood-
The valves permit lymph to flow in only one direction because stream. (Phagocytosis is described in Chapter 6.)
lymphatic vessels are compressed intermittently by contraction of
­skeletal muscles, ­pulsatile expansion of an artery in the same sheath,
and contraction of the smooth muscles in the walls of the lymphatic
vessel.
4 QUICK CHECK 22-8
1. Why is the lymphatic system considered a circulatory system?
As lymph is transported toward the heart, it is filtered through 2. What happens to lymph in lymph nodes?
thousands of bean-shaped lymph nodes clustered along the lymphatic
 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems 581

From heart To venous To heart

system

Lymph
vessel
Arteriole
Venule

Arterial Venous
capillaries capillaries

A FIGURE 22-37  Lymphatic Capillaries. A, Schematic repre-

Lymphatic
capillaries sentation of lymphatic capillaries. B, Anatomic components of
microcirculation.
Fluid Anchoring
exchange filament

Lymph

Blood capillary

DID YOU UNDERSTAND?

The Circulatory System 2. The heart wall, which encloses the heart and divides it into chambers, is
1. The circulatory system is the body’s transport system. It delivers oxygen, made up of three layers: the pericardium (outer layer), the myocardium
nutrients, metabolites, hormones, neurochemicals, proteins, and blood cells (muscular layer), and the endocardium (inner lining).
through the body and carries metabolic wastes to the kidneys and lungs for 3. The myocardial layer of the two atria, which receive blood entering the
excretion. heart, is thinner than the myocardial layer of the ventricles, which have to
2. The circulatory system consists of the heart and blood vessels and is made up be stronger to squeeze blood out of the heart.
of two separate, serially connected systems: the pulmonary circulation and 4. The right and left sides of the heart are separated by portions of the heart
the systemic circulation. wall called the interatrial septum and the interventricular septum.
3. The pulmonary circulation is driven by the right side of the heart; its function 5. Deoxygenated (venous) blood from the systemic circulation enters the right
is to deliver blood to the lungs for oxygenation. atrium through the superior and inferior venae cavae. From the atrium,
4. The systemic circulation is driven by the left side of the heart, and its function the blood passes through the right atrioventricular (tricuspid) valve into
is to move oxygenated blood throughout the body. the right ventricle. In the ventricle, the blood flows from the inflow tract
5. The lymphatic vessels collect fluids from the interstitium and return the fluids to the outflow tract and then through the pulmonary semilunar valve (pul-
to the circulatory system. monary valve) into the pulmonary artery, which delivers it to the lungs for
oxygenation.
The Heart 6. Oxygenated blood from the lungs enters the left atrium through the four
1. The heart consists of four chambers (two atria and two ventricles), four pulmonary veins (two from the left lung and two from the right lung). From
valves (two atrioventricular valves and two semilunar valves), a muscular the left atrium, the blood passes through the left atrioventricular valve
wall, a fibrous skeleton, a conduction system, nerve fibers, systemic ves- (mitral valve) into the left ventricle. In the ventricle, the blood flows from
sels (the coronary circulation), and openings where the great vessels enter the inflow tract to the outflow tract and then through the aortic semilunar
the atria and ventricles.

Continued
582 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems

DID YOU UNDERSTAND?—cont’d

valve (aortic valve) into the aorta, which delivers it to systemic arteries of 21. Contractility is the potential for myocardial fiber shortening during systole.
the entire body. It is determined by the amount of stretch during diastole (i.e., preload) and
7. The heart valves ensure the one-way flow of blood from atrium to ventricle by sympathetic stimulation of the ventricles.
and from ventricle to artery. 22. Heart rate is determined by the sinoatrial node and by components of the
8. Oxygenated blood enters the coronary arteries through an opening in the autonomic nervous system, including cardiovascular control centers in the
aorta, and unoxygenated blood from the coronary veins enters the right brain, neuroreceptors in the atria and aorta, hormones, and catecholamines
atrium through the coronary sinus. (epinephrine, norepinephrine).
9. The pumping action of the heart consists of two phases: diastole, during
which the myocardium relaxes and the ventricles fill with blood; and sys- The Systemic Circulation
tole, during which the myocardium contracts, forcing blood out of the ven- 1. Blood flows from the left ventricle into the aorta and from the aorta into
tricles. A cardiac cycle consists of one systolic contraction and the diastolic arteries that eventually branch into arterioles and capillaries, the smallest
relaxation that follows it. Each cardiac cycle constitutes one “heartbeat.” of the arterial vessels. Oxygen, nutrients, and other substances needed for
10. The conduction system of the heart generates and transmits electrical cellular metabolism pass from the capillaries into the interstitium, where
impulses (cardiac action potentials) that stimulate systolic contractions. they are available for uptake by the cells. Capillaries also absorb products
The autonomic nerves (sympathetic and parasympathetic fibers) can adjust of cellular metabolism from the interstitium.
heart rate and systolic force, but they do not stimulate the heart to beat. 2. Venules, the smallest veins, receive capillary blood. From the venules, the
11. The normal electrocardiogram is the sum of all action potentials. The P venous blood flows into larger and larger veins until it reaches the venae
wave represents atrial depolarization; the QRS complex is the sum of all cavae, through which it enters the right atrium.
ventricular cell depolarizations. The ST interval occurs when the entire ven- 3. Vessel walls consist of three layers: the tunica intima (inner layer), the
tricular myocardium is depolarized. tunica media (middle layer), and the tunica externa (the outer layer).
12. Cardiac action potentials are generated by the sinoatrial node at the rate of 4. Layers of the vessel wall differ in thickness and composition from vessel to
about 75 impulses per minute. The impulses can travel through the conduc- vessel, depending on the vessel’s size and location within the circulatory
tion system of the heart, stimulating myocardial contraction as they go. system. In general, the tunica media of arteries close to the heart contains
13. Cells of the cardiac conduction system possess the properties of automa- a greater proportion of elastic fibers because these arteries must be able
ticity and rhythmicity. Automatic cells return to threshold and depolarize to distend during systole and recoil during diastole. Distributing arteries
rhythmically without an outside stimulus. The cells of the sinoatrial node farther from the heart contain a greater proportion of smooth muscle fibers
depolarize faster than other automatic cells, making it the natural pace- because these arteries must be able to constrict and dilate to control blood
maker of the heart. If the sinoatrial node is disabled, the next fastest pace- pressure and volume within specific capillary beds.
maker, the atrioventricular node, takes over. 5. Blood flow into the capillary beds is controlled by the contraction and
14. Each cardiac action potential travels from the sinoatrial node to the atrio- relaxation of smooth muscle bands (precapillary sphincters) at junctions
ventricular node to the bundle of His (atrioventricular bundle), through the between metarterioles and capillaries.
bundle branches, and finally to the Purkinje fibers. There the impulse is 6. Endothelial cells form the lining or endothelium of blood vessels. The endo-
stopped. It is prevented from reversing its path by the refractory period thelium is a life-support tissue; it functions as a filter (altering permeabil-
of cells that have just been polarized. The refractory period ensures that ity), changes in vasomotion (constriction and dilation), and is involved in
diastole (relaxation) will occur, thereby completing the cardiac cycle. clotting and inflammation.
15. Adrenergic receptor number, type, and function govern autonomic (sympa- 7. Blood flow through the veins is assisted by the contraction of skeletal mus-
thetic) regulation of heart rate, contractile force, and the dilation or con- cles (the muscle pump), and one-way valves prevent backflow in the lower
striction of coronary arteries. The presence of specific receptors (α1, α2, β1, body, particularly in the deep veins of the legs.
β2) on the myocardium and coronary vessels determines the effects of the 8. Blood flow is affected by blood pressure, resistance to flow within the ves-
neurotransmitters norepinephrine and epinephrine. sels, blood consistency (which affects velocity), anatomic features that
16. Unique features that distinguish myocardial cells from skeletal cells enable may cause turbulent or laminar flow, and compliance (distensibility) of the
myocardial cells to transmit action potentials faster (through intercalated vessels.
disks), synthesize more ATP (because of a large number of mitochondria), 9. Poiseuille law describes the relationship of blood flow, pressure, and resis-
and have readier access to ions in the interstitium (because of an abun- tance as the difference between pressure at the inflow end of the vessel
dance of transverse tubules). These combined differences enable the myo- and pressure at the outflow end divided by resistance within the vessel.
cardium to work constantly, which is not required by skeletal muscle. 10. The greater the vessel’s length and the blood’s viscosity and the narrower
17. Cross-bridges between actin and myosin enable contraction. Calcium and the radius of the vessel’s lumen, the greater the resistance within the
its interaction with the troponin complex facilitate the contraction process. vessel.
With troponin release of calcium, myocardial relaxation begins. 11. Total peripheral resistance, or the resistance to flow within the entire sys-
18. Cardiac performance is affected by preload, afterload, myocardial contrac- temic circulatory system, depends on the combined lengths and radii of all
tility, and heart rate. the vessels within the system and on whether the vessels are arranged in
19. Preload, or pressure generated in the ventricles at the end of diastole, series (greater resistance) or in parallel (lesser resistance).
depends on the amount of blood in the ventricle. Afterload is the resistance 12. Peripheral resistance is based on physical laws governing the behavior of
to ejection of the blood from the ventricle. Afterload depends on pressure fluids in a straight tube. In the body, blood flow is also influenced by neural
in the aorta. stimulation (vasoconstriction or vasodilation) and by autonomic features
20. The Frank-Starling law of the heart states that the myocardial stretch that cause turbulence within the vascular lumen (e.g., protrusions from the
determines the force of myocardial contraction (the greater the stretch, the vessel wall, twists and turns, bifurcations).
stronger the contraction).
 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems 583

DID YOU UNDERSTAND?—cont’d

13. Arterial blood pressure is influenced and regulated by factors that affect during diastole rather than systole, because during systole, the cusps of the
cardiac output (heart rate, stroke volume), total resistance within the sys- aortic semilunar valve block the openings of the coronary arteries. Second,
tem, and blood volume. systolic contraction inhibits coronary artery flow by compressing the coro-
14. Antidiuretic hormone, renin-angiotensin system, natriuretic peptides, adre- nary arteries.
nomedullin, and insulin can all alter blood volume and thus blood pressure. 19. Autoregulation enables the coronary vessels to maintain optimal perfusion
15. The tissue renin-angiotensin system is activated in response to tissue pressure despite systolic effects, and myoglobin in heart muscle stores oxy-
injury. Studies examining the relationship between this system and mal- gen for use during the systolic phase of the cardiac cycle.
adaptive alterations, such as ventricular and vascular remodeling, altera-
tions in renal function, and atherosclerosis, are gaining importance. The Lymphatic System
16. Particularly significant is an increased recognition of the role of angiotensin 1. The vessels of the lymphatic system run in the same sheaths with the arter-
II for causing the systemic effects of vasoconstriction, hypertension, activa- ies and veins.
tion of the sympathetic nervous system, and retention of sodium and fluids. 2. Lymph (interstitial fluid) is absorbed by lymphatic venules in the capillary
17. Venous blood pressure is influenced by blood volume within the venous beds and travels through ever larger lymphatic veins until it is emptied
system and compliance of the venous walls. through the right lymphatic duct or thoracic duct into the right or left subcla-
18. Blood flow through the coronary circulation is governed not only by the vian vein, respectively.
same principles as flow through other vascular beds but also by adaptations 3. As lymph travels toward the thoracic ducts, it is filtered by thousands of
dictated by cardiac dynamics. First, blood flows into the coronary arteries lymph nodes clustered around the lymphatic veins. The lymph nodes are sites
of immune function.

 KEY TERMS
•  ctin  561
A •  ardiac output  563
C •  aplace law  563
L
• Adipokines  576 • Cardiac vein  556 • Left atrium  563
• Adrenomedullin (ADM)  576 • Cardioexcitatory center  565 • Left bundle branch (LBB)  557
• Afferent lymphatic vessel  580 • Cardioinhibitory center  565 • Left coronary artery  556
• Afterload  564 • Cardiovascular control center  565 • Left heart  551
• Angiotensin I (Ang I)  574 • Chordae tendineae cordis  554 • Left ventricle  553
• Angiotensin II (Ang II)  574 • Conduction system  557 • Length  570
• Anisotropic band (A band)  561 • Coronary artery  556 • Lumen  569
• Anterior interatrial myocardial band • Coronary circulation  556 • Lymph  579
(Bachmann bundle)  557 • Coronary ostium (pl., ostia)  556 • Lymph node  580
• Anterior internodal pathway  557 • Coronary perfusion pressure  578 • Lymphatic vein  580
• Antidiuretic hormone (ADH)  574 • Coronary sinus  556 • Lymphatic venule  580
• Aorta  554 • Cross-bridge theory of muscle • M line  561
• Aortic semilunar valve  554 contraction  562 • Mean arterial pressure (MAP)  573
• Arteriole  567 • Depolarization  558 • Mediastinum  551
• Artery  567 • Diastole  554 • Metabolic hypothesis  579
• AT1 receptor  576 • Diastolic blood pressure  573 • Metarteriole  569
• AT2 receptor  576 • Diastolic depolarization  560 • Microcirculation  570
• Atrial natriuretic peptide (ANP)  576 • Efferent lymphatic vessel  580 • Middle internodal pathway  557
• Atrioventricular node (AV node)  557 • Ejection fraction  563 • Mitral and tricuspid complex  554
• Atrioventricular valve  553 • Elastic artery  569 • Mitral valve (left atrioventricular valve,
• Automatic cell  559 • Endocardium  553 bicuspid valve)  554
• Automaticity  559 • Endothelial cell  569 • Muscle pump  570
• Autoregulation  578 • Endothelium  569 • Muscular artery  569
• Bainbridge reflex  565 • Excitation-contraction coupling  562 • Myocardial contractility  562
• Baroreceptor reflex  565 • Fenestration  569 • Myocardial oxygen consumption
• Blood flow  570 • Frank-Starling law of the heart  563 ( MV̇O2)  561
• Blood velocity  573 • Great cardiac vein  557 • Myocardium  552
• Brain natriuretic peptide (BNP)  576 • Heart rate  560 • Myogenic hypothesis  579
• Bundle of His (atrioventricular • Inferior vena cava (pl., cavae)  554 • Myoglobin  578
bundle)  557 • Inotropic agent  564 • Myosin  561
• Calcium channel–blocking drug  562 • Insulin  576 • Natriuretic peptide (NP)  576
• Capillary  567 • Intercalated disk  560 • Node  557
• Cardiac action potential  557 • Isotropic band (I band)  561 • P wave  559
• Cardiac cycle  554 • Laminar flow  573 • Papillary muscle  554
584 CHAPTER 22  Structure and Function of the Cardiovascular and Lymphatic Systems

 KEY TERMS—cont’d
•  erfusion  573
P •  esistance  570
R •  roponin C  561
T
• Pericardial cavity  552 • Rhythmicity  560 • Troponin I  561
• Pericardial fluid  552 • Right atrium  553 • Troponin T  561
• Pericardium  552 • Right bundle branch (RBB)  557 • Troponin-tropomyosin complex  561
• Peripheral vascular resistance (PVR)  564 • Right coronary artery  556 • Tunica externa (adventitia; external
• Peripheral vascular system  567 • Right heart  551 layer)  567
• Poiseuille law  570 • Right lymphatic duct  580 • Tunica intima (intimal layer)  567
• Posterior internodal pathway  557 • Right ventricle  553 • Tunica media (medial layer)  567
• PR interval  559 • Semilunar valve  554 • Turbulent flow  573
• Precapillary sphincter  569 • Sinoatrial node (SA node, sinus node)  557 • Vasa vasorum  569
• Preload  563 • ST interval  559 • Vascular compliance  573
• Pressure  570 • Stroke volume  564 • Vasoconstriction  569
• Pulmonary artery  554 • Superior vena cava (pl., cavae)  554 • Vasodilation  569
• Pulmonary circulation  551 • Systemic circulation  551 • Vein  570
• Pulmonary vein  554 • Systole  554 • Ventricular end-diastolic pressure
• Pulmonic semilunar valve  554 • Systolic blood pressure  573 (VEDP)  563
• Purkinje fiber  558 • Systolic compressive effect  578 • Ventricular end-diastolic volume
• QRS complex  559 • Thoracic duct  580 (VEDV)  563
• QT interval  559 • Total peripheral resistance (TPR)  564 • Venule  567
• Radius (diameter)  570 • Total resistance  570 • Viscosity  570
• Refractory period  559 • Tricuspid valve (right atrioventricular • Z line  561
• Renin  574 valve)  554
• Repolarization  558 • Tropomyosin  561

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aldosterone system in chronic kidney disease, Am J Nephrol 31(6):
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6. Benitah JP, Alvarez JL, Gómez AM: L-type Ca(2+) current in ventricular 122(7):717–728, 2010:18 p following 728.
cardiomyocytes, J Mol Cell Cardiol 48(1):26–36, 2010. 24. Lee CY, Burnett JC Jr: Natriuretic peptides and therapeutic applica-
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Mosby Elsevier. uretic ­peptides in the human circulation and relation to cardiac function,
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 CHAPTER

23
Alterations of Cardiovascular
Function
Valentina L. Brashers

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Diseases of the Veins, 585 Disorders of the Heart Wall, 609
Varicose Veins and Chronic Venous Insufficiency, 585 Disorders of the Pericardium, 609
Thrombus Formation in Veins, 586 Disorders of the Myocardium: The Cardiomyopathies, 611
Superior Vena Cava Syndrome, 586 Disorders of the Endocardium, 612
Diseases of the Arteries, 587 Cardiac Complications in Acquired Immunodeficiency Syndrome
Hypertension, 587 (AIDS), 619
Orthostatic (Postural) Hypotension, 591 Manifestations of Heart Disease, 619
Aneurysm, 591 Dysrhythmias, 619
Thrombus Formation, 592 Heart Failure, 622
Embolism, 593 Shock, 627
Peripheral Vascular Disease, 593 Impairment of Cellular Metabolism, 627
Atherosclerosis, 594 Clinical Manifestations of Shock, 629
Peripheral Artery Disease, 597 Treatment for Shock, 629
Coronary Artery Disease, Myocardial Ischemia, Types of Shock, 629
and Acute Coronary Syndromes, 597 Multiple Organ Dysfunction Syndrome, 634

Our understanding of the pathophysiology of cardiovascular diseases (2) gradual venous distention caused by the action of gravity on blood
is evolving rapidly. The role of genetics and its interaction with the in the legs.
environment in the etiology and progression of all forms of cardiovas- If a valve is damaged, a section of the vein is subjected to the pres-
cular disease is just one example of new information that is leading to sure of a larger volume of blood under the influence of gravity. The
improvements in prevention and treatment. vein swells as it becomes engorged and surrounding tissue becomes
edematous because increased hydrostatic pressure pushes plasma
DISEASES OF THE VEINS through the stretched vessel wall. Venous distention can develop over
time in individuals who habitually stand for long periods, wear con-
Varicose Veins and Chronic Venous Insufficiency stricting garments, or cross the legs at the knees, which diminishes
A varicose vein is a vein in which blood has pooled, producing dis- the action of the muscle pump (see Figure 22-27). Risk factors also
tended, tortuous, and palpable vessels (Figure 23-1). Veins are thin- include age, female gender, a family history of varicose veins, obesity,
walled, highly distensible vessels with valves to prevent backflow and pregnancy, deep venous thrombosis, and previous leg injury. Eventu-
pooling of blood (see Figure 22-26). Varicose veins are caused by (1) ally the pressure in the vein damages venous valves, rendering them
trauma to the saphenous veins that damages one or more valves or incompetent and unable to maintain normal venous pressure.

585
586 CHAPTER 23  Alterations of Cardiovascular Function

FIGURE 23-2  Venous Stasis Ulcer. (From Rosai J: Ackerman’s

­surgical pathology, ed 7, vol 2, St Louis, 1989, Mosby.)

conditions can be associated with up to a 100% likelihood of DVT.

Numerous genetic abnormalities are associated with an increased risk
FIGURE 23-1  Varicose Veins of the Leg (arrow). (From Kumar for venous thrombosis primarily related to states of hypercoagulabil-
V, Abbas A, Fausto N: Robbins and Cotran pathologic basis of dis- ity. These inherited abnormalities include factor V Leiden mutation,
ease, ed 8, Philadelphia, 2007, Saunders. Courtesy Dr. Magruder C. prothrombin mutations, and deficiencies of protein C, protein S, and
­Donaldson, Brigham and Women’s Hospital, Boston.) antithrombin; these abnormalities are commonly found in individuals
who develop thrombi in the absence of the usual risk factors.3
Accumulation of clotting factors and platelets leads to thrombus
Varicose veins and valvular incompetence can progress to chronic formation in the vein, often near a venous valve. Inflammation around
venous insufficiency, especially in obese individuals.1 Chronic the thrombus promotes further platelet aggregation, and the thrombus
venous insufficiency (CVI) is inadequate venous return over a long propagates or grows proximally. This inflammation may cause pain
period. Venous hypertension, circulatory stasis, and tissue hypoxia and redness, but because the vein is deep in the leg, it is usually not
cause an inflammatory reaction in vessels and tissue leading to fibro- accompanied by clinical symptoms or signs. If the thrombus creates
sclerotic remodeling of the skin and then to ulceration. Symptoms significant obstruction to venous blood flow, increased pressure in the
include edema of the lower extremities and hyperpigmentation of vein behind the clot may lead to edema of the extremity. Most thrombi
the skin of the feet and ankles. Edema in these areas may extend to will eventually dissolve without treatment; however, untreated DVT
the knees. is associated with a high risk of embolization of a part of the clot to
Circulation to the extremities can become so sluggish that the the lung (pulmonary embolism) (see Chapter 33). Persistent venous
metabolic demands of the cells to obtain oxygen and nutrients and to obstruction may lead to chronic venous insufficiency and post-throm-
remove wastes are barely met. Any trauma or pressure can therefore botic syndrome with associated pain, edema, and ulceration of the
lower the oxygen supply and cause cell death and necrosis (venous affected limb.4
stasis ulcers) (Figure 23-2). Infection can occur because poor circula- Because DVT is usually asymptomatic and difficult to detect clini-
tion impairs the delivery of the cells and biochemicals necessary for the cally, prevention is important in at-risk individuals and includes early
immune and inflammatory responses. This same sluggish circulation ambulation, pneumatic devices, and prophylactic anticoagulation.5 If
makes infection following reparative surgery a significant risk. thrombosis does occur, diagnosis is confirmed by a combination of
Treatment of varicose veins and CVI begins conservatively, and serum D-dimer measurement and Doppler ultrasonography. Manage-
excellent wound healing results have followed noninvasive treatments ment consists of anticoagulation therapy using heparin (low-molecu-
such as elevating the legs, wearing compression stockings, and per- lar-weight heparin) and warfarin. In selected individuals, thrombolytic
forming physical exercise.2 Invasive management includes sclerother- therapy or placement of an inferior vena cava filter may be indicated.6
apy or surgical ligation, conservative vein resection, and vein stripping.
Superior Vena Cava Syndrome
Thrombus Formation in Veins Superior vena cava syndrome (SVCS) is a progressive occlusion of the
A thrombus is a blood clot that remains attached to a vessel wall (see superior vena cava (SVC) that leads to venous distention in the upper
Figure 20-17). A detached thrombus is a thromboembolus. Venous extremities and head. Causes include bronchogenic cancer (75% of
thrombi are more common than arterial thrombi because flow and cases), followed by lymphomas and metastasis of other cancers. Other
pressure are lower in the veins than in the arteries. Deep venous less common causes include tuberculosis, mediastinal fibrosis, cystic
thrombosis (DVT) occurs primarily in the lower extremity. Three fac- fibrosis, and invasive therapies (pacemaker wires, central venous cath-
tors (triad of Virchow) promote venous thrombosis: (1) venous stasis eters, and pulmonary artery catheters). The SVC is a relatively low-
(e.g., immobility, age, congestive heart failure), (2) venous endothe- pressure vessel that lies in the closed thoracic compartment; therefore
lial damage (e.g., trauma, intravenous medications), and (3) hyperco- tissue expansion can easily compress the SVC. The right main stem
agulable states (e.g., inherited disorders, malignancy, pregnancy, use bronchus abuts the SVC so that cancers occurring in this bronchus
of oral contraceptives or hormone replacement therapy). Orthope- may exert pressure on the SVC. Additionally, the SVC is surrounded
dic trauma or surgery, spinal cord injury, and obstetric/gynecologic by lymph nodes and lymph chains that commonly become involved in
 CHAPTER 23  Alterations of Cardiovascular Function 587

thoracic cancers and compress the SVC during tumor growth. Because
TABLE 23-1 CLASSIFICATION OF BLOOD
onset of SVCS is slow, collateral venous drainage to the azygos vein
usually has time to develop.
PRESSURE FOR ADULTS AGE
Clinical manifestations of SVCS are edema and venous distention 18 YEARS AND OLDER
in the upper extremities and face, including the ocular beds. Affected SYSTOLIC DIASTOLIC
persons complain of a feeling of fullness in the head or tightness of CATEGORY (MM HG) (MM HG)
shirt collars, necklaces, and rings. Cerebral edema may cause head- Normal <120 AND <80
ache, visual disturbance, and impaired consciousness. The skin of the Prehypertension 120-139 OR 80-89
face and arms may become purple and taut, and capillary refill time is Stage 1 hypertension 140-159 OR 90-99
prolonged. Respiratory distress may be present because of edema of Stage 2 hypertension ≥160 OR ≥100
bronchial structures or compression of the bronchus by a carcinoma.
In infants, SVCS can lead to hydrocephalus. Data from Chobanian AV et al: The JNC 7 Report, J Am Med Assoc
Diagnosis is made by chest x-ray, Doppler studies, computed 289(19):2560–2572, 2003.
tomography (CT), magnetic resonance imaging (MRI), and ultra-
sound. Because of its slow onset and the development of collateral hypertension is caused by an underlying disorder such as renal disease.
venous drainage, SVCS is generally not a vascular emergency, but it This form of hypertension accounts for only 5% to 8% of cases.
is an oncologic emergency. Treatment for malignant disorders can
include radiation therapy, surgery, chemotherapy, and the administra- Factors Associated With Primary Hypertension
tion of diuretics, steroids, and anticoagulants, as necessary. Treatment A specific cause for primary hypertension has not been identified, and
for nonmalignant causes may include bypass surgery using various a combination of genetic and environmental factors is thought to be
grafts, thrombolysis (both locally and systemically), balloon angio- responsible for its development.12 Genetic predisposition to hyperten-
plasty, and placement of intravascular stents.7 sion is believed to be polygenic. The inherited defects are associated
with renal sodium excretion, insulin and insulin sensitivity, activity of
4 QUICK CHECK 23-1
the sympathetic nervous system (SNS) and the renin-angiotensin-aldo-
sterone system (RAAS), and cell membrane sodium or calcium trans-
1. What is chronic venous insufficiency, and how does it present clinically?
port.13 Factors associated with primary hypertension include (1) family
2. What are the major risk factors for DVT?
history of hypertension; (2) advancing age; (3) gender (men younger
3. Name some causes of superior vena cava syndrome.
than age 55 and women after age 70); (4) black race; (5) high dietary
sodium intake; (6) glucose intolerance (insulin resistance and diabetes
DISEASES OF THE ARTERIES mellitus); (7) cigarette smoking; (8) obesity; (9) heavy alcohol con-
sumption; and (10) low dietary intake of potassium, calcium, and mag-
Hypertension nesium (see Risk Factors: Primary Hypertension). Many of these factors
Hypertension is consistent elevation of systemic arterial blood pres- are also risk factors for other cardiovascular disorders. In fact, obesity,
sure. Hypertension (HTN) is the most common primary diagno- hypertension, dyslipidemia, and glucose intolerance often are found
sis in the United States. One in three Americans has hypertension, together in a condition called the metabolic syndrome (see Chapter 18).
and more than two thirds of those older than age 60 are affected.8
The chance of developing primary hypertension increases with age. RISK FACTORS
Although hypertension is usually considered an adult health problem,
it is important to remember that hypertension does occur in children Primary Hypertension
and is being diagnosed with increasing frequency (see Chapter 24). Family history
The prevalence of HTN is higher in blacks and in those with diabe- Advancing age
tes. Hypertension is defined by the Seventh Joint National Commit- Cigarette smoking
tee Report as a sustained systolic blood pressure of 140 mm Hg or Obesity
greater or a diastolic pressure of 90 mm Hg or greater (Table 23-1).9 Heavy alcohol consumption
Normal blood pressure is associated with the lowest cardiovascular Gender (men > women before age 55, women > men after 55)
risk, whereas those who fall into the prehypertension category (which Black race
includes between 25% and 37% of the U.S. population) are at risk for High dietary sodium intake
developing hypertension and many associated cardiovascular compli- Low dietary intake of potassium, calcium, magnesium
cations unless lifestyle modification and treatment are instituted.8,10 Glucose intolerance
All stages of hypertension are associated with increased risk for target
organ disease events, such as myocardial infarction, kidney disease,
and stroke; thus both stage I and stage II hypertension need effective PATHOPHYSIOLOGY  Hypertension results from a sustained increase
long-term therapy. in peripheral resistance (arteriolar vasoconstriction), an increase in
Isolated systolic hypertension (ISH) is typically defined as a sus- circulating blood volume, or both.
tained systolic blood pressure (BP) reading that is ≥140 mm Hg and a
diastolic BP measurement that is <90 mm Hg. ISH is becoming more Primary Hypertension
prevalent in all age groups and is strongly associated with cardiovascu- Primary hypertension is the result of an extremely complicated inter-
lar and cerebrovascular events.11 action of genetics and the environment mediated by a host of neuro-
Most cases of hypertension are diagnosed as primary hyperten- humoral effects. Multiple pathophysiologic mechanisms mediate these
sion (also called essential or idiopathic hypertension). From 92% to effects, including the sympathetic nervous system (SNS), the renin-
95% of hypertensive individuals have primary disease. Secondary angiotensin-aldosterone system (RAAS), and natriuretic peptides.
588 CHAPTER 23  Alterations of Cardiovascular Function

Inflammation, endothelial dysfunction, obesity-related hormones,

HEALTH ALERT
and insulin resistance also contribute to both increased peripheral
resistance and increased blood volume. Increased vascular volume is The Renin-Angiotensin-Aldosterone System
related to a decrease in renal excretion of salt, often referred to as a shift and Cardiovascular Disease
in the pressure-natriuresis relationship (Figure 23-3). This means
The RAAS has multiple effects on the cardiovascular system. In recent years,
that for a given blood pressure, individuals with hypertension tend to
it has been found that there are two primary RAA systems. The best known is
secrete less salt in their urine.
described in Chapter 22 and includes the synthesis of angiotensin II via angioten-
The sympathetic nervous system has been implicated in both the
sin-converting enzyme (ACE), stimulation of the AT1 receptor (AT1R), and secre-
development and the maintenance of elevated blood pressure and plays
tion of aldosterone. In addition to causing systemic vasoconstriction and renal
a role in hypertensive end-organ damage.14 Increased SNS activity
salt and water retention, this system has direct effects on blood vessel, heart,
causes increased heart rate and systemic vasoconstriction, thus raising
and kidney tissues. Angiotensin II is a vasoconstrictor, a growth factor, and an
the blood pressure. Additional mechanisms of SNS-induced hyperten-
inflammatory mediator. When present in abnormal amounts, it contributes to
sion include structural changes in blood vessels (vascular remodeling),
inflammation and insulin resistance, remodeling of blood vessels with narrow-
renal sodium retention (shift in natriuresis curve), insulin resistance,
ing of blood vessel lumina, and decreased release of endothelial vasodilators
increased renin and angiotensin levels, and procoagulant effects.15
and anticoagulants. In the heart angiotensin II and aldosterone contribute to
In hypertensive individuals, overactivity of the RAAS contributes to
hypertensive hypertrophy and fibrosis of heart muscle, remodeling of myocardial
salt and water retention and increased vascular resistance (see Figure
tissues after ischemia, decreased contractility, and an increased susceptibility
22-32). High levels of angiotensin II contribute to endothelial dysfunc-
to dysrhythmias and heart failure. In the kidney these hormones cause a shift
tion, insulin resistance, and platelet aggregation. Further, angiotensin
in the pressure-natriuresis curve, inflammation, and glomerular remodeling and
II mediates arteriolar remodeling, which is structural change in the
they are a major contributor to renal failure in individuals with hypertension and
vessel wall that results in permanent increases in peripheral resistance16
diabetes. Drugs that block this RAAS pathway include those that interfere with
(see Figure 22-33). Angiotensin II is associated with end-organ effects
angiotensin II and aldosterone synthesis (angiotensin-converting enzyme [ACE]
of hypertension, including atherosclerosis, renal disease, and cardiac
inhibitors and direct renin inhibitors), angiotensin II receptor blockers (ARBs), and
hypertrophy.17 Finally, aldosterone not only contributes to sodium
aldosterone inhibitors. These medications are used widely in the management
retention by the kidney but also has other deleterious effects on the
of hypertension, myocardial infarction, and heart failure to lower blood pressure
cardiovascular system.18 Medications, such as angiotensin-converting
and to protect and improve cardiovascular and renal function. In contrast, the
enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs),
second RAAS serves a counterregulatory system. Activation of a second ACE
oppose the activity of the RAAS and are effective in reducing blood
pathway (ACE2) leads to the synthesis of angiotensin 1-7 from angiotensin II.
pressure and protecting against target organ damage19 (see Health
Angiotensin 1-7 stimulates Mas receptors, which lower blood pressure, reduce
Alert: The Renin-Angiotensin-Aldosterone System and Cardiovascular
inflammation, and prevent remodeling of target organ tissues. This pathway
Disease).
appears to be especially important in protecting renal tissue in those with diabe-
Populations with high dietary sodium intake have long been shown
tes and hypertension. New research is under way to develop genetic and phar-
to have an increased incidence of hypertension. Low dietary potassium,
macologic interventions that will stimulate this second RAAS pathway.
calcium, and magnesium intakes also are risk factors because without
their intake, sodium is retained. The natriuretic hormones modulate Data from Bader M: Annu Rev Pharmacol Toxicol 50:439–465, 2010;
renal sodium (Na+) excretion and require adequate potassium, cal- Bakris G: Am J Cardiol 105(1 suppl):21A–29A, 2010; Ferreira AJ et al:
cium, and magnesium to function properly. The natriuretic hormones Hypertension 55(2):207–213, 2010; Iwai M, Horiuchi M: Hypertens
include atrial natriuretic peptide (ANP), brain natriuretic peptide Res 32(7):533–536, 2009; Oudit GY et al: Diabetes 59(2):529–538,
2010; Wysocki J et al: Hypertension 55(1):90–98, 2010.
(BNP), C-type natriuretic peptide (CNP), and urodilatin. Dysfunction

Decreased dietary
Genetics potassium, magnesium
and calcium

↑ SNS
Increased dietary
sodium intake
Decreased renal salt
↑ RAA
excretion (shift in Insulin
(especially
pressure-natriuresis resistance
aldosterone)
relationship)
Obesity
Endothelial
dysfunction

Dysfunction of Renal glomerular and

the natriuretic tubular inflammation
hormones

FIGURE 23-3  Factors That Cause a Shift in the Pressure-Natriuresis Relationship. Numerous factors
have been implicated in the pathogenesis of sodium retention in individuals with hypertension. These
factors cause less renal excretion of salt than would normally occur with increased blood pressure. This
is called a shift in the pressure-natriuresis relationship and is believed to be a central process in the patho-
genesis of primary hypertension. RAA, Renin-angiotensin-aldosterone; SNS, sympathetic nervous system.
 CHAPTER 23  Alterations of Cardiovascular Function 589

of these hormones, along with alterations in the RAA system and the
HEALTH ALERT
SNS, causes an increase in vascular tone and a shift in the pressure-
natriuresis relationship. When there is inadequate natriuretic function, Obesity and Hypertension
serum levels of the natriuretic peptides are increased. In hypertension, Several hemodynamic and metabolic abnormalities have been implicated in
increased ANP and BNP levels are linked to an increased risk for ven- the development of hypertension in obesity. These include increased inflamma-
tricular hypertrophy, atherosclerosis, and heart failure.20 Salt retention tion, activation of the sympathetic nervous system and the renin-angiotensin-
leads to water retention and increased blood volume, which contributes aldosterone system, insulin resistance, endothelial dysfunction, and renal
to an increase in blood pressure. Subtle renal injury results, with renal function abnormalities. One of the major mechanisms leading to the develop-
vasoconstriction and tissue ischemia. Tissue ischemia causes inflam- ment of obesity-induced hypertension appears to be leptin-mediated effects
mation of the kidney and contributes to dysfunction of the glomeruli on blood vessels and the kidney. Leptin is a circulating peptide hormone that
and tubules, which promotes additional sodium retention. is primarily secreted by adipocytes. Although obesity is generally associ-
Inflammation plays a role in the pathogenesis of hypertension.21 ated with resistance to the weight-reducing actions of leptin, the resultant
Endothelial injury and tissue ischemia result in the release of vasoactive increased levels of this peptide cause an increase in sympathetic nervous sys-
inflammatory cytokines. Although many of these cytokines (e.g., hista- tem activity and adversely shift the renal pressure-natriuresis curve, leading to
mine, prostaglandins) have vasodilatory actions in acute inflammatory sodium retention. Adiponectin is a protein that is produced by adipose tissue
injury, chronic inflammation contributes to vascular remodeling and but is reduced in obesity. Decreased adiponectin is associated with insulin
smooth muscle contraction. Endothelial injury and dysfunction in pri- resistance, decreased endothelial-derived nitric oxide (vasodilator) produc-
mary hypertension is further characterized by a decreased production tion, and activation of both the sympathetic nervous and renin-angiotensin-
of vasodilators, such as nitric oxide, and an increased production of aldosterone systems. Taken together, these obesity-related changes result in
vasoconstrictors, such as endothelin.22 vasoconstriction, salt and water retention, and renal dysfunction; all of these
Obesity is recognized as an important risk factor for hypertension in factors may contribute to the development of hypertension. Further studies
both adults and children and contributes to many of the neurohumoral, aimed at achieving a better understanding of these mechanisms may lead
metabolic, renal, and cardiovascular processes that cause hyperten- to new treatments for obesity-related hypertension.
sion.23 Obesity causes changes in the adipokines (i.e., leptin and adipo-
nectin) and also is associated with increased activity of the SNS and the Data from Bogaert YE, Linas S: Nat Clin Pract Nephrol 5(2):101–111,
RAAS. Obesity is linked to inflammation, endothelial dysfunction, and 2009; Kshatriya S et al: Curr Opin Nephrol Hypertens 19(1):72–78,
insulin resistance and an increased risk for cardiovascular complications 2010; Mathieu P et al: Hypertension 53(4):577–584, 2009;
from hypertension24 (see Health Alert: Obesity and Hypertension). ­Papadopoulos DP et al: J Clin Hypertens 11(2):61–65, 2009; Patel
Finally, insulin resistance is common in hypertension, even in indi- JV et al: Ann Med 41(4):291–300, 2009; Rahmouni K: Hypertension
55(4):844–845, 2010; Sweeney G: Nat Rev Cardiol 7(1):22–29, 2010.
viduals without clinical diabetes.25 Insulin resistance is associated with
decreased endothelial release of nitric oxide and other vasodilators. It
also affects renal function and causes renal salt and water retention. obesity, hypertension, insulin resistance, and lipid disorders in the
Insulin resistance is associated with overactivity of the sympathetic metabolic syndrome result in a high risk of cardiovascular disease.26,27
nervous system and the renin-angiotensin-aldosterone system. It is It is likely that primary hypertension is an interaction between
interesting to note that in many individuals with diabetes treated with many of these factors leading to sustained increases in blood volume
drugs that increase insulin sensitivity, blood pressure often declines, and peripheral resistance. The pathophysiology of primary hyperten-
even in the absence of antihypertensive drugs. The interactions between sion is summarized in Figure 23-4.

Genetics  Environment

Insulin resistance Dysfunction of the SNS, RAA, adducin, Inflammation

and natriuretic hormones

Vasoconstriction Renal salt and water retention

Increased peripheral resistance Increased blood volume

Sustained hypertension

FIGURE 23-4  Pathophysiology of Hypertension. Numerous genetic vulnerabilities have been linked
to hypertension and these, in combination with environmental risks, cause neurohumoral dysfunction
(sympathetic nervous system [SNS], renin-angiotensin-aldosterone [RAA] system, adducin (cytoskel-
eton protein involved with Na/K ATPase), and natriuretic hormones) and promote inflammation and
insulin resistance. Insulin resistance and neurohumoral dysfunction contribute to sustained systemic
vasoconstriction and increased peripheral resistance. Inflammation contributes to renal dysfunction,
which, in combination with the neurohumoral alterations, results in renal salt and water retention and
increased blood volume. Increased peripheral resistance and increased blood volume are two primary
causes of sustained hypertension.
590 CHAPTER 23  Alterations of Cardiovascular Function

Secondary Hypertension If blood pressure is not reduced, cerebral edema and cerebral dys-
Secondary hypertension is caused by an underlying disease process or function (encephalopathy) increase until death occurs. Organ dam-
medication that raises peripheral vascular resistance or cardiac out- age resulting from malignant hypertension is life-threatening. Besides
put. Examples include renal vascular or parenchymal disease, adre- encephalopathy, malignant hypertension can cause papilledema, car-
nocortical tumors, adrenomedullary tumors (pheochromocytoma), diac failure, uremia, retinopathy, and cerebrovascular accident.
and drugs (oral contraceptives, corticosteroids, antihistamines). If the
cause is identified and removed before permanent structural changes CLINICAL MANIFESTATIONS  The early stages of hypertension have
occur, blood pressure returns to normal. no clinical manifestations other than elevated blood pressure; for this
reason, hypertension is called a silent disease. Some hypertensive indi-
Complicated Hypertension viduals never have signs, symptoms, or complications, whereas others
As hypertension becomes more severe and chronic, tissue damage can become very ill, and hypertension can be a cause of death. Still other
occur in the blood vessels and tissues leading to target organ damage individuals have anatomic and physiologic damage caused by past
in the heart, kidney, brain, and eyes.28 Cardiovascular complications hypertensive disease, despite current blood pressure measurements
of sustained hypertension include left ventricular hypertrophy, angina being within normal ranges. If elevated blood pressure is not detected
pectoris, heart failure, coronary artery disease, myocardial infarction, and treated, it becomes established and may begin to accelerate its
and sudden death. Myocardial hypertrophy in response to hyperten- effects on tissues when the individual is 30 to 50 years of age. This sets
sion is mediated by several neurohormonal substances, including the stage for the complications of hypertension that begin to appear
catecholamines from the SNS and angiotensin II. Hypertrophy is char- during the fourth, fifth, and sixth decades of life.
acterized by changes in the myocyte proteins, apoptosis of myocytes, Most clinical manifestations of hypertensive disease are caused by
and deposition of collagen in heart muscle, which causes it to become complications that damage organs and tissues outside the vascular sys-
thickened, scarred, and less able to relax during diastole, leading to tem. Besides elevated blood pressure, the signs and symptoms there-
diastolic heart failure.29,30 In addition, the increased size of the heart fore tend to be specific for the organs or tissues affected. Evidence of
muscle increases demand for oxygen delivery over time, the contractil- heart disease, renal insufficiency, central nervous system dysfunction,
ity of the heart is impaired, and the individual is at increased risk for impaired vision, impaired mobility, vascular occlusion, or edema can
systolic heart failure. Vascular complications include the formation, all be caused by sustained hypertension.
dissection, and rupture of aneurysms (outpouchings in vessel walls)
and atherosclerosis leading to vessel occlusion. EVALUATION AND TREATMENT  A single elevated blood pressure
Renal complications of complicated hypertension include paren- reading does not mean that a person has hypertension. Diagnosis
chymal damage, nephrosclerosis, renal arteriosclerosis, and renal insuf- requires the measurement of blood pressure on at least two separate
ficiency or failure. Microalbuminuria (small amounts of protein in the occasions, averaging two readings at least 2 minutes apart, with the fol-
urine) occurs in 10% to 25% of individuals with primary hypertension lowing conditions: the person is seated, the arm is supported at heart
and is now recognized as an early sign of impending renal dysfunction level, the person must be at rest for at least 5 minutes, and the per-
and significantly increased risk for cardiovascular events, especially in son should not have smoked or ingested any caffeine in the previous
those who also have diabetes.31 Complications specific to the retina 30 minutes.9 Diagnostic tests for further evaluation of hypertension
include retinal vascular sclerosis, exudation, and hemorrhage. Cere- include 24-hour blood pressure monitoring in selected individuals,
brovascular complications include transient ischemia, stroke, cerebral complete blood count, urinalysis, biochemical blood profile (measures
thrombosis, aneurysm, hemorrhage, and dementia.32,33 The pathologic levels of plasma glucose, sodium, potassium, calcium, magnesium,
effects of complicated hypertension are summarized in Table 23-2. creatinine, cholesterol, and triglycerides), and an electrocardiogram
Malignant hypertension is rapidly progressive hypertension in (ECG). Individuals who have elevated blood pressure are assumed to
which diastolic pressure is usually greater than 140 mm Hg. High arte- have primary hypertension unless their history, physical examination,
rial pressure renders the cerebral arterioles incapable of regulating or initial diagnostic screening indicates secondary hypertension. Once
blood flow to the cerebral capillary beds. High hydrostatic pressures in the diagnosis is made, a careful evaluation for other cardiovascular risk
the capillaries cause vascular fluid to exude into the interstitial space. factors and for end-organ damage should be done.

TABLE 23-2 PATHOLOGIC EFFECTS OF SUSTAINED, COMPLICATED PRIMARY

HYPERTENSION
SITE OF INJURY MECHANISM OF INJURY POTENTIAL PATHOLOGIC EFFECT
Heart
Myocardium Increased workload combined with diminished blood flow through Left ventricular hypertrophy, myocardial ischemia, heart failure
coronary arteries
Coronary arteries Accelerated atherosclerosis (coronary artery disease) Myocardial ischemia, myocardial infarction, sudden death
Kidneys Reduced blood flow, increased arteriolar pressure, RAAS and SNS Glomerulosclerosis and decreased glomerular filtration,
stimulation, and inflammation end-stage renal disease
Brain Reduced blood flow and oxygen supply; weakened vessel walls, Transient ischemic attacks, cerebral thrombosis, aneurysm,
­accelerated atherosclerosis hemorrhage, acute brain infarction
Eyes (retinas) Retinal vascular sclerosis, increased retinal artery pressures Hypertensive retinopathy, retinal exudates and hemorrhages
Aorta Weakened vessel wall Dissecting aneurysm (see p. 592)
Arteries of lower Reduced blood flow and high pressures in arterioles, accelerated Intermittent claudication, gangrene
extremities atherosclerosis
 CHAPTER 23  Alterations of Cardiovascular Function 591

Treatment of primary hypertension depends on its severity. Life- insufficiency), metabolic disorders (e.g., porphyria), or diseases of
style modification is important for preventing hypertension (espe- the central or peripheral nervous systems (e.g., intracranial tumors,
cially in those individuals with prehypertension) and for treating cerebral infarcts, Wernicke encephalopathy, peripheral neuropa-
hypertension. Important lifestyle modifications include following an thies). Cardiovascular autonomic neuropathy is a common cause of
exercise program, making dietary modifications, stopping smoking, orthostatic hypotension in persons with diabetes and is a serious and
and losing weight. Pharmacologic treatment of hypertension reduces often overlooked complication. In addition to cardiovascular symp-
the risk of end-organ damage and prevents major diseases, such as toms, associated impotence and bowel and bladder dysfunction are
myocardial infarction and stroke. Diuretics have been shown to be common.
the safest and most effective medications for lowering blood pressure Orthostatic hypotension is often accompanied by dizziness, blur-
and preventing the cardiovascular complications of hypertension.34 ring or loss of vision, and syncope or fainting caused by insufficient
Some individuals will have “compelling indications” for choosing a vasomotor compensation and reduction of blood flow through the
particular antihypertensive as a first-line medication. For example, brain. Although no curative treatment is available for idiopathic
individuals with heart failure, chronic kidney disease, or who have a orthostatic hypotension, often it can be managed adequately with a
history of myocardial infarction or stroke should begin antihyperten- combination of nondrug and drug therapies—increasing fluid and salt
sive treatment with an ACE inhibitor, ARB, or aldosterone antago- intake, wearing thigh-high stockings, and taking mineralocorticoids
nist.9 Some individuals require two drugs for blood pressure control, and vasoconstrictors.37 Both acute and secondary forms of hypoten-
including combinations of diuretics and other antihypertensives, sion resolve when the underlying disorder is corrected.
such as beta-blockers, calcium channel blockers, and ACE inhibi-
tors.35 Careful follow-up to support continued adherence, determine
the response, and monitor for potential side effects of these medica- 4 QUICK CHECK 23-2
tions is important.36 1. What are the major risk factors for hypertension?
2. Summarize the pathophysiology of primary hypertension.
Orthostatic (Postural) Hypotension 3. What is malignant hypertension?
The term orthostatic (postural) hypotension refers to a decrease in 4. What are the causes of orthostatic hypotension?
systolic blood pressure of at least 20 mm Hg or a decrease in diastolic
blood pressure of at least 10 mm Hg within 3 minutes of moving to a
standing position. The term idiopathic, or primary, orthostatic hypo- Aneurysm
tension implies no known initial cause. Some define the disorder as An aneurysm is a localized dilation or outpouching of a vessel wall
a separate entity, whereas others suggest it is a part of a generalized or cardiac chamber (Figure 23-5). The law of Laplace (discussed in
degenerative central nervous system disease. It affects men more often detail in Chapter 22) can provide an understanding of the hemody-
than women and usually occurs between the ages of 40 and 70 years. namics of an aneurysm. True aneurysms involve all three layers of the
Up to 18% of older adults may be affected by primary orthostatic arterial wall and are best described as a weakening of the vessel wall
hypotension, and it is a significant risk factor for falls and associated (Figure 23-6, A). Most are fusiform and circumferential, whereas
injury.37
Normally when an individual stands, the gravitational changes
on the circulation are compensated by such mechanisms as reflex
arteriolar and venous constriction and increased heart rate. Other
compensatory mechanisms include mechanical factors, such as the
closure of valves in the venous system, contraction of the leg mus-
cles, and a decrease in intrathoracic pressure. The normally increased
sympathetic activity during upright posture is mediated through a
stretch receptor (baroreceptor) reflex that responds to shifts in vol-
ume caused by postural changes. This reflex promptly increases heart
rate and constricts the systemic arterioles. Thus, arterial blood pres-
sure is maintained. These mechanisms are dysfunctional or inad-
equate in individuals with orthostatic hypotension; consequently,
upon standing, blood pools and normal arterial pressure cannot be A
maintained.
Orthostatic hypotension may be acute or chronic. Acute orthostatic
hypotension is caused when the normal regulatory mechanisms are
sluggish as a result of (1) altered body chemistry, (2) drug action (e.g.,
antihypertensives, antidepressants), (3) prolonged immobility caused
by illness, (4) starvation, (5) physical exhaustion, (6) any condition
that produces volume depletion (e.g., dehydration, diuresis, potassium LV
or sodium depletion), or (7) any condition that results in venous pool- R
ing (e.g., pregnancy, extensive varicosities of the lower extremities).
Elderly persons are particularly susceptible to this type of orthostatic D
hypotension.
Chronic orthostatic hypotension may be (1) secondary to a spe- FIGURE 23-5  Aneurysm. A three dimensional CT scan shows the
cific disease or (2) idiopathic or primary. The diseases that cause sec- aneurysm (A) involves the ascending thoracic aorta. D, descending
ondary orthostatic hypotension are endocrine disorders (e.g., adrenal aorta; LV, left ventricle.
592 CHAPTER 23  Alterations of Cardiovascular Function

Fusiform, circumferential Fusiform, saccular

Tunica
Tunica media
intima
Adventitia
Lumen

False Dissecting, saccular

Clot

B
A
FIGURE 23-6  Longitudinal Sections Showing Types of Aneurysms. A, The fusiform circumferential
and fusiform saccular aneurysms are true aneurysms, caused by weakening of the vessel wall. False
and saccular aneurysms involve a break in the vessel wall, usually caused by trauma. B, Dissecting
aneurysm of thoracic aorta (arrow). (B from Damjanov I, Linder J, editors: Anderson’s pathology, ed 10,
St Louis, 1996, Mosby.)

saccular aneurysms are basically spherical in shape. False aneurysm is leak. (Cerebral aneurysms are described in Chapter 15.) Aneurysms
an extravascular hematoma that communicates with the intravascular in the heart present with dysrhythmias, heart failure, and embolism of
space. A common cause of this type of lesion is a leak between a vascu- clots to the brain or other vital organs.
lar graft and a natural artery. Aortic aneurysms can be complicated by the acute aortic syn-
The aorta is particularly susceptible to aneurysm formation because dromes, which include aortic dissection, hemorrhage into the ves-
of constant stress on the vessel wall and the absence of penetrating vasa sel wall, or vessel rupture. Dissection of the layers of the arterial wall
vasorum in the media layer. Three fourths of all aneurysms occur in occurs when there is a tear in the intima and blood enters the wall of
the abdominal aorta. Atherosclerosis is the most common cause of the artery (see Figure 23-6, B). Dissections can involve any part of the
arterial aneurysms because plaque formation erodes the vessel wall and aorta (ascending, arch, or descending) and can disrupt flow through
contributes to inflammation and release of proteinases that can further arterial branches, thus creating a surgical emergency.
weaken the vessel. Hypertension also contributes to aneurysm forma- The diagnosis of an aneurysm is usually confirmed by ultraso-
tion by increasing wall stress. Collagen-vascular disorders (e.g., Marfan nography, computed tomography, magnetic resonance imaging, or
syndrome), syphilis, and other infections that affect arterial walls also angiography. Medical treatment is indicated for slow-growing aor-
can cause aneurysms. tic aneurysms, particularly in early stages, and includes cessation of
Cardiac aneurysms most commonly form after myocardial infarc- smoking, reduction of blood pressure and blood volume, and imple-
tion when intraventricular tension stretches the noncontracting mentation of beta-adrenergic blockade. For those aneurysms that are
infarcted muscle. The stretching produces infarct expansion, a weak dilating rapidly or have become large, surgical treatment is indicated
and thin layer of necrotic muscle, and fibrous tissue that bulges with and usually includes replacement with a prosthetic graft. New endo-
each systole. vascular surgical techniques make aneurysm repair possible for more
Clinical manifestations depend upon where the aneurysm is located. individuals.38
Aortic aneurysms often are asymptomatic until they rupture, and then
cause severe pain and hypotension. Thoracic aortic aneurysms can Thrombus Formation
cause dysphagia (difficulty swallowing) and dyspnea (breathlessness). As in venous thrombosis, arterial thrombi tend to develop when intra-
An aneurysm that impairs flow to an extremity causes symptoms of vascular conditions promote activation of coagulation, or when there
ischemia. Cerebral aneurysms, which often occur in the circle of Willis, is stasis of blood flow. These conditions include those in which there
are associated with signs and symptoms of increased intracranial pres- is intimal irritation or roughening (such as in surgical procedures),
sure. Signs and symptoms of stroke occur when cerebral aneurysms inflammation, traumatic injury, infection, low blood pressures, or
 CHAPTER 23  Alterations of Cardiovascular Function 593

obstructions that cause blood stasis and pooling within the vessels.
TABLE 23-3 TYPES OF EMBOLI
(Mechanisms of coagulation are described in Chapter 19.) Inflam-
mation of the endothelium leads to activation of the clotting cascade, TYPE CHARACTERISTICS
causing platelets to adhere readily. An anatomic change in an artery Arteries
(such as an aneurysm) can contribute to thrombus formation, particu- Arterial Dislodged thrombus; source is usually from heart;
larly if the change results in a pooling of arterial blood. Thrombi also ­thromboembolism most common sites of obstruction are lower
form on heart valves altered by calcification or bacterial vegetation. extremities (femoral and popliteal arteries),
Valvular thrombi are most commonly associated with inflammation coronary arteries, and cerebral vasculature
of the endocardium (endocarditis) and rheumatic heart disease. Wide-
spread arterial thrombus formation can occur in shock, particularly Veins
shock resulting from septicemia. In septic shock, systemic inflam- Venous Dislodged thrombus; source is usually from lower
mation activates the intrinsic and extrinsic pathways of coagulation, ­thromboembolism extremities; obstructs branches of pulmonary
resulting in microvascular thrombosis throughout the systemic arterial artery
circulation. Air embolism Bolus of air displaces blood in vasculature; source
Arterial thrombi pose two potential threats to the circulation. First, usually room air entering circulation through IV
the thrombus may grow large enough to occlude the artery, causing lines; trauma to chest also may allow air from
ischemia in tissue supplied by the artery. Second, the thrombus may lungs to enter vascular space
dislodge, becoming a thromboembolus that travels through the vas- Amniotic fluid Bolus of amniotic fluid; extensive intra-abdominal
cular system until it occludes flow into a distal systemic vascular bed. ­embolism pressure attending labor and delivery can
Diagnosis of arterial thrombi is usually accomplished through the force amniotic fluid into bloodstream of
use of Doppler ultrasonography and angiography. Pharmacologic mother; ­introduces antigens, cells, and protein
treatment involves the administration of heparin, warfarin derivatives, ­aggregates that trigger inflammation, coagula-
thrombin inhibitors, or thrombolytics. A balloon-tipped catheter tion, and immune responses
also can be used to remove or compress an arterial thrombus. Vari- Bacterial embolism Aggregates of bacteria in bloodstream; source is
ous combinations of drug and catheter therapies are sometimes used subacute bacterial endocarditis or abscess
concurrently. Fat embolism Globules of fat floating in bloodstream associated
with trauma to long bones; lungs in particular
Embolism are affected
Embolism is the obstruction of a vessel by an embolus—a bolus of Foreign matter Small particles or fibers introduced during
matter circulating in the bloodstream. The embolus may consist of a trauma or through an IV or intra-arterial
dislodged thrombus; an air bubble; an aggregate of amniotic fluid; an line; ­coagulation cascade is initiated and
aggregate of fat, bacteria, or cancer cells; or a foreign substance. An ­thromboemboli form around particles
embolus travels in the bloodstream until it reaches a vessel through
which it cannot fit. No matter how tiny it is, an embolus will eventu-
ally lodge in a systemic or pulmonary vessel determined by its source. vasospasm. Over time, these thrombi become organized and fibrotic
Pulmonary emboli originate on the venous side (mostly from the deep and result in permanent occlusion and obliteration of portions of
veins of the legs) of the systemic circulation or in the right heart; arte- small- and medium-sized arteries in the feet and sometimes in the
rial emboli most commonly originate in the left heart and are asso- hands.39 Although collateral vessels develop in Buerger disease, they
ciated with thrombi after myocardial infarction, valvular disease, left are inadequate to supply the extremities with blood. These collateral
heart failure, endocarditis, and dysrhythmias. vessels have a characteristic corkscrew shape, believed to be a result of
Embolism causes ischemia or infarction in tissues distal to the dilated vasa vasorum in the affected artery.
obstruction, causing organ dysfunction and pain. Infarction and sub- The chief symptom of thromboangiitis obliterans is pain and ten-
sequent necrosis of a central organ are life-threatening. For example, derness of the affected part, usually affecting more than one extremity.
occlusion of a coronary artery will cause a myocardial infarction, Clinical manifestations are caused by sluggish blood flow and include
whereas occlusion of a cerebral artery causes a stroke (see Chapter 15). rubor (redness of the skin), which is caused by dilated capillaries under
The types of emboli are summarized in Table 23-3. the skin, and cyanosis, which is caused by tissue ischemia. Chronic
ischemia causes the skin to thin and become shiny and the nails to

4 QUICK CHECK 23-3

become thickened and malformed. In advanced disease, profound
ischemia of the extremities resulting from vessel obliteration can cause
1. How does the law of Laplace function in aneurysms? gangrene necessitating amputation. Buerger disease has also been asso-
2. What is a thrombus? ciated with cerebrovascular disease (stroke), mesenteric disease, and
3. Why are emboli dangerous? rheumatic symptoms (joint pain).
Diagnosis of thromboangiitis obliterans is made by identification
of the following common features—age <45 years, smoking history,
Peripheral Vascular Disease evidence of peripheral ischemia—and by exclusion of other causes of
Thromboangiitis Obliterans (Buerger disease) arterial insufficiency. The most important part of treatment is cessa-
Thromboangiitis obliterans (Buerger disease) is an inflammatory tion of cigarette smoking. If the person continues to smoke, the likeli-
disease of the peripheral arteries. It is strongly associated with smok- hood of recurrence of the disease and gangrene requiring amputation
ing, and there is some evidence for a link with severe periodontal dis- is high. Other measures are aimed at improving circulation to the foot
ease.39 Thromboangiitis obliterans is characterized by the formation of or hand. Vasodilators are prescribed to alleviate vasospasm, and the
thrombi filled with inflammatory and immune cells and accompanying individual receives instruction in exercises that use gravity to improve
594 CHAPTER 23  Alterations of Cardiovascular Function

Tunica intima
Tunica media

Adventitia
B
A Normal artery Diseased (occluded) artery
FIGURE 23-7  Arteriosclerosis. A, Cross section of a normal artery and an artery altered by disease.
B, A small artery in the myocardium is occluded by a mass of blue-staining platelets, yellow-staining
red cells, and cholesterol bodies. (B from Damjanov I, Linder J, editors: Anderson’s pathology, ed 10,
St Louis, 1996, Mosby.)

blood flow.39 Recently, stem cell therapy to induce angiogenesis has

shown promising results to treat severe ischemia.40
4 QUICK CHECK 23-4
1. What is Buerger disease and why does it occur?
Raynaud Phenomenon and Disease 2. Compare the physical manifestations of Buerger disease and Raynaud
Both Raynaud phenomenon and Raynaud disease are characterized disease.
by attacks of vasospasm in the small arteries and arterioles of the fin-
gers and, less commonly, the toes. Although the clinical manifestations
of the phenomenon and the disease are the same, their causes differ. Atherosclerosis
Raynaud phenomenon is secondary to systemic diseases, particu- Atherosclerosis is a form of arteriosclerosis characterized by thicken-
larly collagen vascular disease (scleroderma), vasculitis, malignancy, ing and hardening of the vessel wall. It is caused by the accumulation
pulmonary hypertension, chemotherapy, cocaine use, hypothyroid- of lipid-laden macrophages within the arterial wall, which leads to the
ism, thoracic outlet syndrome, trauma, serum sickness, or long-term formation of a lesion called a plaque. Atherosclerosis is not a single
exposure to environmental conditions, such as cold or vibrating disease entity but rather a pathologic process that can affect vascular
machinery in the workplace.41 Raynaud disease is a common primary systems throughout the body, resulting in ischemic syndromes that
vasospastic disorder of unknown origin. Blood vessels in affected can vary widely in their severity and clinical manifestations. It is the
individuals demonstrate endothelial dysfunction with an imbalance leading cause of coronary artery and cerebrovascular disease. (Athero-
in endothelium-derived vasodilators (e.g., nitric oxide) and vasocon- sclerosis of the coronary arteries is described later in this chapter, and
strictors (e.g., endothelin-1). Platelet activation also may play a role. atherosclerosis of the cerebral arteries is described in Chapter 15.)
It tends to affect young women and to consist of vasospastic attacks
triggered by brief exposure to cold or by emotional stress. Genetic pre- PATHOPHYSIOLOGY  Atherosclerosis begins with injury to the
disposition may play a role in its development. endothelial cells that line artery walls. Pathologically, the lesions prog-
The clinical manifestations of the vasospastic attacks of either ress from endothelial injury and dysfunction to fatty streak to fibrotic
disorder are changes in skin color and sensation caused by ischemia. plaque to complicated lesion (Figures 23-7 and 23-8). Possible causes
Vasospasm occurs with varying frequency and severity and causes pal- of endothelial injury include the common risk factors for athero-
lor, numbness, and the sensation of coldness in the digits. Attacks tend sclerosis, such as smoking, hypertension, diabetes, increased levels
to be bilateral, and manifestations usually begin at the tips of the digits of low-density lipoprotein (LDL), decreased levels of high-density
and progress to the proximal phalanges. Sluggish blood flow resulting lipoprotein (HDL), and autoimmunity. Other “nontraditional” risk
from ischemia may cause the skin to appear cyanotic. Rubor, throb- factors include elevated levels of highly-sensitive C-reactive protein
bing pain, and paresthesias follow as blood flow returns. Skin color (hs-CRP), increased serum fibrinogen level, insulin resistance, oxida-
returns to normal after the attack, but frequent, prolonged attacks tive stress, infection, and periodontal disease. These risk factors are
interfere with cellular metabolism, causing the skin of the fingertips discussed in more detail in the following section on coronary artery
to thicken and the nails to become brittle. In severe, chronic Raynaud disease (see p. 598).
phenomenon or disease, ischemia can eventually cause ulceration and Injured endothelial cells become inflamed. Inflammation plays a
gangrene. fundamental role in mediating the steps in the initiation and progres-
Treatment for Raynaud phenomenon consists of removing the sion of atherogenesis.43,44 Inflamed endothelial cells cannot make nor-
stimulus or treating the primary disease process. Treatment of Ray­ mal amounts of antithrombic and vasodilating cytokines (see Figures
naud disease begins with avoidance of stimuli that trigger attacks (e.g., 22-24 and 22-25). Recent evidence indicates that individuals with a
cold, emotional stress) and cessation of cigarette smoking to eliminate defect in the production of precursor endothelial cells in the bone mar-
the vasoconstricting effects of nicotine. If attacks of vasospasm become row are at greater risk for atherosclerotic disease because these precur-
frequent or prolonged, vasodilators, such as calcium channel block- sor cells are not available to repair injured endothelium.45
ers, nitric oxide agonists, alpha-blockers, prostaglandin analogs, or The next step in atherogenesis occurs when inflamed endothelial
endothelin antagonists, are administered.42 Sympathectomy may be cells express adhesion molecules that bind macrophages and other
indicated in severe cases, but may not be effective. If ischemia leads to inflammatory and immune cells. Macrophages adhere to the injured
ulceration and gangrene, amputation may be necessary. endothelium and release numerous inflammatory cytokines (e.g.,
 CHAPTER 23  Alterations of Cardiovascular Function 595

Monocyte Lumen
1 LDL of artery Lipid
Endothelium pool

3
Foam cell
Oxidized LDL
4
2

1 LDL enters intima through intact endothelium

5
2 Intimal LDL is oxidized into proinflammatory lipids Cytokines
Smooth muscle
3 Oxidized LDL causes adhesion and entry of
monocytes and T lymphocytes across endothelium

4 Monocytes differentiate into macrophages and then

consume large amounts of LDL, transforming into
foam cells
5 Foam cells release growth factors (cytokines) that
encourage atherosclerosis

FIGURE 23-8  Low-Density Lipoprotein Oxidation. Low-density lipoprotein (LDL) enters the arterial
intima through an intact endothelium. In hypercholesterolemia, the influx of LDL exceeds the eliminat-
ing capacity and an extracellular pool of LDL is formed. This is enhanced by association of LDL with
the extracellular matrix. Intimal LDL is oxidized through the action of free oxygen radicals formed by
enzymatic or nonenzymatic reactions. This generates proinflammatory lipids that induce endothelial
expression of the adhesion molecule (i.e., vascular cell adhesion molecule-1), activate complement,
and stimulate chemokine secretion. All of these factors cause adhesion and entry of mononuclear leu-
kocytes, particularly monocytes and T lymphocytes. Monocytes differentiate into macrophages. Mac-
rophages up-regulate and internalize oxidized LDL and transform into foam cells. Macrophage uptake
of oxidized LDL also leads to presentation of its fragments to antigen-specific T cells. This induces an
autoimmune reaction that leads to production of proinflammatory cytokines. Such cytokines include
interferon-γ, tumor necrosis factor-alpha, and interleukin-1, which act on endothelial cells to stimulate
expression of adhesion molecules and procoagulant activity; on macrophages to activate proteases,
endocytosis, nitric oxide (NO), and cytokines; and on smooth muscle cells (SMCs) to induce NO pro-
duction and inhibit growth and collagen and actin expression. LDL, Low-density lipoprotein. (Modified
from Crawford MH, DiMarco JP, editors: Cardiology, London, 2001, Mosby.)

tumor necrosis factor-alpha [TNF-α], interferons, interleukins, and Macrophages also release growth factors that stimulate smooth
C-reactive protein) and enzymes that further injure the vessel wall.46 muscle cell proliferation.50 Smooth muscle cells in the region of endo-
Toxic oxygen radicals generated by the inflammatory process cause thelial injury proliferate, produce collagen, and migrate over the fatty
oxidation (i.e., addition of oxygen) of LDL that has accumulated in the streak, forming a fibrous plaque (Figure 23-10). The fibrous plaque
vessel intima. Hyperlipidemia, diabetes, smoking, and hypertension may calcify, protrude into the vessel lumen, and obstruct blood flow to
contribute to LDL oxidation and its accumulation in the vessel wall.47 distal tissues (especially during exercise), which may cause symptoms
Oxidized LDL causes additional adhesion molecule expression with (e.g., angina or intermittent claudication).
the recruitment of monocytes that differentiate into macrophages. Many plaques, however, are “unstable,” meaning they are prone
These macrophages penetrate into the intima where they engulf oxi- to rupture even before they affect blood flow significantly and are
dized LDL. These lipid-laden macrophages are now called foam cells, clinically silent until they rupture.51 Plaque rupture occurs because of
and when they accumulate in significant amounts, they form a lesion the inflammatory activation of proteinases, such as the matrix metal-
called a fatty streak (see Figures 23-8 and 23-9).48 These lesions can loproteinases and the cathepsins, and can be accelerated by bleeding
be found in the walls of arteries of most people, even young children. within the lesion (plaque hemorrhage).52 Plaques that have ruptured
Once formed, fatty streaks produce more toxic oxygen radicals, recruit are called complicated plaques (see Figure 23-9). Once rupture occurs,
T cells leading to autoimmunity, and secrete additional inflammatory exposure of underlying tissue results in platelet adhesion, initiation of
mediators resulting in progressive damage to the vessel wall.49 Treat- the clotting cascade, and rapid thrombus formation. The thrombus
ment that lowers LDL levels may reverse this process. may suddenly occlude the affected vessel, resulting in ischemia and
596 CHAPTER 23  Alterations of Cardiovascular Function

Damaged endothelium: Endothelium

Chronic endothelial injury
_ Hypertension Tunica intima
_ Smoking Tunic media Monocyte
_ Hyperlipidemia
Adventitia
_ Hyperhomocysteinemia Damaged
_ Hemodynamic factors endothelium
_ Toxins
_ Viruses Platelets
_ Immune reactions Macrophage
A

Response to injury
Lipids

Platelets attach to
endothelium

Foamy macrophage
ingesting lipids

Migration of
smooth muscle
into the intima
Fatty streak
Lipid accumulation

B Fibroblast

Collagen cap
(fibrous tissue)

Fibroblast

Fissure in plaque

Fibrous plaque Lipid pool

Thrombus

Thinning
collagen cap

Lipid pool

Complicated
lesion

FIGURE 23-9  Progression of Atherosclerosis. A, Damaged endothelium. B, Diagram of fatty streak

and lipid core formation (see Figure 23-8 for a diagram of oxidized low-density lipoprotein [LDL]).  
C, Diagram of fibrous plaque. Raised plaques are visible: some are yellow; others are white. D, Dia-
gram of complicated lesion; thrombus is red; collagen is blue. Plaque is complicated by red thrombus
deposition.
 CHAPTER 23  Alterations of Cardiovascular Function 597

may reveal arterial bruits and evidence of decreased blood flow to tis-
sues. Laboratory data that include measurement of levels of lipids,
blood glucose, and hs-CRP are also indicated. Judicious use of x-ray
films, electrocardiography, ultrasonography, nuclear scanning, CT,
MRI, and angiography may be necessary to identify affected vessels,
particularly coronary vessels.53 New modalities aimed at identifying
vulnerable plaques before the rupture are being evaluated.51,54
Current management of atherosclerosis is focused on detection
and treatment of preclinical lesions with drugs aimed at stabilizing
and reversing plaques before they rupture.55 Once a lesion obstructs
blood flow, the primary goal in the management of atherosclerosis is
to restore adequate blood flow to the affected tissues. If an individual
has presented with acute ischemia (e.g., myocardial infarction, stroke),
interventions are specific to the diseased area and are discussed further
under those topics. In situations where the disease process does not
require immediate intervention, management focuses on reduction of
A risk factors and prevention of plaque progression. This includes imple-
mentation of an exercise program, cessation of smoking, and control
of hypertension and diabetes where appropriate while reducing LDL
cholesterol level by diet or medications, or both. Management of ath-
erosclerotic risk factors is discussed further starting on p. 601.

Peripheral Artery Disease

Peripheral artery disease (PAD) refers to atherosclerotic disease of
arteries that perfuse the limbs, especially the lower extremities. PAD
affects up to 20% of Americans ages 65 or older.8 The risk factors for
PAD are the same as those previously described for atherosclerosis, and
it is especially prevalent in individuals with diabetes.
B Lower extremity ischemia resulting from arterial obstruction in
FIGURE 23-10  Atherosclerosis. A, Concentric coronary plaque. PAD can be gradual or acute. In most individuals, gradually increas-
The lumen is central. There are multiple, new small blood vessels ing obstruction to arterial blood flow to the legs caused by atheroscle-
within the plaque, the late result of disruption. B, Cell types in fibro- rosis in the iliofemoral vessels results in pain with ambulation called
lipid plaque. The plaque cap (brownish color) contains numerous intermittent claudication. If a thrombus forms over the atherosclerotic
elongated, smooth muscle cells; some contain lipid. Macrophages lesion, complete obstruction of blood flow can occur acutely, caus-
are clustered on the edge of the core. (From Damjanov I, Linder J, ing severe pain, loss of pulses, and skin color changes in the affected
editors: Anderson’s pathology, ed 10, St Louis, 1996, Mosby.) extremity.
PAD is often asymptomatic in its early stages; therefore evalua-
infarction. Aspirin or other antithrombotic agents are used to prevent tion for PAD requires a careful history and physical examination that
this complication of atherosclerotic disease. focuses on finding evidence of atherosclerotic disease (e.g., bruits),
determining the ankle-brachial index, and measuring blood flow
CLINICAL MANIFESTATIONS  Atherosclerosis presents with using noninvasive Doppler. Treatment includes risk factor reduc-
symptoms and signs that result from inadequate perfusion of tissues tion (smoking cessation and treatment of diabetes, hypertension, and
because of obstruction of the vessels that supply them. Partial vessel dyslipidemia) and antiplatelet therapy. Symptomatic PAD should be
obstruction may lead to transient ischemic events, often associated managed with vasodilators in combination with antiplatelet or anti-
with exercise or stress. As the lesion becomes complicated, increasing thrombotic medications (aspirin, cilostazol, ticlopidine, or clopido-
obstruction with superimposed thrombosis may result in tissue infarc- grel), cholesterol-lowering medications, and exercise rehabilitation.56
tion. Obstruction of peripheral arteries can cause significant pain and If acute or refractory symptoms occur, emergent percutaneous or
disability. Coronary artery disease (CAD) caused by atherosclerosis is surgical revascularization may be indicated. Newer treatment modali-
the major cause of myocardial ischemia and is one of the most impor- ties that are being explored include autologous stem cell therapies and
tant health issues in the United States. Atherosclerotic obstruction of angiogenesis.57,58
the vessels supplying the brain is the major cause of stroke. Similarly,
any part of the body may become ischemic when its blood supply is Coronary Artery Disease, Myocardial Ischemia,
compromised by atherosclerotic lesions. Often, more than one vessel and Acute Coronary Syndromes
will become involved with this disease process such that an individual Coronary artery disease, myocardial ischemia, and myocardial infarc-
may present with symptoms from several ischemic tissues at the same tion form a pathophysiologic continuum that impairs the pumping
time, and disease in one area may indicate that the individual is at risk ability of the heart by depriving the heart muscle of blood-borne oxy-
for ischemic complications elsewhere. gen and nutrients. The earliest lesions of the continuum are those of
coronary artery disease (CAD), which is usually caused by atheroscle-
EVALUATION AND TREATMENT  In evaluating individuals for the rosis (see Figure 23-10). CAD can diminish the myocardial blood sup-
presence of atherosclerosis, a complete health history (including risk ply until deprivation impairs myocardial metabolism enough to cause
factors and symptoms of ischemia) is essential. Physical examination ischemia, a local state in which the cells are temporarily deprived of
598 CHAPTER 23  Alterations of Cardiovascular Function

blood supply. They remain alive but cannot function normally. Per-
HEALTH ALERT
sistent ischemia or the complete occlusion of a coronary artery causes
the acute coronary syndromes including infarction, or irreversible The Basics on Fats
myocardial damage. Infarction constitutes the often-fatal event known • Saturated fats are found in animal fats (butter, cheese, beef, pork, lamb,
as a heart attack. chicken) and some tropical oils (e.g., palm kernel). Saturated fats consist of
a long chain of atoms that take a longer time to burn than shorter-chained
Development of Coronary Artery Disease
fats. The longer the fat takes to burn, the stickier it becomes. Those fats
Coronary heart disease causes approximately one of every six deaths that become stickiest are more conducive to weight gain and heart disease.
in the United States. In 2010 an estimated 785,000 Americans will Healthy saturated fats for cooking include coconut and palm oils, especially
have a new coronary attack. An American will have a coronary event extra virgin and unrefined versions of these oils.
every 25 seconds, and approximately every minute someone will die • Unsaturated fats consist of two types: monounsaturated and polyunsatu-
of one.8 Risk factors for CAD are the same as those for atherosclerosis rated. Both contain essential fatty acids (EFAs) but polyunsaturated fats
and can be categorized as conventional (major) versus nontraditional have more.
(novel) and as modifiable versus nonmodifiable. The plethora of new • Monounsaturated fats are liquid at room temperature but more solid when
information obtained about the conventional risk factors has mark- refrigerated. They are found in especially high concentration in olive and
edly improved prevention and management of CAD. In addition, non- canola oils, which are high in the healthy oleic acid, a common monoun-
traditional risk factors have been identified that have provided insight saturated fat. Monounsaturated fats are known to decrease levels of low-
into the pathogenesis of CAD and may lead to future more effective density lipoproteins (LDLs) and increase levels of high-density lipoproteins
interventions. (HDLs). They are more stable in heat than other oils; thus they are often
Conventional or major risk factors for CAD that are nonmodifi- used for stir-frying and baking. Avocados are high in oleic oil. For healthy
able include: (1) advanced age, (2) male gender or women after meno- cooking, avoid refined oils and chemically treated oils.
pause, and (3) family history. Aging and menopause are associated • Polyunsaturated fats are liquid at any temperature and are found in vegetable
with increased exposure to risk factors and poor endothelial healing. oils, soy, fish, walnuts, pumpkin seeds, and flaxseed oil. They contain both
Family history may contribute to CAD through genetics and shared omega-6 and omega-3 EFAs in varying ratios. People are currently eating many
environmental exposures. Many gene polymorphisms have been asso- more omega-6 EFAs than omega-3. Too much omega-6 can contribute to clot
ciated with CAD and its risk factors.59 Modifiable major risks include formation; omega-3 fats have the opposite effect; therefore to reduce the risk
(1) dyslipidemia, (2) hypertension, (3) cigarette smoking, (4) diabe- of heart disease, more omega-3 EFAs and less omega-6 EFAs are encouraged.
tes and insulin resistance, (5) obesity, (6) sedentary lifestyle, and (7) • Omega-3 EFAs are found in fish oil, flaxseed (and flaxseed oil), canola
atherogenic diet (see Health Alert: The Basics on Fats). Fortunately, oil, walnuts, pumpkins, and green leafy vegetables. Soy contains both
modification of these factors can dramatically reduce the risk for CAD. omega-6 and omega-3. Populations that eat high amounts of omega-3
Dyslipidemia. The link between CAD and abnormal levels of lipo- EFAs have a lower risk of heart disease.
proteins is well documented.60 The term lipoprotein refers to lipids, • Omega-6 EFAs are found in vegetable oils such as corn, safflower, sun-
phospholipids, cholesterol, and triglycerides bound to carrier proteins. flower, cottonseed, peanut, sesame, grape seed, borage, primrose, and
Lipids (cholesterol in particular) are required by most cells for the soy. Omega-6 EFAs have protective effects only when they are combined
manufacture and repair of plasma membranes. Cholesterol is also a with omega-3 EFAs. Many advocate only using cold-pressed EFAs; high
necessary component for the manufacture of such essential substances heat damages these fats.
as bile acids and steroid hormones. Although cholesterol can easily be • Trans-fats are primarily found in artificially solidified (hydrogenated) oils (e.g.,
obtained from dietary fat intake, most body cells also can manufacture margarine and vegetable shortening). By becoming more solid they lose EFAs.
cholesterol. They can raise LDL and lower HDL levels, and also can raise lipoprotein A lev-
The cycle of lipid metabolism is complex. Dietary fat is packaged els, which increases the risk of heart disease. Trans-fats raise blood glucose
into particles known as chylomicrons in the small intestine. Chylomi- levels and contribute to more weight gain than the same amount of other fats.
crons are required for absorption of fat; they function by transport- “Partially hydrogenated” or “hydrogenated” on a food label means the food
ing exogenous lipid from the intestine to the liver and peripheral cells. contains trans-fatty acids (e.g., cakes, cookies, crackers, processed cheese).
Chylomicrons are the least dense of the lipoproteins and primarily
contain triglyceride. Some of the triglyceride may be removed and
either stored by adipose tissue or used by muscle as an energy source.
The chylomicron remnants, composed mainly of cholesterol, are taken cholesterol and protein; and high-density lipoproteins (HDLs), mainly
up by the liver. A series of chemical reactions in the liver results in phospholipids and protein.
the production of several lipoproteins that vary in density and func- Dyslipidemia (or dyslipoproteinemia) refers to abnormal concen-
tion. These include very-low-density lipoproteins (VLDLs), primar- trations of serum lipoproteins as defined by the Third Report of the
ily triglyceride and protein; low-density lipoproteins (LDLs), mostly National Cholesterol Education Program60 (Table 23-4). An estimated

TABLE 23-4 CRITERIA FOR DYSLIPIDEMIA

OPTIMAL NEAR OPTIMAL DESIRABLE LOW BORDERLINE HIGH VERY HIGH
Total cholesterol <200 200-239 ≥240
LDL <100 100-129 130-159 160-189 ≥190
Triglycerides <150 150-199 200-499 ≥500
HDL <40 ≥60

Data from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, JAMA 285:2486–2497, 2001.
 CHAPTER 23  Alterations of Cardiovascular Function 599

16% of adults ages 20 years or older have total serum cholesterol levels Diabetes mellitus. Diabetes mellitus is an extremely important risk
greater than 240 mg/dl.8 These abnormalities are the result of a com- factor for CAD. Insulin resistance and diabetes have multiple effects
bination of genetic and dietary factors. Primary or familial dyslipo- on the cardiovascular system including endothelial damage, thickening
proteinemias result from genetic defects that cause abnormalities in of the vessel wall, increased inflammation, increased thrombosis, gly-
lipid-metabolizing enzymes and abnormal cellular lipid receptors. Sec- cation of vascular proteins, and decreased production of endothelial-
ondary causes of dyslipidemia include the existence of several common derived vasodilators such as nitric oxide (see Chapter 18). Diabetes is
systemic disorders, such as diabetes, hypothyroidism, pancreatitis, and also associated with dyslipidemia.
renal nephrosis, as well as the use of certain medications, such as some Obesity/sedentary lifestyle. It is estimated that 65% of the adult
diuretics, glucocorticoids, interferons, and antiretrovirals. population in the United States is overweight or obese, and an esti-
An increased serum concentration of LDL is a strong indicator of mated 47 million U.S. residents have a combination of obesity, dys-
coronary risk.60 Serum levels of LDL are normally controlled by hepatic lipidemia, hypertension, and insulin resistance, called the metabolic
receptors that bind LDL and limit liver synthesis of this lipoprotein. syndrome, which is associated with an even higher risk for CAD
High dietary intake of cholesterol and fats, often in combination with a events.8 Abdominal obesity has the strongest link with increased CAD
genetic predisposition to accumulations of LDL in the serum (e.g., dys- risk and is related to inflammation, insulin resistance, decreased HDL
function of the hepatic LDL receptor), results in high levels of LDL in level, increased blood pressure, and fewer changes in hormones called
the bloodstream. The term LDL actually describes several types of LDL adipokines (leptin and adiponectin).68,69 A sedentary lifestyle not only
molecules of which the “small dense” LDL particles are the most athero- increases the risk of obesity but also has an independent effect on
genic. LDL migration into the vessel wall, oxidation, and phagocytosis increasing CAD risk. Physical activity and weight loss offer substantial
by macrophages are key steps in the pathogenesis of atherosclerosis (see reductions in risk factors for CAD.
Figure 23-8). LDL also plays a role in endothelial injury, inflammation, Nontraditional risk factors. Nontraditional, or novel, risk factors
and immune responses that have been identified as being important for CAD include (1) increased serum markers for inflammation and
in atherogenesis. Aggressive reduction of LDL levels by implement- thrombosis, (2) hyperhomocysteinemia, (3) adipokines, and (4) infec-
ing a reduced fat diet and using cholesterol-lowering drugs such as the tion. The amount of risk conferred by these relatively newly identified
statins is associated with a decrease in risk for CAD.61,62 factors is still being explored.
Low levels of HDL cholesterol also are a strong indicator of coronary Markers of inflammation and thrombosis. Of the numerous
risk, and high levels of HDL may be more protective for the develop- markers of inflammation that have been linked to an increase in CAD
ment of atherosclerosis than low levels of LDL.63,64 HDL is responsible risk (hs-CRP, fibrinogen, protein C, plasminogen activator inhibitor),
for “reverse cholesterol transport,” which returns excess cholesterol the relationship between serum levels of hs-CRP and CAD has been
from the tissues to the liver for processing or elimination in the bile. explored in the greatest depth. Highly-sensitive C-reactive protein
HDL also participates in endothelial repair and decreases thrombo- (hs-CRP) is a protein mostly synthesized in the liver and is used as
sis. It can be fractionated into several particle densities (HDL-2 and an indirect measure of atherosclerotic plaque–related inflammation.
HDL-3) that have different effects on vascular function. Exercise, An elevated serum level of hs-CRP is correlated with an increased risk
weight loss, fish oil consumption, and moderate alcohol use result in for coronary events, but is a nonspecific measure of inflammation and
modest increases in HDL level. Niacin, fibrates, and statins are drugs may indicate the presence of other inflammatory conditions. The pri-
that can cause modest increases in HDL level. Newer drugs aimed at mary use of hs-CRP is as an aid to decision-making about pharmaco-
directly increasing HDL activity include recombinant apolipoprotein logic interventions for individuals with other risk factors for coronary
A-I (ApoA-I) mimetics, thiazolidinediones, and cholesterol transfer- disease.70 Other markers of inflammation associated with CAD include
ase protein inhibitors, although the safety of these medications is still the erythrocyte sedimentation rate and concentrations of von Wil-
being evaluated.65,66 Other lipoproteins associated with increased car- lebrand factor, interleukin-6, interleukin-18, tumor necrosis factor,
diovascular risk include elevated levels of serum VLDLs (triglycerides) fibrinogen, and CD 40 ligand (see Health Alert: Inflammatory Markers
and increased lipoprotein(a) levels. Triglycerides are associated with for Cardiovascular Risk).71
an increased risk for CAD, especially in combination with other risk Hyperhomocysteinemia. Hyperhomocysteinemia occurs
factors such as diabetes. Lipoprotein(a) (Lp[a]) is a genetically deter- because of a genetic lack of the enzyme that metabolizes homocysteine
mined molecular complex between LDL and a serum glycoprotein (an amino acid) or because of a nutritional deficiency of folate, cobala-
called apolipoprotein A and has been shown to be an important risk min (vitamin B12), or pyridoxine (vitamin B6). It has been identified as
factor for atherosclerosis, especially in women.67 a risk factor for CAD, although the effectiveness of treatments aimed
Hypertension. Hypertension is responsible for a twofold to three- at reducing homocysteine levels to lessen CAD has not been shown.
fold increased risk of atherosclerotic cardiovascular disease. It contrib- Therefore the significance of hyperhomocysteinemia as a risk factor for
utes to endothelial injury, a key step in atherogenesis (see p. 594). It CAD and stroke continues to be explored.72
also can cause myocardial hypertrophy, which increases myocardial Adipokines. Adipokines are a group of hormones released from
demand for coronary flow. Overactivity of the SNS and RAAS com- adipose cells. The two that are the most studied are leptin and adipo-
monly found in hypertension also contributes to the genesis of CAD. nectin. Obesity causes increased levels of leptin, which is implicated
Cigarette smoking. Both direct and passive (environmental) smok- in hypertension and diabetes.69 Obesity also causes decreased levels of
ing increase the risk of CAD. Nicotine stimulates the release of cat- adiponectin, which is a hormone that functions to protect the vascular
echolamines (epinephrine and norepinephrine), which increase heart endothelium and is anti-inflammatory.73,74 A less well-studied adipo-
rate and peripheral vascular constriction. As a result, blood pressure kine is called resistin, which has been linked to inflammation in endo-
increases, as do cardiac workload and oxygen demand. Cigarette thelial cells. Weight loss, exercise, and healthy diet improve adipokine
smoking is associated with an increase in LDL level, a decrease in HDL levels.
level, and generation of toxic oxygen radicals, which contribute to Infection. Infection may play a role in atherogenesis and CAD risk,
vessel inflammation and thrombosis. The risk of CAD increases with although cause and effect has not been proved. Several microorgan-
heavy smoking and decreases when smoking is stopped. isms, especially Chlamydia pneumoniae and Helicobacter pylori, are
600 CHAPTER 23  Alterations of Cardiovascular Function

Imbalance between coronary

supply and myocardial
demand
Sudden Myocardial O2 deficit
death

Impaired cardiac Less than 20 min: Greater than 20 min:

pumping ischemic attack myocardial infarction

Heart
failure Abnormal response to
Dysrhythmias
electrical impulses

Lack of response to
Failure to contract electrical impulses
FIGURE 23-11  Cycle of Ischemic Events.

often present in atherosclerotic lesions. Serum antibodies to micro-

HEALTH ALERT organisms have been linked to an increased risk for CAD as has the
Inflammatory Markers for Cardiovascular Risk presence of periodontal disease. Unfortunately, the use of antibiotics
for the prevention and treatment of CAD has not yielded consistently
New Serum Markers of Cardiovascular Risk
positive results.
A number of serum markers of inflammation have been found to be excel-
lent predictors of cardiovascular risk, especially highly-sensitive C-reactive Myocardial Ischemia
protein (hs-CRP). Other inflammatory markers determined to be predictive of
PATHOPHYSIOLOGY  The coronary arteries normally supply blood
cardiovascular risk include fibrinogen, erythrocyte sedimentation rate, von
flow sufficient to meet the demands of the myocardium as it labors
Willebrand factor, interleukin-6, interleukin-1, tumor necrosis factor-alpha,
under varying workloads. Oxygen is extracted from these vessels with
uric acid, adhesion molecules (selectins, intercellular adhesion molecules
maximal efficiency. If demand increases, healthy coronary arteries can
[ICAMs]), and serum amyloid A. hs-CRP is made by the liver in response to
dilate to increase the flow of oxygenated blood to the myocardium.
inflammatory stimuli and has been demonstrated convincingly to be a good
Narrowing of a major coronary artery by more than 50% impairs
predictor of coronary artery disease. However, several problems remain
blood flow enough to hamper cellular metabolism when myocardial
in determining its use in clinical practice. hs-CRP must be measured by a
demand increases.
high-sensitivity technique and it is a nonspecific marker of inflammation. It
Myocardial ischemia develops if the flow or oxygen content of
can, therefore, be elevated in many other inflammatory states and its use
coronary blood is insufficient to meet the metabolic demands of
for the diagnosis of CAD is limited to helping identify high-risk individu-
myocardial cells (Figure 23-11). Imbalances between coronary blood
als and for following disease progression in individuals with known coro-
supply and myocardial demand can result from a number of condi-
nary disease. It should not be used to screen the general population. The
tions. The most common cause of decreased coronary blood flow
HMG-CoA reductase drugs (statins) reduce hs-CRP levels. Another group of
and resultant myocardial ischemia is the formation of atherosclerotic
serum markers of cardiovascular risk are the adipokines, especially adipo-
plaques in the coronary circulation. As the plaque increases in size, it
nectin. This hormone is secreted by fat cells and has anti-inflammatory and
may partially occlude the vessel lumina, thus limiting coronary flow
antiatherogenic properties. It is decreased in obesity and low levels have
and causing ischemia especially during exercise. Some plaques are
been linked to coronary artery disease. Other adipokines being evaluated
“unstable,” meaning they are prone to ulceration or rupture. When
for their association with atherosclerotic disease include leptin, resistin,
this ulceration or rupture occurs, underlying tissues of the vessel wall
visfatin, apelin, vaspin, and hepcidin. Brain natriuretic peptide also is linked
are exposed, resulting in platelet adhesion and thrombus formation
with increased cardiovascular risk, especially in those with known coronary
(see Figures 23-9 and 23-17). Thrombus formation can suddenly stop
artery disease. A better understanding of the role of these serum biomark-
blood supply to the heart muscle, resulting in acute myocardial isch-
ers in cardiovascular disease may lead to earlier detection and more effec-
emia, and if the vessel obstruction cannot be reversed rapidly, isch-
tive therapies.
emia will progress to infarction. Myocardial ischemia also can result
Data from Corrado E et al: J Atheroscler Thromb 17(1):1–11, 2010; from other causes of decreased blood and oxygen delivery to the
Ferri C et al: Curr Pharm Des 13(16):1631–1645, 2007; Menzaghi C myocardium, such as coronary spasm, hypotension, dysrhythmias,
et al: Diabetes 56(5):1198–1209, 2007; Palazzuoli A et al: Minerva and decreased oxygen-carrying capacity of the blood (e.g., anemia,
Cardioangiol 55(4):491–496, 2007; Selcuk MT et al: Coron Artery hypoxemia). Common causes of increased myocardial demand for
Dis 19(2):79–84, 2008; Singh SK et al: Ann Med 40:110–120, 2008; blood include tachycardia, exercise, hypertension (hypertrophy), and
­Steffens S et al: Circulation Res 102(2):140–142, 2008; Virani SS et al: valvular disease.
Curr Atheroscler Rep 10(2):164–170, 2008.
Myocardial cells become ischemic within 10 seconds of coronary
occlusion, thus hampering pump function and depriving the myocar-
dium of a glucose source necessary for aerobic metabolism. Anaerobic
 CHAPTER 23  Alterations of Cardiovascular Function 601

A B C
FIGURE 23-12  Angiogram of Coronary Arteries. A, Baseline. B, Transient total occlusion of left
anterior descending branch of the left coronary artery after mental stress. C, After nitrates and nifedi­
pine, artery reopened to same diameter as baseline. (Modified from Stern S, editor: Silent myocardial
ischemia, St Louis, 1998, Mosby.)

processes take over, and lactic acid accumulates. After several minutes, activity.77 Other causes include altered calcium channel function
the heart cells lose the ability to contract and cardiac output decreases. in arterial smooth muscle or impaired production or release of
Cardiac cells remain viable for approximately 20 minutes under isch- inflammatory mediators, such as serotonin, histamine, endothelin,
emic conditions. If blood flow is restored, aerobic metabolism resumes, or thromboxane. Serum markers of inflammation, such as CRP
contractility is restored, and cellular repair begins. If perfusion is not and interleukin-6 (IL-6), are elevated in individuals with this form
restored, then myocardial infarction occurs (see Figure 23-11). of angina.75 Prinzmetal angina is usually a benign condition, but
can occasionally cause serious dysrhythmias.
CLINICAL MANIFESTATIONS  Individuals with reversible myo- 3. Silent ischemia and mental stress–induced ischemia. Myocar-
cardial ischemia present clinically in several ways. Chronic coronary dial ischemia may not cause detectable symptoms such as angina.
obstruction results in recurrent predictable chest pain called stable Ischemia can be totally asymptomatic and referred to as silent
angina. Abnormal vasospasm of coronary vessels results in unpredict- ischemia, or individuals may complain of fatigue, dyspnea, or a
able chest pain called Prinzmetal angina. Myocardial ischemia that feeling of unease.78 Silent ischemia and atypical symptoms are
does not cause detectable symptoms is called silent ischemia. more common in women (see Health Alert: Women and Coronary
1. Stable angina pectoris. Angina is chest pain caused by myocardial Artery Disease). Some individuals only have silent ischemia, and
ischemia. Stable angina is caused by gradual luminal narrowing and episodes of silent ischemia are common in individuals who also
hardening of the arterial walls, so that affected vessels cannot dilate experience angina. One proposed mechanism for the absence of
in response to increased myocardial demand associated with physi- angina in silent myocardial ischemia is the presence of a global or
cal exertion or emotional stress. With rest, blood flow is restored regional abnormality in left ventricular sympathetic afferent inner-
and no necrosis of myocardial cells results. Angina pectoris is typi- vation. The most common cause of autonomic dysfunction leading
cally experienced as transient substernal chest discomfort, ranging to silent ischemia is diabetes mellitus. Other causes include surgi-
from a sensation of heaviness or pressure to moderately severe pain. cal denervation during coronary artery bypass grafting (CABG) or
Individuals often describe the sensation by clenching a fist over the cardiac transplantation, or following ischemic local nerve injury by
left sternal border. The discomfort may be mistaken for indigestion. myocardial infarction.
The pain is caused by the buildup of lactic acid or abnormal stretch- Also of interest is silent ischemia occurring in some individu-
ing of the ischemic myocardium that irritates myocardial nerve als during mental stress (Figures 23-12, 23-13, and 23-14). Chronic
fibers. These afferent sympathetic fibers enter the spinal cord from stress has been linked to an increase in the number of inflammatory
levels C3 to T4, accounting for a variety of locations and radiation cytokines and a hypercoagulable state that may contribute to acute
patterns of anginal pain. Discomfort may radiate to the neck, lower ischemic events.79 Silent ischemia can be detected by stress radionucle-
jaw, left arm, and left shoulder, or occasionally to the back or down otide imaging. Detection and management of silent ischemia caused
the right arm. Pallor, diaphoresis, and dyspnea may be associated by coronary disease is important because it is an indicator of increased
with the pain.75 The pain is usually relieved by rest and nitrates; lack risk for serious cardiovascular events80 (see Health Alert: Women and
of relief indicates an individual may be developing infarction. Coronary Artery Disease).
Myocardial ischemia in women may not present with typical
anginal pain. Common symptoms in women include atypical chest EVALUATION AND TREATMENT  Many individuals with reversible
pain, palpitations, sense of unease, and severe fatigue. Similarly, in myocardial ischemia will have a normal physical examination between
individuals with autonomic nervous system dysfunction, such as events. Physical examination of those experiencing myocardial isch-
older adults or those with diabetes, angina may be mild, atypical, emia may disclose rapid pulse rate or extra heart sounds (gallops or
or silent.76 murmurs), and pulmonary congestion indicating impaired left ven-
2. Prinzmetal angina. Prinzmetal angina (also called variant angina) tricular function. The presence of xanthelasmas (small fat deposits)
is chest pain attributable to transient ischemia of the myocardium around the eyelids or arcus senilis of the eyes (a yellow lipid ring
that occurs unpredictably and often at rest. Pain is caused by vaso- around the cornea) suggests dyslipidemia and possible atherosclero-
spasm of one or more major coronary arteries with or without asso- sis. The presence of peripheral or carotid artery bruits suggests prob-
ciated atherosclerosis. The pain often occurs at night during rapid able atherosclerotic disease and increases the likelihood that CAD is
eye movement sleep and may have a cyclic pattern of occurrence. present.
The angina may result from decreased vagal activity, hyperactiv- Electrocardiography is a critical tool for the diagnosis of myocardial
ity of the sympathetic nervous system, or decreased nitric oxide ischemia. Because many individuals have normal electrocardiograms
602 CHAPTER 23  Alterations of Cardiovascular Function

Mental stress
HEALTH ALERT
Women and Coronary Artery Disease
Women and Heart Disease
More women in the United States die from coronary artery disease (CAD) and
stroke than from all cancers combined. Women have a higher rate of CAD-
related mortality than men, in part because of underdiagnosis and treatment.
Nearly two thirds of women who die from CAD had no prior warning symp-
toms. When women do have symptoms, they are often different from those
classically seen in men. Common symptoms in women may include atypical
chest pain, palpitations, sense of unease, weakness, mild discomfort in the
back, and severe or sudden fatigue. In addition, women may not have angina.
Women with CAD tend to have more diffuse disease, endothelial dysfunction,
Ischemia usually
Coronary and microvascular disease than men, which may cause fewer and less recog-
painless
vasoconstriction nizable symptoms. These differences also may account for the observation
that women tend to be less responsive to standard therapies for CAD.
Women have a higher prevalence of avoidable risk factors than men, espe-
cially elevated cholesterol level and physical inactivity, and women are less
likely to receive counseling about nutrition, exercise, and weight control.
Lifestyle changes (eating a healthy diet, exercising, avoiding smoking) are the
most effective interventions to reduce cardiovascular risk. CAD risk rises dra-
matically after menopause. Although many studies suggest that endogenous
estrogen is protective of vascular function, several large prospective studies
have determined that estrogen replacement regimens do not reduce the risk
Myocardial of CAD in postmenopausal women. The role of HMG-CoA reductase drugs
ischemia (statins) in the primary prevention of CAD, especially in women, remains a
topic of considerable debate. Several recent studies suggest that statins are
not effective in primary prevention of CAD and are associated with potential
serious side effects, including muscle pain and liver damage, especially in
women. Their role in the management of dyslipidemia in women who have
documented CAD (secondary prevention) is less controversial but the risks ver-
Electrocardiogram
sus the benefits of statin therapy must be considered for all women.

S-T shift Data from Bugiardini R et al: Gender bias in acute coronary syndromes,
Curr Vasc Pharmacol 8(2):276–284, 2010; Bukkapatnam RN, Gabler
NB, Lewis WR: Statins for primary prevention of cardiovascular mortal-
ity in women: a systematic review and meta-analysis, Prev Cardiol
13(2):84–90, 2010; Collins P: HDL-C in post-menopausal women:
an important therapeutic target, Int J Cardiol 124(3):275–282, 2008;
Myocardial Leuzzi C, Modena MG: Coronary artery disease: clinical presenta-
Normal ischemia tion, diagnosis and prognosis in women, Nutr Metab Cardiovasc Dis
FIGURE 23-13  Ischemic Cost of Aggravation. Linkages among 20(6):426–435, 2010; Miracle VA: Coronary artery disease in women:
daily mental and emotional stimuli, brain activity, and coronary and the myth still exists, unfortunately, Dimens Crit Care Nurs 29(5):
myocardial physiology. (Modified from Papodemetrion V et al: Am 215–221, 2010; Szerlip M, Grines CL: Sex differences in response to
Heart J 132:1299, 1996.) treatments for chronic coronary artery disease, Rev Cardiovasc Med
10(suppl 2):S14–S23, 2009.

when there is no pain, diagnosis requires that electrocardiography be indicator of myocardial ischemia. Currently, the diagnostic modality of
performed during an attack of angina or during exercise stress test- choice for the diagnosis of myocardial ischemia is single photon emis-
ing. The ST segment and the T wave segments of the electrocardio- sion computerized tomography (SPECT), which is effective at identify-
gram correlate with ventricular contraction and relaxation (see Figure ing ischemia and estimating coronary risk. Radioisotope imaging with
22-10). Transient ST segment depression and T wave inversion are thallium-201 and stress echocardiography are other techniques used
characteristic signs of subendocardial ischemia. ST elevation, indica- to diagnose CAD. Unfortunately, although all of these tests are help-
tive of transmural ischemia, is seen in individuals with Prinzmetal ful in documenting coronary obstruction, they cannot detect the pres-
angina, but is more common in transmural myocardial infarction ence of vulnerable plaques, which are the cause of the majority of acute
(Figure 23-15). The electrocardiogram also can identify the coronary coronary syndromes. Noninvasive tests for evaluating coronary ath-
artery that is involved. erosclerotic lesions include measurement of coronary artery calcium
Exercise stress testing is indicated to detect ischemic changes in concentration by computed tomography (CT), noninvasive coronary
asymptomatic individuals with multiple risk factors for coronary angiography using electron beam CT, protein-weighted magnetic res-
disease, such as diabetes and dyslipidemia, and for older individuals onance imaging, and intravascular ultrasound; however, the sensitivity
who plan to start a vigorous exercise regimen. Stress testing is made and specificity of these tests vary widely and are not recommended for
more sensitive when radioisotope imaging is added to the ECG as an routine evaluation of CAD.75 Coronary angiography helps determine
 CHAPTER 23  Alterations of Cardiovascular Function 603

FIGURE 23-14  Pathophysiologic Model of the Effects of Acute Stress as a Trigger of Cardiac Clin-
ical Events. Acting via the central and autonomic nervous systems, stress can produce a cascade of
physiologic responses that may lead to myocardial ischemia, especially in persons with coronary artery
disease; potentially fatal dysrhythmia; plaque rupture; or coronary thrombosis. LV, Left ventricular;
MI, myocardial infarction; VF, ventricular fibrillation; VT, ventricular tachycardia. (From Krantz DS et al:
Mental stress as a trigger of myocardial ischemia and infarction. In Deedwania PC, Tofler GH, editors:
Triggers and timing of cardiac events, ed 2, London, 1996, Saunders.)

Normal ECG deflections R

P T

QS

Atrial Ventricular
depolarization repolarization
A Ventricular depolarization
ST segment depression T wave inversion ST segment elevation
R R R

P T P T P

Q Q S Q

S
B
FIGURE 23-15  Electrocardiogram (ECG) and Ischemia. A, Normal ECG. B, Electrocardiographic
alterations associated with ischemia.

the anatomic extent of CAD, but the procedure is expensive and carries vasoconstriction, reducing plaque growth and rupture, and prevent-
some risk. It is used primarily to determine whether possible percu- ing clotting. Myocardial oxygen demand is reduced by manipulation
taneous coronary intervention (PCI) or coronary artery bypass graft of blood pressure, heart rate, contractility, and left ventricular vol-
(CABG) surgery is warranted for individuals whose noninvasive stud- ume. Several classes of drugs are useful for increasing coronary flow
ies suggest severe disease. and decreasing myocardial demand, especially nitrates, beta-blockers,
The primary aims of therapy for myocardial ischemia and angina and calcium channel blockers.81,82 Ranolazine represents a relatively
are to increase coronary blood flow and to reduce myocardial oxy- new class of antianginal drugs known as sodium ion channel inhibi-
gen consumption. Coronary blood flow is improved by reversing tors and has been found to improve exercise tolerance, lessen anginal
604 CHAPTER 23  Alterations of Cardiovascular Function

symptoms, and reduce the need for nitrates in many individuals with spectroscopy.51,85 Medications such as statins, angiotensin-converting
chronic stable angina.83 enzyme inhibitors, and beta-blockers can be used to help stabilize
Percutaneous coronary intervention (PCI) is a procedure whereby plaques and prevent rupture.51
stenotic (narrowed) coronary vessels are dilated with a catheter. Several Unstable angina. Unstable angina is a form of acute coronary syn-
different types of catheters can be used to open the blocked vessel. PCI drome that results from reversible myocardial ischemia. It is important
most often is used to treat single-vessel disease, but it can be effective
with multiple-vessel disease or restenosis of a coronary artery bypass
graft.82 Restenosis of the artery is the major complication of the proce- Atherosclerotic plaque partially obstructs
coronary blood flow
dure; however, placement of a coronary stent can reduce this risk. (See
Box 23-2 for PCI-related myocardial infarction.) Pharmacologic treat-
ment with antithrombotics, such as aspirin, clopidogrel, or glycoprotein
Stable plaque Unstable plaque with ulceration
IIb/IIIa receptor antagonists, after stenting also can improve outcomes.
or rupture and thrombosis
Severe CAD can be surgically treated by a coronary artery bypass
graft (CABG), usually using the saphenous vein from the lower leg.
In selected individuals, a modified CABG procedure called mini- Stable angina Acute coronary syndromes
mally invasive direct coronary artery bypass (MIDCAB) can be used
with much less surgical morbidity and more rapid recovery. In those
individuals with refractory angina not amenable to standard bypass Transient Sustained
surgery, new techniques, such as laser revascularization, enhanced ischemia ischemia
external counterpulsation, and myocardial gene therapy, are providing
promising results.75,84
Unstable angina Myocardial
infarction
4 QUICK CHECK 23-5
Stunned myocytes
1. Define atherosclerosis, and briefly describe how it develops.
2. Why do hypertension and increased cholesterol level increase the likeli- Myocardial
Hibernating myocytes inflammation
hood of developing coronary artery disease?
and necrosis
3. Discuss the relationships among myocardial ischemia, angina, and silent
ischemia. Myocardial remodeling

FIGURE 23-16  Pathophysiology of Acute Coronary Syndromes.

The atherosclerotic process can lead to stable plaque formation and
Acute Coronary Syndromes stable angina or can result in unstable plaques that are prone to
The process of atherosclerotic plaque progression can be gradual. How- rupture and thrombus. Thrombus formation on a ruptured plaque
ever, when there is sudden coronary obstruction caused by thrombus that disperses in less than 20 minutes leads to transient ischemia
formation over a ruptured or ulcerated atherosclerotic plaque, the and unstable angina. If the vessel obstruction is sustained, myocar-
dial infarction with inflammation and necrosis of the myocardium
acute coronary syndromes result (Figure 23-16). Unstable angina
results. In addition, myocardial infarction is associated with other
is the result of reversible myocardial ischemia and is a harbinger of
structural and functional changes, including myocyte stunning and
impending infarction. Myocardial infarction (MI) results when there hibernation and myocardial remodeling (see Figure 23-35).
is prolonged ischemia causing irreversible damage to the heart muscle.
MI can be further subdivided into non-ST elevation MI (non-STEMI)
and ST elevation MI (STEMI). Sudden cardiac death can occur as a Atherosclerotic plaque
result of any of the acute coronary syndromes. with a lipid-rich core
and a thin fibrous cap
An atherosclerotic plaque that is prone to rupture is called “unsta-
ble” and has a core that is especially rich in deposited oxidized LDL and Shear forces, inflammation,
a thin fibrous cap51 (Figure 23-17). These unstable plaques may not apoptosis, macrophage-derived
extend into the lumen of the vessel and may be clinically silent until degradative enzymes
they rupture. Plaque disruption (ulceration or rupture) occurs because Rupture of plaque
of the effects of shear forces, inflammation with release of multiple Increased inflammation with
inflammatory mediators, secretion of macrophage-derived degradative release of multiple cytokines,
enzymes, and apoptosis of cells at the edges of the lesions. Exposure of platelet activation and
adherence, production of
the plaque substrate activates the clotting cascade. In addition, platelet thrombin and vasoconstrictors
activation results in the release of coagulants and exposure of plate- Thrombus formation over lesion
let glycoprotein IIb/IIIa surface receptors, resulting in further plate- plus vasoconstriction of vessel
let aggregation and adherence. The resulting thrombus can form very
quickly (Figure 23-18, A). Vessel obstruction is further exacerbated by Acute decrease in coronary
the release of vasoconstrictors, such as thromboxane A2 and endothe- blood flow
lin. The thrombus may shatter before permanent myocyte damage has
occurred (unstable angina) or it may cause prolonged ischemia with Unstable angina or
myocardial infarction
infarction of the heart muscle (myocardial infarction) (Figure 23-18,
B). Diagnostic tests aimed at identifying unstable plaques before they FIGURE 23-17  Pathogenesis of Unstable Plaques and Throm-
rupture include intravascular ultrasound or MRI, angioscopy, and bus Formation.
 CHAPTER 23  Alterations of Cardiovascular Function 605

may be used. Anticoagulants (such as low-molecular-weight heparin)

BOX 23-1 THREE PRINCIPAL
or direct thrombin inhibitors (e.g., fondaparinux) also can be given.
PRESENTATIONS OF UNSTABLE Individuals with refractory angina and those with electrical or hemo-
ANGINA dynamic instability require immediate intervention with percutane-
1. Rest angina—Angina occurring at rest and prolonged, usually ous coronary intervention (PCI) or coronary artery bypass grafting
>20 minutes (CABG).
2. New-onset angina—New-onset angina of at least CCS Class III severity Myocardial infarction. When coronary blood flow is interrupted
3. Increasing angina—Previously diagnosed angina that has become distinctly for an extended period of time, myocyte necrosis occurs. This results
more frequent, longer in duration, or lower in threshold (i.e., increased by ≥1 in myocardial infarction (MI). Plaque progression, disruption, and
CCS class to at least CCS Class III severity) subsequent clot formation are the same for myocardial infarction as
they are for unstable angina (see Figures 23-16, 23-17, and 23-18). In
From Anderson J et al: J Am Coll Cardiol 50:e1–e157, 2007. Originally this case, however, the thrombus is less labile and occludes the vessel
adapted from Braunwald E: Circulation 80:410–414, 1989.
for a prolonged period, such that myocardial ischemia progresses to
CCS, Canadian Cardiovascular Society.
myocyte necrosis and death. Pathologically, there are two major types
of myocardial infarction: subendocardial infarction and transmural
to recognize this syndrome because it signals that the atherosclerotic infarction. Clinically, however, myocardial infarction is categorized as
plaque has become complicated, and infarction may soon follow. non-ST segment elevation myocardial infarction (non-STEMI) or ST
Unstable angina occurs when a fairly small fissuring or superficial segment elevation MI (STEMI).
erosion of the plaque leads to transient episodes of thrombotic ves- If the thrombus disintegrates before complete distal tissue necrosis
sel occlusion and vasoconstriction at the site of plaque damage. This has occurred, the infarction will involve only the myocardium directly
thrombus is labile and occludes the vessel for no more than 10 to 20 beneath the endocardium (subendocardial MI). This infarction will usu-
minutes, with return of perfusion before significant myocardial necro- ally present with ST segment depression and T wave inversion without
sis occurs. Unstable angina presents as new-onset angina, angina that Q waves; therefore it is termed non-STEMI. It is especially important
is occurring at rest, or angina that is increasing in severity or frequency to recognize this form of acute coronary syndrome because recurrent
(Box 23-1). Individuals may experience increased dyspnea, diaphore- clot formation on the disrupted atherosclerotic plaque is likely. If the
sis, and anxiety as the angina worsens. Physical examination may reveal thrombus lodges permanently in the vessel, the infarction will extend
evidence of ischemic myocardial dysfunction such as tachycardia, or through the myocardium all the way from endocardium to epicardium,
pulmonary congestion. The ECG most commonly shows ST segment resulting in severe cardiac dysfunction (transmural MI). Transmural
depression and T wave inversion during pain that resolve as the pain myocardial infarction will usually result in marked elevations in the
is relieved. The concentrations of serum cardiac biomarkers (tropo- ST segments on ECG and these individuals are categorized as having ST
nins, creatine phosphokinase-myocardial bound [CPK-MB], and lac- segment elevation MI, or STEMI. Clinically, it is important to identify
tate dehydrogenase [LDH1]) remain normal.86 Approximately 20% of those individuals with STEMI because they are at highest risk for serious
persons with unstable angina will progress to myocardial infarction or complications and should receive definitive intervention without delay.
death. Management of unstable angina requires immediate hospital-
ization with administration of oxygen, aspirin (if not contraindicated), PATHOPHYSIOLOGY
nitrates, and morphine if pain is still present.87 Additional antithrom- Cellular injury. After 8 to 10 seconds of decreased blood flow, the
botic therapy with clopidogrel or glycoprotein IIb/IIIa platelet receptor affected myocardium becomes cyanotic and cooler. Myocardial oxy-
antagonists may be indicated. Beta-blockers and ACE inhibitors also gen reserves are used quickly (within about 8 seconds) after complete

A B
FIGURE 23-18  Plaque Disruption and Myocardial Infarction. A, Plaque disruption. The cap of the
lipid-rich plaque has become torn with the formation of a thrombus, mostly inside the plaque. B, Myo-
cardial infarction. This infarct is 6 days old. The center is yellow and necrotic with a hemorrhagic red
rim. The responsible arterial occlusion is probably in the right coronary artery. The infarct is on the pos-
terior wall. (From Damjanov I, Linder J, editors: Anderson’s pathology, ed 10, St Louis, 1996, Mosby.)
606 CHAPTER 23  Alterations of Cardiovascular Function

cessation of coronary flow. Glycogen stores decrease as anaerobic membranes into the interstitial spaces. The lymphatics absorb the
metabolism begins. Unfortunately, glycolysis can supply only 65% to enzymes and transport them into the bloodstream, where they can be
70% of the total myocardial energy requirement and produces much detected by serologic tests.
less adenosine triphosphate (ATP) than aerobic processes. Hydrogen Structural and functional changes. Myocardial infarction results
ions and lactic acid accumulate. Because myocardial tissues have poor in both structural and functional changes of cardiac tissues (Figure
buffering capabilities and myocardial cells are sensitive to low cellular 23-19). Gross tissue changes at the area of infarction may not become
pH, accumulation of these products further compromises the myo- apparent for several hours, despite almost immediate onset (within
cardium. Acidosis may make the myocardium more vulnerable to the 30 to 60 seconds) of electrocardiographic changes. Cardiac tissue sur-
damaging effects of lysosomal enzymes and may suppress impulse con- rounding the area of infarction also undergoes changes that can be
duction and contractile function, thereby leading to heart failure. categorized into (1) myocardial stunning—a temporary loss of con-
Oxygen deprivation also is accompanied by electrolyte disturbances, tractile function that persists for hours to days after perfusion has been
specifically the loss of potassium, calcium, and magnesium from cells. restored;91 (2) hibernating myocardium—tissue that is persistently
Myocardial cells deprived of necessary oxygen and nutrients lose con- ischemic and undergoes metabolic adaptation to prolong myocyte
tractility, thereby diminishing the pumping ability of the heart. Ischemia survival until perfusion can be restored;92 and (3) myocardial remod-
causes the myocardial cells to release catecholamines, predisposing the eling—a process mediated by angiotensin II, aldosterone, catechol-
individual to serious imbalances of sympathetic and parasympathetic amines, adenosine, and inflammatory cytokines that causes myocyte
function, irregular heartbeats (dysrhythmia), and heart failure. Catechol- hypertrophy and loss of contractile function in the areas of the heart
amines mediate the release of glycogen, glucose, and stored fat from body distant from the site of infarction.89 All of these changes can be limited
cells. Therefore plasma concentrations of free fatty acids and glycerol rise through rapid restoration of coronary flow and the use of ACE inhibi-
within 1 hour after the onset of acute myocardial infarction. Excessive tors or ARBs and beta-blockers after MI.
levels of free fatty acids can have a harmful detergent effect on cell mem- The severity of functional impairment depends on the size of the
branes. Norepinephrine elevates blood glucose levels through stimula- lesion and the site of infarction. Functional changes can include (1)
tion of liver and skeletal muscle cells and suppresses pancreatic beta-cell decreased cardiac contractility with abnormal wall motion, (2) altered
activity, which reduces insulin secretion and elevates blood glucose left ventricular compliance, (3) decreased stroke volume, (4) decreased
further. Hyperglycemia is noted approximately 72 hours after an acute ejection fraction, (5) increased left ventricular end-diastolic pressure,
myocardial infarction and is associated with an increased risk of death; and (6) sinoatrial node malfunction. Life-threatening dysrhythmias
therefore careful glucose monitoring and control after MI is essential.88 and heart failure often follow myocardial infarction.
Angiotensin II is released during myocardial ischemia and con- With infarction, ventricular function is abnormal and the ejection
tributes to the pathogenesis of myocardial infarction in several ways. fraction falls, resulting in increases in ventricular end-diastolic volume
First, it results in the systemic effects of peripheral vasoconstriction (VEDV). If the coronary obstruction involves the perfusion to the left
and fluid retention, which increase myocardial workload. Second, it ventricle, pulmonary venous congestion ensues; if the right ventricle is
is a growth factor for vascular smooth muscle cells, myocytes, and ischemic, increases in systemic venous pressures occur.
cardiac fibroblasts resulting in structural changes in the myocardium Repair. Myocardial infarction causes a severe inflammatory
called “remodeling.”89 Finally, angiotensin II promotes catecholamine response that ends with wound repair (see Chapter 5). Damaged cells
release and causes coronary artery spasm. undergo degradation, fibroblasts proliferate, and scar tissue is synthe-
Cellular death. Cardiac cells can withstand ischemic conditions sized.93 Many cell types, hormones, and nutrient substrates must be
for about 20 minutes before irreversible hypoxic injury causes cellular available for optimal healing to proceed. Within 24 hours, leukocytes
death (apoptosis) and tissue necrosis.90 This results in the release of infiltrate the necrotic area, and proteolytic enzymes from scavenger
intracellular enzymes such as creatine phosphokinase MB (CPK-MB) neutrophils degrade necrotic tissue. The collagen matrix that is depos-
and myocyte proteins such as the troponins through the damaged cell ited is initially weak, mushy, and vulnerable to reinjury. Unfortunately,

A B
FIGURE 23-19  Myocardial Infarction. A, Local infarct confined to one region. B, Massive large infarct
caused by occlusion of three coronary arteries. (From Damjanov I, Linder J, editors: Anderson’s pathol-
ogy, ed 10, St Louis, 1996, Mosby.)
 CHAPTER 23  Alterations of Cardiovascular Function 607

it is at this time in the recovery period (10 to 14 days after infarction) Complications. The number and severity of postinfarction com-
that individuals feel more like increasing activities and may stress the plications depend on the location and extent of necrosis, the individ-
newly formed scar tissue. After 6 weeks, the necrotic area is completely ual’s physiologic condition before the infarction, and the availability
replaced by scar tissue, which is strong but cannot contract and relax of swift therapeutic intervention. Sudden cardiac death can occur in
like healthy myocardial tissue. individuals with myocardial ischemia even if infarction is absent or
minimal and is a multifactorial problem. Risk factors for sudden death
CLINICAL MANIFESTATIONS  The first symptom of acute myocar- are related to three factors: ischemia, left ventricular dysfunction, and
dial infarction is usually sudden, severe chest pain. The pain is similar electrical instability. These factors interact with each other (Figure
to that of angina pectoris but more severe and prolonged. It may be 23-20). Table 23-5 lists the most common complications.
described as heavy and crushing, such as a “truck sitting on my chest.”
Radiation to the neck, jaw, back, shoulder, or left arm is common. EVALUATION AND TREATMENT  The diagnosis of acute myocardial
Some individuals, especially those who are elderly or have diabetes, infarction is made on the basis of history, physical examination, ECG,
experience no pain, thereby having a “silent” infarction. Infarction and serial cardiac biomarker alterations (Box 23-2).94 The cardiac tro-
often simulates a sensation of unrelenting indigestion. Nausea and ponins (troponin I and troponin T) are the most specific indicators of
vomiting may occur because of reflex stimulation of vomiting centers MI.70 A transient rise in these plasma enzyme levels can confirm the
by pain fibers. Vasovagal reflexes from the area of the infarcted myo- occurrence of MI and indicate its severity. Other enzymes released by
cardium also may affect the gastrointestinal tract. myocardial cells include CPK-MB and LDH. These enzymes exist in
Various cardiovascular changes are found on physical examination: several different active molecular forms called isoenzymes, which are
1. The sympathetic nervous system is reflexively activated to com- present in different amounts within particular tissues. Blood is drawn
pensate, resulting in a temporary increase in heart rate and blood for troponin and isoenzyme determinations as soon as possible after
pressure. the onset of symptoms, and serial serum levels of these markers are
2. Abnormal extra heart sounds reflect left ventricular dysfunction. assessed for several days. If serologic tests show abnormally high lev-
3. Pulmonary findings of congestion including dullness to percussion els of troponin and isoenzymes, acute myocardial infarction probably
and inspiratory crackles at the lung bases can occur if the individual has occurred. CK-MB is less specific than troponins and may increase
develops heart failure. in individuals with certain other conditions (e.g., muscular dystro-
4. Peripheral vasoconstriction may cause the skin to become cool and phy, hypothermia, chronic obstructive pulmonary disease [COPD]
clammy. associated with left heart failure and pulmonary embolism, extensive

w
flo
at od
t r lo
e
ar b

w res

Ischemia
he ry

flo su
↑ na

d s
d ro

e
oo pr

*Hibernating myocardium —
an Co

bl c i
↓
es —

↓ ol
d st
rin s in

*Myocardial stunning —
—

a
s

an Di
cto ge

↑
fra n

ty
re Cha

Ischemic cascade —
—
ili

n —
ab

tio g
cit

uc in
nd low
Ex
↑

co S

— ↑ Ischemia Electrical Instability

Lo on

secondary
ss tra
c

to exercise
He

of cti
at on
m alte

ria
od ra

— ↓ Cardiac
St (he
l—
yn tio

ru a

output
a

ctu rt
m s

—
ic

ra lo
n
—

l p ck
↑ dr

— ↑ Diastolic
b
Dy ug

ro )
of
—

pressure and
bl
sr s
hy

em
↑ do

↓ blood flow
t
Re ste

hm
al

s
—

n
Io

ic
in n
ni

-a e

ef
—

Left Ventricular
fe
r
n
N

o
d

gi xis

ct
eu

ist

ot

Dysfunction
ur
ro

en
a
b
hu

sin
an
m

-
c
or

es
al
fa
cto

*See Figure 23-16.

rs

FIGURE 23-20  Three Interacting Factors Related to Sudden Cardiac Death. The three factors are
ischemia, left ventricular dysfunction, and electrical instability.
608 CHAPTER 23  Alterations of Cardiovascular Function

TABLE 23-5 COMPLICATIONS WITH MYOCARDIAL INFARCTIONS

TYPE CHARACTERISTICS
Dysrhythmias Disturbances of cardiac rhythm that affect 90% of persons with cardiac infarction
Caused by ischemia, hypoxia, autonomic nervous system imbalances, lactic acidosis, electrolyte a­ bnormalities,
alterations of impulse conduction pathways or conduction abnormalities, drug toxicity, or hemodynamic
abnormalities
Left ventricular failure (congestive heart failure) Characterized by pulmonary congestion, reduced myocardial contractility, and abnormal heart wall motion
Cardiogenic shock can develop
Inflammation of pericardium (pericarditis) Includes pericardial friction rubs
Often noted 2 to 3 days later and associated with anterior chest pain that worsens with respiratory effort
Dressler postinfarction syndrome Essentially a delayed form of pericarditis that occurs 1 week to several months after acute MI syndrome
Thought to be immunologic response to necrotic myocardium marked by pain, fever, friction rub, pleural
­effusion, and arthralgias
Organic brain syndrome Occurs if blood flow to brain is impaired secondary to MI
Transient ischemic attacks or cerebrovascular Occur if thromboemboli detach from clots that form in cardiac chambers or on cardiac valves
accident
Rupture of heart structures Caused by necrosis of tissue in or around papillary muscles
Affects papillary muscles of chordae tendineae cordis
Predisposing factors include thinning of wall, poor collateral flow, shearing effect of muscular contraction
against stiffened necrotic area, marked necrosis at terminal end of blood supply, and aging of myocardium
with laceration of myocardial microstructure
Rupture of wall of infarcted ventricle Can be caused by aneurysm formation when pressure becomes too great
Left ventricular aneurysm Late (month to years) complication of MI that can contribute to heart failure and thromboemboli
Infarctions around septal structures Occur in those structures that separate heart chambers and lead to septal rupture
Associated with audible, harsh cardiac murmurs; increased left ventricular end-diastolic pressure; and
­decreased systemic blood pressure
Systemic thromboembolism May disseminate from debris and clots that collect inside dilated aneurysmal sacs or from infarcted
­endocardium
Pulmonary thromboembolism Usually from deep venous thrombi of legs
Reduced incidence associated with early mobilization and prophylactic anticoagulation therapy
Sudden death Dysrhythmias frequently causative, particularly ventricular fibrillation
Risk of death increased by age more than 65 years, previous angina pectoris, hypotension or cardiogenic shock,
acute systolic hypertension at time of admission, diabetes mellitus, dysrhythmias, and previous MI

MI, Myocardial infarction.

BOX 23-2 UNIVERSAL DEFINITION OF MYOCARDIAL INFARCTION

The term myocardial infarction should be used when there is evidence of myocar- • For percutaneous coronary interventions (PCI) in persons with normal baseline
dial necrosis in a clinical setting with myocardial ischemia. Under these conditions troponin values, elevations of cardiac biomarkers above the 99th percentile
any one of the following criteria meets the diagnosis for myocardial infarction: URL are indicative of peri-procedural myocardial necrosis. By convention,
• Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with increases of biomarkers greater than 3 × 99th percentile URL have been des-
at least one value above the 99th percentile of the upper reference limit ignated as defining PCI-related myocardial infarction. A subtype related to a
(URL) together with evidence of myocardial ischemia with at least one of the documented stent thrombosis is recognized.
following: • For coronary artery bypass grafting (CABG) in persons with normal baseline
• Symptoms of ischemia troponin values, elevations of cardiac biomarkers above the 99th percentile
• ECG changes indicative of new ischemia (new ST-T changes or new left URL are indicative of peri-procedural myocardial necrosis. By convention,
bundle branch block [LBBB]) increases of biomarkers greater than 5 × 99th percentile URL plus either new
• Development of pathologic Q waves in the ECG pathologic Q waves or new LBBB, or angiographically documented new graft
• Imaging evidence of new loss of viable myocardium or new regional wall or native coronary artery occlusion, or imaging evidence of new loss of viable
motion abnormality myocardium have been designated as defining CABG-related myocardial
• Sudden, unexpected cardiac death, involving cardiac arrest, often with infarction.
symptoms suggestive of myocardial ischemia, and accompanied by presum- • Pathologic findings of an acute myocardial infarction.
ably new ST elevation, or new LBBB, and/or evidence of fresh thrombus by
coronary angiography and/or at autopsy; but death occurring before blood
samples could be obtained, or at a time before the appearance of cardiac
biomarkers in the blood.

Data from Thygesen K, Alpert J, White H: J Am Coll Cardiol 50:2173–2195, 2007.

 CHAPTER 23  Alterations of Cardiovascular Function 609

Zone of ischemia
Zone of infarction
and necrosis

Zone of hypoxic
injury

Normal Ischemia Injury Infarction/necrosis

FIGURE 23-21  Electrocardiographic Alterations Associated With the Three Zones of Myocardial Infarction.

third-degree burns, small bowel infarction). Elevation of troponin, receive deep venous thrombosis prophylaxis as long as their activity
CK-MB, and LDH1 levels may not occur immediately after infarction is significantly limited. Stool softeners are given to eliminate the need
and laboratory confirmation that an infarction has occurred may be for straining, which can precipitate bradycardia and can be followed
delayed up to 12 hours. by increased venous return to the heart, causing possible cardiac over-
Myocardial infarction can occur in various regions of the heart load. Hyperglycemia is treated with insulin.
wall and may be described as anterior, inferior, posterior, lateral, Treatment of dyslipidemia with hydroxymethylglutaryl coenzyme
subendocardial, or transmural, depending on the anatomic loca- A (HMG Co-A) reductase inhibitors (statins) can reduce the risk of
tion and extent of tissue damage from infarction. Twelve-lead elec- future cardiovascular events.87,95 Education regarding appropriate diet
trocardiograms (ECGs) help to localize the affected area through and caffeine intake, smoking cessation, exercise, and other aspects of
identification of Q waves and changes in ST segments and T waves risk factor reduction is crucial for secondary prevention of recurrent
(Figure 23-21). The infarcted myocardium is surrounded by a zone myocardial ischemia.
of hypoxic injury, which may progress to necrosis or return to nor-
mal condition. Adjacent to this zone of hypoxic injury is a zone of
reversible ischemia. Ischemic and injured myocardial tissue causes 4 QUICK CHECK 23-6
ST and T wave changes. Myocardial infarction documented by ele- 1. Describe the coronary artery disease–myocardial ischemia continuum.
vated levels of troponins and isoenzymes but with no elevation of 2. Describe the pathophysiology of myocardial infarction.
the ST segment on electrocardiogram (ECG) is termed non-STEMI. 3. What complications are associated with the period after infarction?
It is especially important to recognize this form of acute coronary
syndrome because recurrent clot formation on the disrupted athero-
sclerotic plaque is likely, with resultant infarct expansion. Transmu- DISORDERS OF THE HEART WALL
ral infarction presents with significant ST segment elevation on ECG
(STEMI). A characteristic Q wave often will develop on ECG several Disorders of the Pericardium
hours later (Q wave MI). STEMI requires rapid intervention to pre- Pericardial disease is a localized manifestation of another disorder,
vent serious complications and sequelae, such as dysrhythmias and such as infection (bacterial, viral, fungal, rickettsial, or parasitic);
heart failure. trauma or surgery; neoplasm; or a metabolic, immunologic, or vascu-
Acute myocardial infarction requires admission to the hospital, lar disorder (uremia, rheumatoid arthritis, systemic lupus erythemato-
often directly into a coronary care unit. The individual should be sus, periarteritis nodosa). The pericardial response to injury from these
placed on supplemental oxygen and given an aspirin immediately diverse causes may consist of acute pericarditis, pericardial effusion, or
(ticlopidine if allergic to aspirin). Pain relief is of utmost importance constrictive pericarditis.96
and involves the use of sublingual nitroglycerin and morphine sulfate.
Continuous monitoring of cardiac rhythms and enzymatic changes Acute Pericarditis
is essential, because the first 24 hours after onset of symptoms is the Acute pericarditis is acute inflammation of the pericardium. The eti-
time of highest risk for sudden death. Both non-STEMI and STEMI are ology of acute pericarditis is most often idiopathic or caused by viral
managed with the urgent administration of thrombolytics or by PCI infection by coxsackie, influenza, hepatitis, measles, mumps, or vari-
along with antithrombotics. Further management may include ACE cella viruses. It also is the most common cardiovascular complication
inhibitors and beta-blockers. Individuals who are in shock require of human immunodeficiency virus (HIV) infection. Other causes
aggressive fluid resuscitation, ionotropic drugs, and possible emergent include myocardial infarction, trauma, neoplasm, surgery, uremia,
invasive procedures.87 bacterial infection (especially tuberculosis), connective tissue disease
Bed rest, followed by gradual return to activities of daily living, (especially systemic lupus erythematosus and rheumatoid arthritis), or
reduces the myocardial oxygen demands of the compromised heart. radiation therapy.97 The pericardial membranes become inflamed and
Individuals not receiving thrombolytic or heparin infusion must roughened, and a pericardial effusion may develop that can be serous,
610 CHAPTER 23  Alterations of Cardiovascular Function

FIGURE 23-23  Exudate of Blood in the Pericardial Sac from

Rupture of Aneurysm. (From Damjanov I, Linder J: Pathology: a
color atlas, St Louis, 2000, Mosby.)

failure, overhydration, or hypoproteinemia. More often, however, the

FIGURE 23-22  Acute Pericarditis. Note shaggy coat of fibers cov-
ering the surface of heart. (From Damjanov I, Linder J: Pathology: a fluid is an exudate, which reflects pericardial inflammation like that
color atlas, St Louis, 2000, Mosby.) seen with acute pericarditis, heart surgery, some chemotherapeutic
agents, infections, and autoimmune disorders such as systemic lupus
erythematosus. (Types of exudate are described in Chapter 5.) If the
purulent, or fibrinous (Figure 23-22). Possible sequelae of pericardi- fluid is serosanguineous, the underlying cause is likely to be tuberculo-
tis include recurrent pericarditis, pericardial constriction, and cardiac sis, neoplasm, uremia, or radiation. Idiopathic serosanguineous (cause
tamponade. unknown) effusion is possible, however. Effusions of frank blood are
Symptoms may follow several days of fever and usually begin with generally related to aneurysms, trauma, or coagulation defects (Figure
the sudden onset of severe retrosternal chest pain that worsens with 23-23). If chyle leaks from the thoracic duct, it may enter the pericar-
respiratory movements and when assuming a recumbent position. The dium and lead to cholesterol pericarditis.
pain may radiate to the back as a result of irritation of the phrenic Pericardial effusion, even in large amounts, is not necessarily clini-
nerve (innervates the trapezius muscles) as it traverses the pericar- cally significant, except that it indicates an underlying disorder. If an
dium. Individuals with acute pericarditis also report dysphagia, rest- effusion develops gradually, the pericardium can stretch to accommo-
lessness, irritability, anxiety, weakness, and malaise. date large quantities of fluid without compressing the heart. If the fluid
Physical examination often discloses low-grade fever (<38° C) and accumulates rapidly, however, even a small amount (50 to 100 ml)
sinus tachycardia. A friction rub—a scratchy, grating sound—may be may create sufficient pressure to cause cardiac compression, a serious
heard at the cardiac apex and left sternal border and is highly sugges- condition known as tamponade. The danger is that pressure exerted
tive of pericarditis. The rub is caused by the roughened pericardial by the pericardial fluid eventually will equal diastolic pressure within
membranes rubbing against each other. Friction rubs are not always the heart chambers, which will interfere with right atrial filling during
present and may be intermittently heard and transient. Hypotension diastole. This causes increased venous pressure, systemic venous con-
or the presence of a pulsus paradoxus (a decrease in systolic blood gestion, and signs and symptoms of right heart failure (distention of
pressure of >10 mm Hg with inspiration) is suggestive of cardiac tam- the jugular veins, edema, hepatomegaly). Decreased atrial filling leads
ponade, which can be life-threatening. Electrocardiographic changes to decreased ventricular filling, decreased stroke volume, and reduced
may reflect inflammatory processes through PR segment depression cardiac output. Life-threatening circulatory collapse may occur.
and diffuse ST segment elevation without Q waves, and they may An important clinical finding is pulsus paradoxus, in which arte-
remain abnormal for days or even weeks. CT scanning and MRI may rial blood pressure during expiration exceeds arterial pressure during
be used as diagnostic modalities.97 inspiration by more than 10 mm Hg. Pulsus paradoxus in the setting
Treatment for uncomplicated acute pericarditis consists of reliev- of a pericardial effusion indicates tamponade and reflects impairment
ing symptoms and includes administration of anti-inflammatory of diastolic filling of the left ventricle plus reduction of blood volume
agents, such as salicylates and nonsteroidal anti-inflammatory drugs.98 within all four cardiac chambers. The presence of a large pericardial
Colchicine may be added to prevent fibrosis. Exploration of the under- effusion or tamponade magnifies the normally insignificant effect of
lying cause is important. If pericardial effusion develops, aspiration of inspiration on intracardiac flow and volume.
the excessive fluid may be necessary. Other clinical manifestations of pericardial effusion are distant or
muffled heart sounds, poorly palpable apical pulse, dyspnea on exer-
Pericardial Effusion tion, and dull chest pain. A chest x-ray film may disclose a “water-
Pericardial effusion is the accumulation of fluid in the pericardial bottle configuration” of the cardiac silhouette. An echocardiogram can
cavity and can occur in all forms of pericarditis. The fluid may be a detect an effusion as small as 20 ml and is a reliable and accurate diag-
transudate, such as the serous effusion that develops with left heart nostic test, although CT scans also may be done.
 CHAPTER 23  Alterations of Cardiovascular Function 611

Normal Dilated cardiomyopathy

AO
Aorta
LA
(AO) Left
atrium
Left (LA) LV
ventricle
(LV)
A B

AO AO
LA LA

LV LV

C Hypertrophic D Restrictive
cardiomyopathy cardiomyopathy
FIGURE 23-24  Constrictive Pericarditis. The fibrotic pericardium (amyloid)
encases the heart in a rigid shell. (From Damjanov I, Linder J:
FIGURE 23-25  Diagram Showing Major Distinguishing Patho-
Pathology: a color atlas, St Louis, 2000, Mosby.)
physiologic Features of the Three Types of Cardiomyopathy.
A, The normal heart. B, In the dilated type of cardiomyopathy, the
Treatment of pericardial effusion or tamponade generally consists heart has a globular shape and the largest circumference of the left
of pericardiocentesis (aspiration of excessive pericardial fluid) and ventricle is not at its base but midway between apex and base.
C, In the hypertrophic type, the wall of the left ventricle is greatly
treatment of the underlying condition. Persistent pain may be treated
thickened; the left ventricular cavity is small, but the left atrium
with analgesics, anti-inflammatory medications, or steroids. Surgery may be dilated because of poor diastolic relaxation of the ventricle. 
may be required if the underlying cause of tamponade is trauma or D, In the restrictive (constrictive) type, the left ventricular cavity is
aneurysm. A pericardial “window” may be surgically created to pre- of normal size, but, again, the left atrium is dilated because of the
vent tamponade.96 reduced diastolic compliance of the ventricle. (From Kissane JM,
editor: Anderson’s pathology, ed 9, St Louis, 1990, Mosby.)
Constrictive Pericarditis
Constrictive pericarditis, or restrictive pericarditis (chronic pericar-
ditis), was synonymous with tuberculosis years ago, and tuberculosis Initial treatment for constrictive pericarditis consists of restriction
continues to be an important cause of pericarditis in immunocompro- of dietary sodium intake and administration of digitalis glycosides and
mised individuals. Currently in the United States, this form of pericar- diuretics to improve cardiac output. Management also may include use
dial disease is more commonly idiopathic or associated with radiation of anti-inflammatory drugs and treatment of any underlying disorder.
exposure, rheumatoid arthritis, uremia, or coronary artery bypass graft If these modalities are unsuccessful, surgical excision of the restrictive
surgery.96 In constrictive pericarditis, fibrous scarring with occasional pericardium is indicated (pericardial decortication).100
calcification of the pericardium causes the visceral and parietal peri-
cardial layers to adhere, obliterating the pericardial cavity. The fibrotic Disorders of the Myocardium: The Cardiomyopathies
lesions encase the heart in a rigid shell (Figure 23-24). Like tamponade, The cardiomyopathies are a diverse group of diseases that primarily
constrictive pericarditis compresses the heart and eventually reduces affect the myocardium itself. Most are the result of remodeling caused
cardiac output. Unlike tamponade, however, constrictive pericarditis by the effect of the neurohumoral responses to ischemic heart disease
always develops gradually. or hypertension on the heart muscle. They may, however, be second-
Symptoms tend to be exercise intolerance, dyspnea on exertion, ary to infectious disease, exposure to toxins, systemic connective tissue
fatigue, and anorexia.99 Clinical assessment shows edema, distention disease, infiltrative and proliferative disorders, or nutritional deficien-
of the jugular vein, and hepatic congestion. Restricted ventricular fill- cies. Many cases are idiopathic—that is, their cause is unknown. The
ing may cause a pericardial knock (early diastolic sound). cardiomyopathies are categorized as dilated (formerly, congestive),
ECG findings include T wave inversions and atrial fibrillation. hypertrophic, or restrictive, depending on their physiologic effects on
Chest x-ray films often disclose prominent pulmonary vessels and cal- the heart (Figure 23-25).
cification of the pericardium. CT, MRI, and transesophageal echocar- Dilated cardiomyopathy is usually the result of ischemic heart
diography are used to detect pericardial thickening and constriction disease, valvular disease, diabetes, renal failure, alcohol or drug tox-
and to distinguish constrictive pericarditis from restrictive cardiomy- icity, peripartum complications, genetic disorder, or infection.101 It
opathy. Pericardial biopsy may be needed to determine the etiology. is characterized by impaired systolic function leading to increases in
612 CHAPTER 23  Alterations of Cardiovascular Function

FIGURE 23-27  Hypertrophic cardiomyopathy. There is marked

left ventricular hypertrophy. This often affects the septum (S).
(From Stevens A, Lowe J: Pathology, St Louis, 1995, Mosby.)

FIGURE 23-26  Dilated cardiomyopathy. The dilated left ventricle

has a thin wall (V). (From Stevens A, Lowe J: Pathology, St Louis, idiopathically or as a cardiac manifestation of systemic diseases, such
1995, Mosby.) as scleroderma, amyloidosis, sarcoidosis, lymphoma, and hemochro-
matosis, or a number of inherited storage diseases. The myocardium
becomes rigid and noncompliant, impeding ventricular filling and
intracardiac volume, ventricular dilation, and systolic heart failure raising filling pressures during diastole. The overall clinical and hemo-
(Figure 23-26) (see p. 622). Individuals complain of dyspnea, fatigue, dynamic picture mimics and may be confused with that of constrictive
and pedal edema. Findings on examination include a displaced apical pericarditis.
pulse, S3 gallop, peripheral edema, jugular venous distention, and pul-
monary congestion. Diagnosis is confirmed by chest x-ray and echo-
cardiogram, and management is focused on reducing blood volume,
4 QUICK CHECK 23-7
1. Why does pericarditis develop?
increasing contractility, and reversing the underlying disorder if pos-
2. What are the cardiomyopathies? List the major disorders.
sible.101 Heart transplant is required in severe cases.
3. Briefly describe the pathophysiologic effects of the cardiomyopathies.
Hypertrophic cardiomyopathy refers to two major categories
of thickening of the myocardium: (1) hypertrophic obstructive car-
diomyopathy (asymmetric septal hypertrophic cardiomyopathy or
subaortic stenosis) and (2) hypertensive or valvular hypertrophic car- Disorders of the Endocardium
diomyopathy. Hypertrophic obstructive cardiomyopathy is the most Valvular Dysfunction
commonly inherited cardiac disorder. It is characterized by thickening Disorders of the endocardium (the innermost lining of the heart wall)
of the septal wall (Figure 23-27), which may cause outflow obstruc- damage the heart valves, which are composed of endocardial tissue.
tion to the left ventricle outflow tract.102 Obstruction of left ventricu- Endocardial damage can be either congenital or acquired. The acquired
lar outflow can occur when heart rate is increased and intravascular forms result from inflammatory, ischemic, traumatic, degenerative,
volume is decreased. This type of hypertrophic cardiomyopathy is a or infectious alterations of valvular structure and function. One of
significant risk factor for serious ventricular dysrhythmias and sudden the most common causes of acquired valvular dysfunction is degen-
death, and has been implicated in more than 33% of sudden deaths in eration or inflammation of the endocardium secondary to rheumatic
young athletes.8,103 Hypertensive or valvular hypertrophic cardiomy- heart disease (Table 23-6). Structural alterations of the heart valves are
opathy occurs because of increased resistance to ventricular ejection, caused by remodeling changes in the valvular extracellular matrix and
which is commonly seen in individuals with hypertension or valvular lead to stenosis, incompetence, or both.
stenosis (usually aortic). In this case, hypertrophy of the myocytes is an In valvular stenosis, the valve orifice is constricted and narrowed,
attempt to compensate for increased myocardial workload. Long-term so blood cannot flow forward and the workload of the cardiac cham-
dysfunction of the myocytes develops over time, with first diastolic ber proximal to the diseased valve increases (Figure 23-28). Pressure
dysfunction leading eventually to systolic dysfunction of the ventricle (intraventricular or atrial) rises in the chamber to overcome resistance
(see “Heart Failure,” p. 622). Individuals with hypertrophic cardio- to flow through the valve, necessitating greater exertion by the myocar-
myopathy may be asymptomatic or may complain of angina, syncope, dium and producing myocardial hypertrophy.
dyspnea on exertion, and palpitations. Examination may reveal extra Although all four heart valves may be affected, in adults those of the
heart sounds and murmurs. Echocardiography and cardiac catheter- left heart (mitral and aortic valves) are far more commonly affected
ization can confirm the diagnosis. than those of the right heart (tricuspid and pulmonic valves). In valvu-
Restrictive cardiomyopathy is characterized by restrictive filling lar regurgitation (also called insufficiency or incompetence), the valve
and increased diastolic pressure of either or both ventricles with nor- leaflets, or cusps, fail to shut completely, permitting blood flow to
mal or near-normal systolic function and wall thickness. It may occur continue even when the valve is presumably closed (see Figure 23-28).
 CHAPTER 23  Alterations of Cardiovascular Function 613

TABLE 23-6 CLINICAL MANIFESTATIONS OF VALVULAR STENOSIS AND REGURGITATION

MITRAL AORTIC MITRAL TRICUSPID
MANIFESTATION AORTIC STENOSIS STENOSIS REGURGITATION REGURGITATION REGURGITATION
Most common cause Congenital bicuspid valve, Rheumatic heart Infective endocarditis; aortic Myxomatous Congenital
degenerative (calcific) disease root disease (connective ­degeneration (mitral
changes with aging, tissue diseases, Marfan syn­ valve prolapse)
rheumatic heart disease drome); dilation of aortic root
from hypertension and aging
Cardiovascular outcome Left ventricular hyper- Left atrial hypertrophy Left ventricular hypertrophy Left atrial ­hypertrophy Right heart failure
(untreated) trophy followed by left and dilation with and dilation, followed by and dilation,
heart failure; decreased ­fibrillation, followed by left heart failure ­followed by left heart
coronary blood flow with right ventricular failure failure
myocardial ischemia
Pulmonary effects Pulmonary edema: Pulmonary edema: dyspnea Pulmonary edema with Pulmonary edema with Dyspnea
­dyspnea on exertion on exertion, orthopnea, dyspnea on exertion dyspnea on exertion
paroxysmal nocturnal
dyspnea, predisposi-
tion to respiratory tract
infections, hemoptysis,
pulmonary hypertension
Central nervous system Syncope, especially on Neural deficits only Syncope None None
effects exertion ­associated with emboli
(e.g., hemiparesis)
Pain Angina pectoris Atypical chest pain Angina pectoris Atypical chest pain Palpitations
Heart sounds Systolic murmur heard Low rumbling diastolic mur- Diastolic murmur heard best Murmur throughout Murmur throughout
best at right parasternal mur heard best at apex at right parasternal second systole heard best at systole heard
second intercostal space and radiating to axilla, intercostal space and apex and radiating best at left lower
and radiating to neck accentuated first heart radiating to neck to axilla sternal border
sound, opening snap

With data from Braunwald E, editor: Heart disease: a textbook of cardiovascular medicine, ed 5, Philadelphia, 1997, Saunders; Carabello BA, Paulus WJ:
Valvular heart disease. In Crawford MH, DiMarco JP, editors: Cardiology, London, 2001, Mosby.

Fused cusps Cusp During systole or diastole, some blood leaks back into the chamber
Cusp
proximal to the diseased valve, which increases the volume of blood
the heart must pump and increases the workload of both atrium and
ventricle. Increased volume leads to chamber dilation, and increased
Orifice Orifice workload leads to hypertrophy, both of which are compensatory
Normal Normal Stenosed Regurgitant mechanisms intended to increase the pumping capability of the heart
valve valve valve valve but that lead to cardiac dysfunction over time. Eventually, myocardial
(open) (closed) (open) (closed) contractility diminishes, ejection fraction is reduced, diastolic pressure
A B increases, and the ventricles fail from being overworked. Depending
on the severity of the valvular dysfunction and the capacity of the heart
to compensate, valvular alterations cause a range of symptoms and
Stenosed
some degree of incapacitation (see Table 23-6).
mitral valve In general, valvular disease is diagnosed by echocardiography,
which can be used to assess the severity of valvular obstruction or
Mitral valve regurgitation before the onset of symptoms. Management almost
does not always includes careful fluid management, valvular repair, or valve
close replacement with a prosthetic valve followed by long-term anticoagu-
completely
lation therapy and prophylaxis for endocarditis as needed.104,105
C D
Stenosis
FIGURE 23-28  Valvular Stenosis and Regurgitation. A, Normal Aortic stenosis. Aortic stenosis is the most common valvular
position of the valve leaflets, or cusps, when the valve is open and abnormality, affecting nearly 2% of adults older than 65 years of age.8
closed. B, Open position of a stenosed valve (left) and open posi-
It has three common causes: (1) congenital bicuspid valve, (2) degen-
tion of a closed regurgitant valve (right). C, Hemodynamic effect of
mitral stenosis. The stenosed valve is unable to open sufficiently eration with aging, and (3) inflammatory damage caused by rheumatic
during left atrial systole, inhibiting left ventricular filling. D, Hemo- heart disease. Numerous gene abnormalities have been associated with
dynamic effect of mitral regurgitation. The mitral valve does not aortic stenosis. Aortic stenosis is also associated with many risk factors
close completely during left ventricular systole, permitting blood to for coronary artery disease.8 Aortic valve degeneration with aging is
reenter the left atrium. associated with chronic inflammation, lipoprotein deposition in the
614 CHAPTER 23  Alterations of Cardiovascular Function

FIGURE 23-29  Aortic Stenosis. Mild stenosis in valve leaflets of a FIGURE 23-30  Mitral Stenosis With Classic “Fish Mouth” Ori-
young adult. (From Damjanov I, Linder J: Pathophysiology: a color fice. (From Kumar V, Abbas A, Fausto N et al: Pathologic basis of
atlas, St Louis, 2000, Mosby.) disease, ed 8, St Louis, 2010, Mosby.)

tissue, and leaflet calcification. The orifice of the aortic valve narrows, the pulmonary circulation. If untreated, chronic mitral stenosis devel-
causing resistance to blood flow from the left ventricle into the aorta ops into pulmonary hypertension, pulmonary edema, and right ven-
(Figure 23-29). Outflow obstruction increases pressure within the left tricular failure.
ventricle as it tries to eject blood through the narrowed opening. Left Blood flow through the stenotic valve results in a rumbling decre-
ventricular hypertrophy develops to compensate for the increased scendo diastolic murmur heard best over the cardiac apex and radiat-
workload. Eventually, hypertrophy increases myocardial oxygen ing to the left axilla. If the mitral valve is forced open during diastole, it
demand, which the coronary arteries may not be able to supply. If this may make a sharp noise called an opening snap. The first heart sound
occurs, ischemia may cause attacks of angina. In addition, aortic ste- (S1) is often accentuated and somewhat delayed because of increased
nosis is frequently accompanied by atherosclerotic coronary disease, left atrial pressure. Other signs and symptoms are generally those of
further contributing to inadequate coronary perfusion. Untreated aor- pulmonary congestion and right heart failure. Atrial enlargement and
tic stenosis can lead to hypertrophic cardiomyopathy, dysrhythmias, valvular obstruction are demonstrated by chest x-ray films, electrocar-
myocardial infarction, and heart failure.105 diography, and echocardiography. Management includes anticoagula-
Aortic stenosis usually develops gradually. Classic symptoms include tion therapy and endocarditis prophylaxis along with beta-blockers or
angina, syncope, and dyspnea. Clinical manifestations include decreased calcium channel blockers to slow the heart rate. Mitral stenosis can
stroke volume and narrowed pulse pressure (the difference between often be repaired surgically but may require valve replacement (usually
systolic and diastolic pressure). Heart rate is often slow, and pulses are porcine) in advanced cases.105
delayed. Resistance to flow leads to a crescendo-decrescendo systolic Regurgitation
heart murmur heard best at the right parasternal second intercostal Aortic regurgitation. Aortic regurgitation results from an inability
space and may radiate to the neck. Echocardiography can be used to of the aortic valve leaflets to close properly during diastole because of
assess the severity of valvular obstruction before the onset of symptoms, abnormalities of the leaflets, the aortic root and annulus, or both. It can
and management almost always includes valve replacement with a pros- be congenital (bicuspid valve) or acquired. Acquired aortic regurgita-
thetic valve followed by long-term anticoagulation therapy and prophy- tion may be idiopathic, or it can be caused by rheumatic heart disease,
laxis for endocarditis as needed. Percutaneous placement of a prosthetic bacterial endocarditis, syphilis, hypertension, connective tissue disor-
valve avoids major heart surgery in selected individuals.106 Once indi- ders (e.g., Marfan syndrome and ankylosing spondylitis), appetite-sup-
viduals become symptomatic from aortic stenosis, the prognosis is poor. pressing medications, trauma, or atherosclerosis. During systole, blood
Mitral stenosis. Mitral stenosis impairs the flow of blood from is ejected from the left ventricle into the aorta. During diastole, some
the left atrium to the left ventricle. Mitral stenosis is more common in of the ejected blood flows back into the left ventricle through the leak-
women and occurs in 40% of individuals with a history of rheumatic ing valve. Volume overload occurs in the ventricle because it receives
heart disease.8 Autoimmunity in response to group A β-hemolytic blood both from the left atrium and from the aorta during diastole. The
streptococcal M protein antigens leads to inflammation and scarring hemodynamic abnormalities depend on the amount of regurgitation.
of the valvular leaflets. Scarring causes the leaflets to become fibrous As the end-diastolic volume of the left ventricle increases, myocardial
and fused, and the chordae tendineae cordis become shortened fibers stretch to accommodate the extra fluid. Compensatory dilation
(Figure 23-30). permits the left ventricle to increase its stroke volume and maintain
Impedance to blood flow results in incomplete emptying of the left cardiac output. Ventricular hypertrophy also occurs as an adaptation
atrium and elevated atrial pressure as the chamber tries to force blood to the increased volume and because of increased afterload created by
through the stenotic valve. Continued increases in left atrial volume the high stroke volume and resultant systolic hypertension. Over time,
and pressure cause atrial dilation and hypertrophy. The risk of devel- ventricular dilation and hypertrophy eventually cannot compensate
oping atrial dysrhythmias (especially fibrillation) and dysrhythmia- for aortic incompetence, and heart failure develops.
induced thrombi is high. As mitral stenosis progresses, symptoms of Clinical manifestations include widened pulse pressure resulting
decreased cardiac output occur, especially during exertion. Continued from increased stroke volume and diastolic backflow. Turbulence
elevation of left atrial pressure and volume causes pressure to rise in across the aortic valve during diastole produces a decrescendo murmur
 CHAPTER 23  Alterations of Cardiovascular Function 615

A B
FIGURE 23-31  Mitral Valve Prolapse. A, Prolapsed mitral valve. Prolapse permits the valve leaflets
to billow back (arrow) into the atrium during left ventricular systole. The billowing causes the leaflets
to part slightly, permitting regurgitation into the atrium. B, Looking down into the mitral valve, the bal-
looning (arrows) of the leaflets is seen. (From Kumar V: Pathologic basis of disease, ed 8, St Louis,
2010, Mosby.)

in the second, third, or fourth intercostal spaces parasternally and may dilation of the right ventricle secondary to pulmonary hypertension
radiate to the neck. Large stroke volume and rapid runoff of blood (see p. 700). Rheumatic heart disease and infective endocarditis are less
from the aorta cause prominent carotid pulsations and bounding common causes. Tricuspid valve incompetence leads to volume over-
peripheral pulses (Corrigan pulse). Other symptoms are usually asso- load in the right atrium and ventricle, increased systemic venous blood
ciated with heart failure that occurs when the ventricle can no longer pressure, and right heart failure. Pulmonic valve dysfunction can have
pump adequately. Dysrhythmias are a common complication of aortic the same consequences as tricuspid valve dysfunction.
regurgitation. The severity of regurgitation can be estimated by echo-
cardiography, and valve replacement may be delayed for many years Mitral Valve Prolapse Syndrome
through careful use of vasodilators and inotropic agents.105 In mitral valve prolapse syndrome (MVPS), one or both of the cusps
Mitral regurgitation. Mitral regurgitation has many possible of the mitral valve billow upward (prolapse) into the left atrium dur-
causes, including mitral valve prolapse, rheumatic heart disease, infec- ing systole (Figure 23-31). The most common cause of mitral valve
tive endocarditis, MI, connective tissue diseases (Marfan syndrome), prolapse is myxomatous degeneration of the leaflets in which the cusps
and dilated cardiomyopathy. Mitral regurgitation permits backflow are redundant, thickened, and scalloped because of changes in tissue
of blood from the left ventricle into the left atrium during ventricu- proteoglycans, increased levels of proteinases, and infiltration by myo-
lar systole, producing a holosystolic (throughout systole) murmur fibroblasts. Mitral regurgitation occurs if the ballooning valve permits
heard best at the apex, which radiates into the back and axilla. Because blood to leak into the atrium.107
of increased volume from the left atrium, the left ventricle becomes Mitral valve prolapse is the most common valve disorder in the
dilated and hypertrophied to maintain adequate cardiac output. The United States, with a prevalence of 2.4% of adults.8 Studies suggest an
volume of backflow reentering the left atrium gradually increases, autosomal dominant inheritance pattern. Because mitral valve pro-
causing atrial dilation and associated atrial fibrillation. As the left lapse can be associated with other inherited connective tissue disorders
atrium enlarges, the valve structures stretch and become deformed, (Marfan syndrome, Ehlers-Danlos syndrome, osteogenesis imper-
leading to further backflow. As mitral valve regurgitation progresses, fecta), it has been suggested that it results from a genetic or environ-
left ventricular function may become impaired to the point of failure. mental disruption of valvular development during the fifth or sixth
Eventually, increased atrial pressure leads to pulmonary hypertension week of gestation. There also may be a relationship between symptom-
and failure of the right ventricle.105 Mitral incompetence is usually well atic mitral valve prolapse and hyperthyroidism.
tolerated—often for years—until ventricular failure occurs. Most clin- Many cases of mitral valve prolapse are completely asymptomatic.
ical manifestations are caused by heart failure. The severity of regur- Cardiac auscultation on routine physical examination may disclose a
gitation can be estimated by echocardiography, and surgical repair or regurgitant murmur or midsystolic click in an otherwise healthy indi-
valve replacement may become necessary. In acute mitral regurgitation vidual, or echocardiography may demonstrate the condition in the
due to MI, surgical repair must be done emergently. absence of auscultatory findings. Symptomatic mitral valve prolapse
Tricuspid regurgitation. Tricuspid regurgitation is more com- can cause palpitations related to dysrhythmias, tachycardia, light-
mon than tricuspid stenosis and is usually associated with failure and headedness, syncope, fatigue (especially in the morning), lethargy,
616 CHAPTER 23  Alterations of Cardiovascular Function

weakness, dyspnea, chest tightness, hyperventilation, anxiety, depres-

sion, panic attacks, and atypical chest pain. Many symptoms are vague
and puzzling and are unrelated to the degree of prolapse. Most indi-
viduals with mitral valve prolapse have an excellent prognosis, do
not develop symptoms, and do not require any restriction in activ-
ity or medical management. Occasionally, beta-blockers are needed
Streptococcal to alleviate syncope, severe chest pain, or palpitations. A subset of
pharyngitis individuals have an increased risk for complications such as infective
Group A Streptococcus
endocarditis, cardioembolic stroke, and sudden death. These high-
risk individuals can be identified by clinical and echocardiographic
Activation of findings.105
T cells by
streptococcal Acute Rheumatic Fever and Rheumatic Heart Disease
antigen
Rheumatic fever is a systemic, inflammatory disease caused by a
delayed exaggerated immune response to infection by the group A
Synthesis of β-hemolytic streptococcus in genetically predisposed individuals. In its
antistreptococcal acute form, rheumatic fever is a febrile illness characterized by inflam-
antibodies by
B cells mation of the joints, skin, nervous system, and heart.108 If untreated,
rheumatic fever can cause scarring and deformity of cardiac structures,
resulting in rheumatic heart disease (RHD).
Inflammation The incidence of acute rheumatic fever declined in the United
Vegetation States during the 1960s, 1970s, and early 1980s because of medical and
Mitral leaflet socioeconomic improvements. More recent outbreaks in the United
States and abroad corresponded to the reappearance of highly virulent
Short, thickened strains of the streptococcal microorganisms. The acute disease occurs
chordae tendineae most often in children between the ages of 5 and 15 years. Appropri-
ate antibiotic therapy given within the first 9 days of infection usually
prevents rheumatic fever.

PATHOPHYSIOLOGY  Acute rheumatic fever can develop only as

1 ENDOCARDITIS
a sequel to pharyngeal infection by group A β-hemolytic strepto-
Fibrinoid coccus. Streptococcal skin infections do not progress to acute rheu-
Fibrosis material Giant matic fever, although both skin and pharyngeal infections can cause
cell acute glomerulonephritis. This is because the strains of the micro-
organism that affect the skin do not have the same antigenic mol-
Aschoff ecules in their cell membranes as those that cause pharyngitis and,
bodies therefore, do not elicit the same kind of immune response. Acute
rheumatic fever is the result of an abnormal humoral and cell-medi-
Lymphocyte ated immune response to group A streptococcal cell membrane
FIBRINOUS antigens called M proteins (Figure 23-32). This immune response
3 PERICARDITIS Macrophage cross-reacts with molecularly similar self-antigens in heart, muscle,
2 MYOCARDITIS brain, and joints, causing an autoimmune response that results in
diffuse, proliferative, and exudative inflammatory lesions in these
FIGURE 23-32  Pathogenesis and Structural Alterations of
tissues.108 The inflammation may subside before treatment, leaving
Acute Rheumatic Heart Disease. Beginning usually with a sore
throat, rheumatic fever can develop only as a sequel to pharyngeal
behind damage to the heart valves. Repeated attacks of acute rheu-
infection by group A β-hemolytic streptococcus. Suspected as a matic fever cause chronic proliferative changes in the previously
hypersensitivity reaction, it is proposed that antibodies directed mentioned organs with resultant tissue scarring, granuloma forma-
against the M proteins of certain strains of streptococci cross-react tion, and thrombosis.
with tissue glycoproteins in the heart, joints, and other tissues. Approximately 10% of individuals with rheumatic fever develop
The exact nature of cross-reacting antigens has been difficult to rheumatic heart disease (RHD). In developed countries, the peak
define, but it appears that the streptococcal infection causes an incidence of the development of RHD occurs in adults between the
autoimmune response against self-antigens. Inflammatory lesions ages of 25 and 34. Although rheumatic fever can cause carditis in
are found in various sites; the most distinctive within the heart are all three layers of the heart wall, the primary lesion usually involves
called Aschoff bodies. The chronic sequelae result from progres-
the endocardium. Endocardial inflammation causes swelling of the
sive fibrosis because of healing of the inflammatory lesions and the
changes induced by valvular deformities. (From Damjanov I: Pathol-
valve leaflets, with secondary erosion along the lines of leaflet con-
ogy for the health professions, ed 3, St Louis, 2006, Saunders.) tact. Small, beadlike clumps of vegetation containing platelets and
fibrin are deposited on eroded valvular tissue and on the chordae
tendineae cordis. These lesions can become progressively adherent.
Scarring and shortening of the involved structures occur over time.
The valves lose their elasticity, and the leaflets may adhere to each
other.
 CHAPTER 23  Alterations of Cardiovascular Function 617

TABLE 23-7 JONES CRITERIA (UPDATED) USED FOR DIAGNOSIS OF INITIAL ATTACK

OF RHEUMATIC FEVER
CRITERIA DESCRIPTION
Major Manifestations
Carditis Previously undetected murmur, chest pain, pericardial effusion with audible friction rub, extra heart sounds, conduction delays,
atrial fibrillation, and prolonged PR interval; valvular diseases (stenosis and regurgitation); recurrent infective endocarditis
Polyarthritis Migratory polyarthritis (especially large joints of extremities); each joint simultaneously or in succession symptomatic for
­approximately 2 to 3 days; polyarthritis continued for up to 3 weeks; exudative synovitis (heat, redness, swelling, severe pain)
Chorea Sudden, aimless, irregular, involuntary movements; more common in females than in males; may occur several months after
streptococcal infection; self-limiting, lasting weeks or months; no permanent neural sequelae
Erythema marginatum Nonpruritic, pink, erythematous macules on trunk that do not occur on face or hands; transitory and may change in appearance
within minutes or hours; heat darkens rash; macules may fade in center and be mistaken for ringworm
Subcutaneous nodules Palpable subcutaneous nodes over bony prominences and along extensor tendons

Minor Manifestations
Arthralgias Pain and stiffness in joints without heat, redness, or swelling
Fever >39° C
Elevated CRP Indicates inflammation
Prolonged PR interval Change in ECG consistent with abnormal conduction
Supporting evidence of Increased titer of streptococcal antibodies: antistreptolysin O (ASO), positive throat streptococcal infection culture for group A
­streptococcal infection Streptococcus

Data from Guidelines for the diagnosis of rheumatic fever: Jones Criteria, 1992 update; Special Writing Group of the Committee on Rheumatic
Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association, JAMA
268(15):2069–2073, 1992.

If inflammation penetrates the myocardium, called myocarditis, erythromycin administration. Nonsteroidal anti-inflammatory drugs
localized fibrin deposits develop that are surrounded by areas of necro- are used as anti-inflammatory agents for both rheumatic carditis and
sis. These fibrinoid necrotic deposits are called Aschoff bodies. Peri- arthritis. Serious carditis may require corticosteroids and diuretics.
cardial inflammation is usually characterized by serofibrinous effusion Because recurrent rheumatic fever occurs in more than half of affected
within the pericardial cavity. Cardiomegaly and left heart failure may children, continuous prophylactic antibiotic therapy may be necessary
occur during episodes of untreated acute or recurrent rheumatic fever. for as long as 5 years. Several potential group A streptococcus vaccines
Conduction defects and atrial fibrillation often are associated with are being developed.111 RHD may require surgical repair of damaged
rheumatic heart disease. valves.

CLINICAL MANIFESTATIONS  The common symptoms of acute

rheumatic fever are fever, lymphadenopathy, arthralgia, nausea, vom-
iting, epistaxis (nosebleed), abdominal pain, and tachycardia. The 4 QUICK CHECK 23-8
major clinical manifestations of acute rheumatic fever usually occur 1. Compare the effect of aortic stenosis with mitral stenosis on the left ven-
singly or in combination 1 to 5 weeks after streptococcal infection of tricle and atrium.
the pharynx. They are carditis, acute migratory polyarthritis, chorea, 2. Describe aortic regurgitation, mitral regurgitation, and tricuspid
erythema marginatum, and subcutaneous nodules. Criteria for the regurgitation.
diagnosis of rheumatic fever have been developed and updated by both 3. What are the common symptoms of mitral prolapse?
the American Heart Association (Jones criteria; Table 23-7) and the 4. What is the cause of rheumatic heart disease?
World Health Organization (WHO).109,110

EVALUATION AND TREATMENT  As described in Table 23-7, sup-

portive evidence for group A β-hemolytic streptococci includes posi- Infective Endocarditis
tive throat cultures and measurement of serum antibodies against the Infective endocarditis is a general term used to describe infection
hemolytic factor streptolysin O. Cultures may be negative when the and inflammation of the endocardium—especially the cardiac valves.
rheumatic attack begins, however. Several other antibody tests are sen- There are approximately 15,000 new cases of infective endocarditis
sitive prognosticators of streptococcal infection, including antideoxyri- per year in the United States and it accounts for approximately 1 in
bonuclease B (anti-DNase B), antihyaluronidase, and antistreptozyme 1000 admissions to the hospital.112 Bacteria are the most common
(ASTZ). Elevated measurements of white blood cell count, erythrocyte cause of infective endocarditis, especially streptococci, staphylococci,
sedimentation rate, and C-reactive protein indicate inflammation. All and enterococci. Other causes include viruses, fungi, rickettsia, and
three are usually increased at the time cardiac or joint symptoms begin parasites. Infective endocarditis was once a lethal disease, but morbid-
to appear. ity and mortality diminished significantly with the advent of antibi-
Therapy for acute rheumatic fever is aimed at eradicating the strep- otics and improved diagnostic techniques (see Risk Factors: Infective
tococcal infection and involves a 10-day regimen of oral penicillin or Endocarditis).
618 CHAPTER 23  Alterations of Cardiovascular Function

PATHOPHYSIOLOGY  The pathogenesis of infective endocarditis

RISK FACTORS
requires at least three critical elements (Figure 23-33):
Infective Endocarditis 1. Endocardial damage. Trauma, congenital heart disease, valvular
• Acquired valvular heart disease (especially mitral valve prolapse) heart disease, and the presence of prosthetic valves are the most
• Implantation of prosthetic heart valves common risk factors for endocardial damage that leads to infective
• Congenital lesions associated with highly turbulent flow (e.g., ventricular endocarditis. Turbulent blood caused by these abnormalities usu-
septal defect) ally affects the atrial surface of atrioventricular valves or the ven-
• Previous attack of infective endocarditis tricular surface of semilunar valves.112 Endocardial damage exposes
• Intravenous drug use the endothelial basement membrane, which contains a type of col-
• Long-term indwelling intravenous catheterization (e.g., for pressure lagen that attracts platelets and thereby stimulates sterile thrombus
­monitoring, feeding, hemodialysis) formation on the membrane. This causes an inflammatory reaction
• Implantable cardiac pacemakers (nonbacterial thrombotic endocarditis).
• Heart transplant with defective valve 2. Adherence of blood-borne microorganisms to the damaged endocar-
dial surface. Bacteria may enter the bloodstream during injection
drug use, trauma, dental procedures that involve manipulation
of the gingiva, cardiac surgery, genitourinary procedures and

Pathophysiology of Infective Endocarditis

Congenital heart Valvular heart Trauma Prosthetic

disease disease (procedure) valve

Endocardial damage

Dental, GU
or cardiac Inflammation and thrombus formation
procedures

Skin, wound, Sterile thrombotic endocarditis

lung, or GU
infection
Bacteremia

Indwelling
catheters Bacterial adherence

Injection
Fibrin and thrombus formation
drug use

Formation of vegetations

Embolization Fever, Murmurs,

night sweats, regurgitant
malaise, valve, heart
weight loss failure

Abscesses, petechiae, splinter hemorrhages,

Osler nodes, Janeway lesions

FIGURE 23-33  Pathogenesis of Infective Endocarditis.

 CHAPTER 23  Alterations of Cardiovascular Function 619

indwelling catheters in the presence of infection, or gastrointestinal suggested, scans can be performed to confirm their presence. Antimicro-
instrumentation, or they may spread from uncomplicated upper bial therapy is generally given for several weeks, beginning with intrave-
respiratory tract or skin infections. Bacteria adhere to the damaged nous and ending with oral administration. In some cases, two different
endocardium using adhesins.112 antibiotics are given simultaneously to eliminate the offending microor-
3. Formation of infective endocardial vegetations (Figure 23-34). Bac- ganism and prevent the development of drug resistance. Other drugs may
teria infiltrate the sterile thrombi and accelerate fibrin formation be necessary to treat left heart failure secondary to valvular dysfunction.114
by activating the clotting cascade. These vegetative lesions can form Surgery that involves excision of infected tissue with or without
anywhere on the endocardium but usually occur on heart valves and valve replacement improves outcomes in many persons with infective
surrounding structures. Although endocardial tissue is constantly endocarditis, especially those with severe heart failure or persistent
bathed in antibody-containing blood and is surrounded by scaveng- bacteremia despite antibiotic therapy.115 Unfortunately, valve failure
ing monocytes and polymorphonuclear leukocytes, bacterial colo- and valve-induced embolization are known consequences of pros-
nies are inaccessible to host defenses because they are embedded in thetic valve placement, and the presence of an artificial valve is itself a
the protective fibrin clots. Embolization from these vegetations can significant risk factor for infective endocarditis.
lead to abscesses and characteristic skin changes, such as petechiae, In the past, individuals with valvular heart disease received prophy-
splinter hemorrhages, Osler nodes, and Janeway lesions. lactic antibiotics for dental, genitourinary, or gastrointestinal procedures
to prevent infective endocarditis. However, in 2008 the recommenda-
CLINICAL MANIFESTATIONS  Infective endocarditis may be acute, tions were changed such that only “high risk” individuals (history of
subacute, or chronic. It causes varying degrees of valvular dysfunction infective endocarditis, prosthetic valves, cyanotic congenital heart dis-
and may be associated with manifestations involving several organ ease, heart transplant with valvular defect) receive antibiotic prophy-
systems (respiratory [lungs], sensory [eyes], genitourinary [kidneys], laxis, and only in the setting of gingival procedures or in the presence of
musculoskeletal [bones, joints], and central nervous systems), making documented acute gastrointestinal or genitourinary infection.116
diagnosis exceedingly difficult. Signs and symptoms of infective endo-
carditis are caused by infection and inflammation, systemic spread of Cardiac Complications in Acquired Immunodeficiency
microemboli, and immune complex deposition. The “classic” findings Syndrome (AIDS)
are fever; new or changed cardiac murmur; and petechial lesions of Individuals with HIV infection and AIDS are at risk for cardiac com-
the skin, conjunctiva, and oral mucosa. Characteristic physical find- plications including dilated cardiomyopathy, myocarditis, pericardial
ings include Osler nodes (painful erythematous nodules on the pads effusion, endocarditis, pulmonary hypertension, and nonantiretroviral
of the fingers and toes) and Janeway lesions (nonpainful hemorrhagic drug–related cardiotoxicity. In addition, cardiac involvement may be
lesions on the palms and soles).113 Other manifestations include weight induced by various bacterial, viral, protozoal, mycobacterial, and fungal
loss, back pain, night sweats, and heart failure. Central nervous system, pathogens that complicate AIDS. Malignancies, such as lymphoma and
splenic, renal, pulmonary peripheral arterial, coronary, and ocular Kaposi sarcoma, are seen often in individuals with AIDS and can affect
emboli may lead to a wide variety of signs and symptoms. the heart. Furthermore, treatment with highly active antiretroviral ther-
apy (HAART) can cause hyperlipidemia and atherosclerotic disease.
EVALUATION AND TREATMENT  The criteria for the diagnosis of Left heart failure is the most common complication of HIV infec-
infective endocarditis include recognized risk factors, fever, repetitive tion and is related to left ventricular dilation and dysfunction. Pericar-
blood cultures positive for bacteria, appropriate physical examination dial effusion, ventricular dysrhythmias, electrocardiographic changes,
findings (murmur, skin findings), vascular complications, and echo- and right ventricular dilation and hypertrophy are other less common
cardiographic documentation.112 If infective endocarditis extends into findings.
the heart wall and invades the conduction system, electrocardiography
may show significant conduction delays. If emboli to other organs are
4 QUICK CHECK 23-9
1. What three critical elements are required for the pathogenesis of infective
endocarditis?
2. Why does infective endocarditis involve several organ systems?
3. What effect does AIDS have on the heart?

MANIFESTATIONS OF HEART DISEASE

Dysrhythmias
A dysrhythmia, or arrhythmia, is a disturbance of heart rhythm. Nor-
mal heart rhythms are generated by the sinoatrial (SA) node and travel
through the heart’s conduction system, causing the atrial and ventricu-
lar myocardium to contract and relax at a regular rate that is appro-
priate to maintain circulation at various levels of physical activity (see
Chapter 22). Dysrhythmias range in severity from occasional “missed”
or rapid beats to serious disturbances that impair the pumping abil-
ity of the heart, contributing to heart failure and death. Dysrhythmias
can be caused either by an abnormal rate of impulse generation (Table
FIGURE 23-34  Bacterial Endocarditis of Mitral Valve. The valve 23-8) from the SA node or other pacemaker or by the abnormal con-
is covered with large, irregular vegetations (arrow). (From ­Damjanov I, duction of impulses (Table 23-9) through the heart’s conduction sys-
Linder J: Pathology: a color atlas, St Louis, 2000, Mosby.) tem, including the myocardial cells themselves.
620 CHAPTER 23  Alterations of Cardiovascular Function

TABLE 23-8 DISORDERS OF IMPULSE FORMATION

TYPE ELECTROCARDIOGRAM EFFECT PATHOPHYSIOLOGY TREATMENT
Sinus bradycardia P rate 60 or less Increased preload Hyperkalemia: slows depolarization If hypotensive, treat
PR interval normal Decreased mean arterial Vagal hyperactivity: unknown cause
QRS for each P pressure Digoxin toxicity common Sympathomimetics,
Late hypoxia: lack of adenosine anticholinergics
triphosphate (ATP) Pacemaker placement
Simple sinus P rate 100-150 Decreased filling times Catecholamines: rise in resting Oxygen, bed rest
­tachycardia PR interval normal Decreased mean arterial ­potential and calcium influx Calcium blockers
QRS for each P pressure Fever: unknown
Increased myocardial Early heart failure: compensatory
demand response to decreased stroke volume
Lung disease: hypoxic cell metabolism
Hypercalcemia
Premature atrial Early P waves that may have Occasional decreased filling Electrolyte disturbances (especially Treat underlying cause
contractions (PACs) morphologic changes time and mean arterial ­hypercalcemia): alter action potentials Digoxin
or beats* PR interval normal pressure Hypoxia and elevated preload: cell
QRS for each P membrane disturbances
Sinus dysrhythmias Rate varies Variable filling times Unknown None
P-P regularly irregular, short Variable mean arterial Common in young children and young
with inspiration, long with pressure adults
exhalation Variable oxygen demand
PR interval normal
QRS for each P
Atrial tachycardia P rate 151-250 Decreased filling time Same as PACs: leads to increased Control ventricular rate
(includes premature P morphology may differ from Decreased mean arterial atrial automaticity, atrial reentry Digoxin, calcium
atrial tachycardia if sinus P pressure Digoxin toxicity: common ­channel blockers,
onset is abrupt) PR interval normal Increased myocardial Aging vagus stimulation
P/QRS ratio variable demand Pacemaker to override
atrial conduction
Cardioversion
Atrial flutter* P rate 251-300, morphology Decreased filling time Same as atrial tachycardia Same as atrial tachy-
may vary from sinus P Decreased mean arterial cardia
PR interval usually not pressure
­observable
P/QRS ratio variable
Atrial fibrillation* P rate >300 and usually not Same as atrial flutter Same as atrial tachycardia Same as atrial
observable ­tachycardia
No PR interval
QRS rate variable and rhythm
irregular
Idiojunctional rhythm P absent or independent Decreased cardiac output Atrial and sinus bradycardia, standstill, Same as sinus
QRS normal, rate 41-59, from loss of atrial contribu- or block ­bradycardia
regular tion to ventricular preload
Junctional bradycardia P absent or independent Same as idiojunctional Same as idiojunctional rhythm Same as sinus
QRS normal, rate 40 or less rhythm Vagal hyperactivity ­bradycardia
Premature junctional Early beats without P waves Decreased cardiac Hyperkalemia (5.4-6 mEq/L) Same as PAC
contractions (PJCs) QRS morphology normal output from loss of atrial Hypercalcemia, hypoxia, and elevated
or beats ­contribution to ventricular preload (see PACs)
preload for that beat
Accelerated junctional P absent or independent Decreased cardiac output Same as PJCs Same as PAC
rhythm QRS morphology normal, rate from loss of atrial contribu-
60-99 tion to ventricular preload
Junctional tachycardia P absent or independent Decreased cardiac output Same as PJCs Same as PAC
QRS morphology normal, rate from loss of atrial contribu-
100 or more tion to ventricular preload
Increased myocar-
dial demand because of
­tachycardia
 CHAPTER 23  Alterations of Cardiovascular Function 621

TABLE 23-8 DISORDERS OF IMPULSE FORMATION—cont’d

TYPE ELECTROCARDIOGRAM EFFECT PATHOPHYSIOLOGY TREATMENT
Idioventricular rhythm† P absent or independent Same as idiojunctional Sinus, atrial, and junctional bradycar- Same as sinus
QRS >0.11 and rate 20-39 rhythm dia, standstill, or block ­bradycardia
Ventricular P absent or independent Same as idiojunctional Same as idiojunctional rhythm Same as sinus
­bradycardia† QRS >0.11 and rate 60-<60 rhythm ­bradycardia
Agonal rhythm/ P absent or independent Absent or barely present Depolarization and contraction not Vigorous pharmacolog-
electromechanical QRS >0.11 and rate 20 or less cardiac output and pulse coupled: electrical activity present ic treatment aimed
dissociation† Not compatible with life with little or no mechanical activity at restoring rate and
Usually caused by profound hypoxia force
Usually ineffective
May attempt to use
pacemaker
Ventricular standstill or P absent or independent No cardiac output Profound ischemia, hyperkalemia, Same as agonal
asystole† QRS absent Not compatible with life acidosis rhythm, plus electri-
cal defibrillation
Premature ventricular Early beats with P waves Same as premature Same as PJCs, aging and induction of Pharmacologic inter-
contractions (PVCs) QRS occasionally opposite in ­junctional contractions anesthesia ventions to change
or depolarizations* deflection from usual QRS Impulse originates in cell outside nor- thresholds, refrac-
mal conduction system and spreads tory periods; reduce
through intercalated disks myocardial demand,
increase supply
Accelerated ventricular P absent or independent Same as accelerated Same as PVCs Removal of cause
rhythm QRS >0.11 and rate of 41–99 ­junctional rhythm Same as PVCs
Ventricular P absent or independent Same as junctional tachy- Same as PVCs Same as PVCs,
­tachycardia† QRS >0.11 and rate 100 or cardia plus electrical
more ­cardioversion
Ventricular fibrillation† P absent Same as ventricular Same as PVCs Same as PVCs, plus
QRS >300 and usually not standstill Rapid infusion of potassium electrical cardiover-
observable sion

*Most common in adults.

†Life-threatening in adults.

TABLE 23-9 DISORDERS OF IMPULSE CONDUCTION

TYPE ECG EFFECT PATHOPHYSIOLOGY TREATMENT
Sinus block Occasionally absent P, Occasional decrease in Local hypoxia, scarring of intra-atrial Conservative
with loss of QRS for cardiac output conduction pathways, electrolyte Usually do not progress in severity
that beat Increase in preload for imbalances Pharmacologic treatment includes
following beat Increased atrial preload vagolytics, sympathomimetics, pacing
First-degree PRI >0.2 sec None Same as sinus block Conservative
block* Hyperkalemia (>7 mEq/L) Discovery and correction of cause
Hypokalemia (<3.5 mEq/L)
Formation of myocardial abscess in
endocarditis
Second-degree Progressive prolonga- Same as sinus block Hypokalemia (<3.5 mEq/L) Same as sinus block
block, Mobitz tion of PRI until one Faulty cell metabolism in AV node
I, or Wencke- QRS is dropped Severity increases as heart rate increases
bach* Pattern of prolonga- Supports theory that AV node is fatiguing
tion resumes Digoxin toxicity, beta blockade
CAD, MI, hypoxia, increased preload,
valvular surgery and disease, diabetes
Second-degree Same as sinus block Same as sinus block Hypokalemia (<3.5 mEq/L) More aggressively than Mobitz I,
block or Faulty cell metabolism below AV node because can progress to type III
Mobitz II Antidysrhythmics, tricyclic Pacemaker after pharmacologic
­antidepressants ­treatment
CAD, MI, hypoxia, increased preload,
valvular surgery and disease, diabetes

Continued
622 CHAPTER 23  Alterations of Cardiovascular Function

TABLE 23-9 DISORDERS OF IMPULSE CONDUCTION—cont’d

TYPE ECG EFFECT PATHOPHYSIOLOGY TREATMENT
Third-degree P waves present and Same as idiojunctional Hypokalemia (<3.5 mEq/L) Pacemaker after pharmacologic
block† independent of QRS rhythm Faulty cell metabolism low in bundle of ­treatment
No observed His MI, especially inferior wall, as nodal Temporary pacing if caused by
­relationship be- artery interrupted; results in ischemia inferior MI, because ischemia usually
tween P and QRS of AV node resolves
Always AV dissocia-
tion
Atrioventricular P waves present and Decreased cardiac May result from third-degree block or Treat according to cause
dissociation independent of output from loss of accelerated junctional or ventricular Pacemaker or reducing rate of AV or
QRS, but not always atrial contribution to rhythm or be caused by sinus, atrial, and ventricular discharge, or increasing
because of block ventricular preload junctional bradycardias rate of sinus or AV node discharge
(e.g., ventricular Variable effect on
tachycardia) myocardial demand,
AV dissociation not depending on
always third-degree ­ventricular rate
block
Ventricular block QRS >0.11 sec None Faulty cell metabolism in right and left Isolated RBBB or LBBB or hemiblock
R-S-R′ in V1, V2, V5, V6 bundle branches not treated
RBBB more common than LBBB because If acute and/or associated with acute
of dual blood supply to left bundle anterior MI, treated with permanent
branch pacer and vigorous pharmacologic
CHF, MR, especially anterior MI, because therapy
of infarct of fascicles
Left anterior hemiblock more common
than left posterior hemiblock because
posterior fascicles have dual blood
supply
Aberrant conduc- QRS >0.11 sec None, unless Conduction of impulse through inter- Correct underlying cause
tion ­ventricular rate calated disks because conduction
­abnormalities system transiently blocked as a result
present of hypoxia, electrolyte imbalances,
digoxin toxicity, excessively rapid rate
of discharge
Preexcitation P present with QRS None Congenital presence of accessory Aimed at aligning refractory periods of
­syndromes for each P pathways (bundle of Kent and fiber accessory pathway and AV node to
(Wolff-­ PRI <0.12 sec and QRS of Mahaim) that conduct very rapidly prevent reentry
Parkinson- <0.11 sec because and bypass AV node, causing early May slow rate with drug therapy
White and of delta wave in PRI ventricular depolarization in relation to May surgically cut pathways
Lown- atrial depolarization
Ganong-Levine) Prone to tachycardias and atrial fibrillation
that can result in very rapid ventricular
rates (reason unknown)

*Most common in adults.

†Life-threatening in adults.

AV, Atrioventricular; CAD, coronary artery disease; CHF, congestive heart failure; LBBB, left bundle branch block; MI, myocardial infarction;
MR, mitral regurgitation; PRI, PR interval; RBBB, right bundle branch block.

Heart Failure alcohol use. Numerous genetic polymorphisms have been linked to an
Heart failure is when the heart is unable to generate an adequate car- increased risk for heart failure, including genes for cardiomyopathies,
diac output, causing inadequate perfusion of tissues or increased dia- myocyte contractility, and neurohumoral receptors. Recently, genetic
stolic filling pressure of the left ventricle, or both, so that pulmonary changes in kinases, phosphatases, and cellular calcium cycling are
capillary pressures are increased. It affects nearly 10% of individuals being explored.117 Most causes of heart failure result from dysfunc-
older than age 65 and is the most common reason for admission to the tion of the left ventricle (systolic and diastolic heart failure). The right
hospital in that age group. Ischemic heart disease and hypertension ventricle also may be dysfunctional, especially in pulmonary disease
are the most important predisposing risk factors.8 Other risk factors (right ventricular failure). Finally, some conditions cause inadequate
include age, obesity, diabetes, renal failure, valvular heart disease, car- perfusion despite normal or elevated cardiac output (high-output
diomyopathies, myocarditis, congenital heart disease, and excessive failure).
 CHAPTER 23  Alterations of Cardiovascular Function 623

Left Heart Failure (Congestive Heart Failure)

BOX 23-3 INFLAMMATION, IMMUNITY,
Left heart failure is commonly called congestive heart failure and can
be further categorized as systolic heart failure or diastolic heart failure.
AND HUMORAL FACTORS IN
It is possible for these two types of heart failure to occur simultane- THE PATHOGENESIS OF HEART
ously in one individual. FAILURE
Systolic heart failure is defined as an inability of the heart to gener- The treatment of the hemodynamic abnormalities of heart failure (HF) can provide
ate an adequate cardiac output to perfuse vital tissues. Cardiac output short-term improvement in symptoms but will not prevent the progression of myo-
depends on the heart rate and stroke volume. Stroke volume is influ- cardial dysfunction over time. Studies have shown that the neurohumoral responses
enced by three major determinants: contractility, preload, and after- to heart failure (including changes in the renin-angiotensin-aldosterone system, cat-
load (see Chapter 22). echolamines, natriuretic peptides, and vasopressin) exert direct cardiotoxicity that
Contractility is reduced by diseases that disrupt myocyte activity. results in progressive damage to the heart muscle. Drugs such as ACE inhibitors,
Myocardial infarction is the most common primary cause of decreased angiotensin receptor blockers, spironolactone, and beta-blockers can slow disease
contractility, and other causes include myocarditis and cardiomyopa- progression and are now the standard of care for HF. More recently, inflamma-
thies. Secondary causes of decreased contractility, such as recurrent tory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukins have
myocardial ischemia and increased myocardial workload, contribute been implicated in the pathogenesis of heart failure and its systemic complications
to inflammatory, immune, and neurohumoral changes (activation of (such as cachexia and malaise). Early trials with anticytokine drugs are under way.
the SNS and RAAS) that mediate a process called ventricular remodel-
ing (Box 23-3).89,118 Ventricular remodeling results in disruption of Data from McMurray JJ: N Engl J Med 362:228–238, 2010; Picano E
the normal myocardial extracellular structure with resultant dilation et al: Ann N Y Acad Sci 1207:107–115, 2010; Rehsia NS, Dhalla NS:
of the myocardium and causes progressive myocyte contractile dys- Heart Failure Rev 15(1):85–101, 2010; Sciarretta S et al: Clin Sci
116(6):467–477, 2009; Sun Y: Cardiovasc Res 81(3):482–490, 2009;
function over time (Figure 23-35).119 When contractility is decreased,
Triposkiadis F et al: J Am Coll Cardiol 54(19):1747–1762, 2009.

Myocardial dysfunction
• Myocardial infarction
• Ischemic heart disease
• Hypertension
• Other

Cardiac output Perfusion to kidneys

Systemic blood pressure

Baroreceptors activated Renin-angiotensin-aldosterone system activated

• Left ventricle
• Aortic arch
• Carotid sinus
Angiotensin II
FIGURE 23-35  Pathophysiology of Ven­
Aldosterone tric­ular Remodeling. Myocardial dysfunction
Vasomotor regulatory centers
in medulla stimulated
activates the renin-angiotensin-aldosterone
Lungs and sympathetic nervous systems, releasing
neurohormones (angiotensin II, aldosterone,
Renin Angiotensin I
catecholamines, and cytokines). These neu-
Sympathetic rohormones contribute to ventricular remod-
nervous system
activated Angiotensin II
Angiotensinogen eling. (Redrawn from Carelock J, Clark AP:
Aldosterone Heart failure: pathophysiologic mechanisms, 
Am J Nurs 101[12]:27, 2001.)

Catecholamines • Retain sodium and water

(epinephrine and Vasoconstriction
• Arginine vasopressin
norepinephrine) • Endothelin
• Cytokines
Afterload
(tumor necrosis factor-α)
Blood pressure
Heart rate

Ventricular remodeling
• Hypertrophy and dilation of ventricle
• Genetically large cells
Remodeled
• Impaired contractility

Normal
624 CHAPTER 23  Alterations of Cardiovascular Function

↑Preload (↑ LVEDV) Increased peripheral vascular resistance

↓ Lumen of Increased resistance to ventricular ejection (afterload)

coronary arteries
Stretching of
myocardium Increased workload for the left ventricle

Myocardial
ischemia
Neurohumoral changes
(↑ RAA and SNS)

↓ Contractility
Hypertrophy
FIGURE 23-36  Effect of Elevated Preload on Myocardial Oxy-
gen Supply and Demand. LVEDV, Left ventricular end-diastolic
volume. Increased myocyte demand for oxygen
(relative ischemia)

stroke volume falls and left ventricular end-diastolic volume (LVEDV)

increases. This causes dilation of the heart and an increase in preload. Ventricular remodeling
Preload, or LVEDV, increases with decreased contractility or an
excess of plasma volume (intravenous fluid administration, renal fail-
ure, mitral valvular disease). Increases in LVEDV can actually improve Decreased contractility
cardiac output up to a certain point, but as preload continues to rise, (↓ cardiac output & underperfusion of vital tissues)
it causes a stretching of the myocardium that eventually can lead to
dysfunction of the sarcomeres and decreased contractility. This rela- FIGURE 23-37  Role of Increased Afterload in the Pathogenesis
tionship is described by the Frank-Starling law of the heart (see Figure of Heart Failure.
22-16). Decreased contractility leads to further increases in preload
(Figure 23-36).
Increased afterload is most commonly a result of increased periph- increase salt excretion in an effort to prevent long-term damage to the
eral vascular resistance (PVR), such as that seen with hypertension. It myocardium.181,121 Drugs that block vasopressin are also being used
also can be the result of aortic valvular disease. With increased after- in selected individuals. Immune and inflammatory processes also play
load, there is resistance to ventricular emptying and more workload for an important role in the pathogenesis of heart failure and its systemic
the ventricle, which responds with hypertrophy of the myocardium. complications, such as weakness and cachexia (see Box 23-3). Other
Hypertrophy is mediated by angiotensin II and catecholamines and metabolic alterations in the myocardium include changes in calcium
results in an increase in oxygen demand by the thickened myocar- transport and insulin resistance (see Health Alert: Metabolic Changes
dium. A state of relative ischemia develops that further contributes in Heart Failure).
to changes in the myocytes themselves and ventricular remodeling The interaction of these hemodynamic, neurohumoral, inflamma-
(­Figure 23-37).118,120 In addition, hypertrophy results in the deposition tory, and metabolic processes results in a steady decline in myocardial
of collagen between the myocytes, which can disrupt the integrity of function. Pathologically, the heart muscle exhibits gradual changes in
the muscle, decrease contractility, and increase the likelihood that the myocyte structure and function, with apoptosis of cells, deposition
ventricle will dilate and fail. These changes in ventricular structure and of fibrin, and remodeling of the myocardium such that contractility
function are referred to as hypertensive hypertrophic cardiomyopathy and cardiac output decline.118 A vicious cycle of decreasing contractil-
(see p. 612). ity, increasing preload, and increasing afterload develops, causing the
As cardiac output falls, renal perfusion diminishes with activation progressive worsening of symptoms associated with left heart failure
of the RAAS, which acts to increase PVR and plasma volume, thus (Figure 23-38).
further increasing afterload and preload. In addition, baroreceptors The clinical manifestations of left heart failure are the result of
in the central circulation detect the decrease in perfusion and stimu- pulmonary vascular congestion and inadequate perfusion of the sys-
late the SNS to cause yet more vasoconstriction and the hypothala- temic circulation. Individuals experience dyspnea, orthopnea, cough
mus to produce antidiuretic hormone. It is believed that angiotensin, of frothy sputum, fatigue, decreased urine output, and edema. Physi-
aldosterone, and the catecholamines not only disturb cardiac hemo- cal examination often reveals pulmonary edema (cyanosis, inspiratory
dynamics but also are directly cardiotoxic. Arginine vasopressin has crackles, pleural effusions), hypotension or hypertension, an S3 gal-
been implicated in worsening electrolyte disturbances and edema, lop, and evidence of underlying CAD or hypertension. The diagnosis
which are common complications of heart failure. Furthermore, can be further confirmed with echocardiography showing decreased
natriuretic peptides are released in an effort to improve renal salt and cardiac output and cardiomegaly. The level of serum brain natriuretic
water excretion but are inadequate to compensate for these neuro- peptide (BNP) can also help make the diagnosis of heart failure and
humoral perturbations. These neurohumoral aspects of left systolic give some insight into its severity.122
heart failure have led to the routine use of combinations of medica- Management of systolic left heart failure is aimed at interrupting
tions that inhibit angiotensin, aldosterone, and catecholamines and the worsening cycle of decreasing contractility, increasing preload,
 CHAPTER 23  Alterations of Cardiovascular Function 625

Myocardial infarction HEALTH ALERT

Metabolic Changes in Heart Failure
Contractility The heart is the largest consumer of energy in the body and relies on the
efficient production of adenosine triphosphate (ATP). The heart has very little
Renal perfusion capacity for energy storage. In the failing heart, increased demand for oxygen
Ejection fraction
LVEDV Renin and and energy is coupled with a decreased ability to utilize fatty acids as an energy
angiotensin source. As a result, several genes are activated that alter the ability of myo-
cytes to use lipids and glucose as fuel sources, the most studied of which are
the peroxisome proliferator-activated receptor (PPAR) family of genes. These
Preload Afterload genes control fatty acid oxidation and are of particular importance in heart
failure associated with insulin resistance and diabetes. Energy starvation and
high levels of catecholamines associated with heart failure lead to altered
Renal failure Hypertension
fatty acid oxidation and decreased effective ATP generation and utilization.
FIGURE 23-38  Vicious Cycle of Systolic Heart Failure. Although This results in decreased myocardial contractility and structural changes in
the initial insult may be one of primary decreased contractility (e.g., the myocardium (remodeling). Increasing knowledge of these mechanisms has
myocardial infarction), increased preload (e.g., renal failure), or led to the exploration of potential new therapies for heart failure. For example,
increased afterload (e.g., hypertension), all three factors play a role although currently available PPAR-γ agonists (thiazolidinediones) are contrain-
in the progression of left heart failure (LHF). LVEDV, Left ventricular dicated in worsening heart failure because of increased fluid retention at the
end-diastolic volume. renal tubule, new insulin sensitizers are being explored that may improve myo-
cardial metabolic function. In addition, inhibitors of fatty acid oxidation (e.g.,
trimetazidine) have been tried in several small studies with some improve-
and increasing afterload. The acute onset of left heart failure is most ment in cardiac function. Many new potential pharmacologic interventions are
often the result of acute myocardial ischemia and must be managed under investigation, but in the meantime most researchers agree that exercise
in conjunction with management of the underlying coronary disease and a healthy diet can improve myocardial metabolic function.
(see p. 601). Oxygen, nitrate, and morphine administration improves
myocardial oxygenation and helps relieve coronary spasm while low- Data from Abozguia K et al: Curr Pharm Des 15(8):827–835, 2009;
ering preload through systemic venodilation. Intravenous inotropic ­Adachi T: Adv Pharmacol 59:165–195, 2010; Ashrafian H et al: Circula-
drugs, such as dopamine or dobutamine, increase contractility and tion 116(4):434–448, 2007; Boudina S et al: Circulation 115(25):
can help raise the blood pressure in hypotensive individuals, and new 3213–3223, 2007; Lehnart SE, Maier LS, Hasenfuss G: Heart Fail Rev
inotropic drugs (e.g., levosimendan) are being evaluated. Diuret- 14(4):213–224, 2009; Neubauer S: N Engl J Med 356(11):1140–1151,
ics reduce preload. ACE inhibitors, ARBs, and aldosterone blockers 2007; Mudd JO et al: Nature 451(7181):919–928, 2008; Nass RD et al:
Nat Clin Pract Cardiovasc Med 5(4):196–207, 2008; Tang WH et al:
reduce both preload and afterload by decreasing aldosterone lev-
Diabetes Obes Metab 9(4):447–454, 2007.
els and reducing PVR. Short-acting intravenous beta-blockers also
have been found to reduce mortality in selected people. Intravenous
human recombinant brain natriuretic peptide (BNP) also may be improve perfusion to ischemic myocardium (hibernating myo-
used in acute heart failure, although the benefits of this therapy con- cardium) and improve cardiac output. Surgical interventions that
tinue to be debated.123 Finally, individuals with severe systolic failure improve ventricular geometry or heart transplantation may need to
may benefit from acute coronary bypass or percutaneous coronary be considered. Experimental therapies including gene and stem cell
intervention (PCI). These people often are supported with the intra- therapies are being explored.
aortic balloon pump (IABP) until surgery can be performed. The Diastolic heart failure is also known as heart failure with preserved
IABP is positioned in the aorta just distal to the aortic valve and is systolic function or heart failure with normal ejection fraction (HFNEF).
inflated during diastole to improve coronary perfusion and deflated Diastolic heart failure can occur singly or along with systolic heart fail-
during systole to reduce afterload. ure. Isolated diastolic heart failure is defined as pulmonary congestion
Management of chronic left heart failure relies on reducing pre- despite a normal stroke volume and cardiac output. It is the cause of 40%
load and afterload. Salt restriction and diuretics (especially spirono- to 50% of all cases of left heart failure and is more common in women. It
lactone) are effective in reducing preload. ACE inhibitors (or Ang results from decreased compliance of the left ventricle and abnormal dia-
II receptor blockers) reduce preload and afterload and have been stolic relaxation such that a normal left ventricular end-diastolic volume
shown to significantly reduce mortality in individuals with chronic (LVEDV) results in an increased left ventricular end-diastolic pressure
left heart failure. Aldosterone blockers are also associated with (LVEDP). This pressure is reflected back into the pulmonary circula-
improved outcomes. Beta-blockers improve symptoms and increase tion and results in pulmonary edema. The major causes of diastolic
survival but must be used carefully to avoid hypotension.121,124 The dysfunction include hypertension-induced myocardial hypertrophy and
inotropic drug digoxin may be considered in selected individuals, myocardial ischemia–induced ventricular remodeling. Hypertrophy
especially those with atrial fibrillation. Although many individuals and ischemia cause a decreased ability of the myocytes to actively pump
with left heart failure die suddenly from dysrhythmias, prophylactic calcium from the cytosol, resulting in impaired relaxation. Other causes
administration of antidysrhythmics has not been shown to improve include aortic valvular disease, mitral valve disease, pericardial diseases,
survival. In individuals with sustained ventricular tachycardia, and cardiomyopathies. Diabetes also increases the risk for diastolic dys-
amiodarone or implantable cardioverter-defibrillators should be function. Like systolic heart failure, diastolic failure is characterized by
considered. Cardiac resynchronization therapy is proving to be an sustained activation of the RAAS and the SNS.
important modality in selected individuals. For those individuals Individuals with diastolic dysfunction present with dyspnea on
with coronary artery disease, coronary bypass surgery or PCI may exertion, fatigue, and evidence of pulmonary edema (inspiratory
626 CHAPTER 23  Alterations of Cardiovascular Function

crackles on auscultation, pleural effusions). There also may be evidence Lung disease
of underlying coronary disease, hypertension, or valvular disease.
Diagnosis is based upon three factors: signs and symptoms of heart
failure, normal left ventricular (LV) ejection fraction, and evidence of
diastolic dysfunction. The diagnosis is made initially by echocardiogra- ↑ Pulmonary vascular ↓ Oxygen supply
phy, which demonstrates poor ventricular filling with normal ejection resistance
fractions. Management is aimed at improving ventricular relaxation
and prolonging diastolic filling times to reduce diastolic pressure. Cal-
cium channel blockers, beta-blockers, ACE inhibitors, and ARBs have ↑ Force of RV contraction
been used with varying success. Treatment with the HMG Co-A reduc-
tase inhibitors (statins) has consistently resulted in improvements in
LV diastolic function.125 Inotropic drugs are not indicated in isolated ↑ RV oxygen demand RV hypoxia
diastolic heart failure because contractility and ejection fraction are
not affected; however, digoxin may be used to slow the heart rate in
individuals with atrial fibrillation. Outcomes for individuals with dia-
stolic heart failure are as poor as those with systolic heart failure, and ↓ Force of RV contraction
there has been no improvement in prognosis despite numerous new
treatment trials.125
↑ RV end-diastolic
Right Heart Failure pressure
Right heart failure is defined as the inability of the right ventricle
to provide adequate blood flow into the pulmonary circulation at a
normal central venous pressure. It can result from left heart failure ↑ RV preload
when an increase in left ventricular filling pressure is reflected back
into the pulmonary circulation. As pressure in the pulmonary cir-
culation rises, the resistance to right ventricular emptying increases
↑ RA preload
(Figure 23-39). The right ventricle is poorly prepared to compensate
for this increased afterload and will dilate and fail. When this hap-
pens, pressure will rise in the systemic venous circulation, result-
ing in peripheral edema and hepatosplenomegaly. Treatment relies Peripheral edema
on management of the left ventricular dysfunction as just outlined. FIGURE 23-39  Right Heart Failure. RA, Right atrial; RV, right
When right heart failure occurs in the absence of left heart failure, ventricular.
it is typically attributable to diffuse hypoxic pulmonary disease such
as chronic obstructive pulmonary disease (COPD), cystic fibrosis,
and acute respiratory distress syndrome (ARDS). These disorders for vasodilation. Body tissues show signs of inadequate blood supply
result in an increase in right ventricular afterload. The mechanisms despite a high cardiac output.
for this type of right ventricular failure (cor pulmonale) are discussed Hyperthyroidism accelerates cellular metabolism through the
in Chapter 26. Finally, myocardial infarction, cardiomyopathies, and actions of elevated levels of thyroxine from the thyroid gland. This may
pulmonic valvular disease interfere with right ventricular contractility occur chronically (thyrotoxicosis) or acutely (thyroid storm). Because
and can lead to right heart failure. the body’s increased demand for oxygen threatens to cause metabolic
acidosis, cardiac output increases. If blood levels of thyroxine are high
High-Output Failure and the metabolic response to thyroxine is vigorous, even an abnor-
High-output failure is the inability of the heart to adequately supply mally elevated cardiac output may be inadequate.
the body with blood-borne nutrients, despite adequate blood volume In the United States, beriberi (thiamine deficiency) usually is caused
and normal or elevated myocardial contractility. In high-output fail- by malnutrition secondary to chronic alcoholism. Beriberi actually
ure, the heart increases its output but the body’s metabolic needs are causes a mixed type of heart failure. Thiamine deficiency impairs cel-
still not met. Common causes of high-output failure are anemia, septi- lular metabolism in all tissues, including the myocardium. In the heart,
cemia, hyperthyroidism, and beriberi (Figure 23-40). impaired cardiac metabolism leads to insufficient contractile strength.
Anemia decreases the oxygen-carrying capacity of the blood. In blood vessels, thiamine deficiency leads to peripheral vasodilation,
Metabolic acidosis occurs as the body’s cells switch to anaerobic which decreases SVR. Heart failure ensues as decreased SVR triggers
metabolism (see Chapter 4). In response to metabolic acidosis, increased cardiac output, which the impaired myocardium is unable
heart rate and stroke volume increase in an attempt to improve to deliver. The strain of demands for increased output in the face of
tissue perfusion. If anemia is severe, however, even maximum impaired metabolism may deplete cardiac reserves until low-output
cardiac output does not supply the cells with enough oxygen for failure begins.
metabolism.
In septicemia, disturbed metabolism, bacterial toxins, and the
inflammatory process cause systemic vasodilation and fever. Faced
with a lowered systemic vascular resistance (SVR) and an elevated
4 QUICK CHECK 23-10
1. Why are changes in LVEDV important for left heart failure?
metabolic rate, cardiac output increases to maintain blood pressure 2. What is ventricular remodeling?
and prevent metabolic acidosis. In overwhelming septicemia, however, 3. What is the vicious cycle of systolic heart failure?
the heart may not be able to raise its output enough to compensate
 CHAPTER 23  Alterations of Cardiovascular Function 627

Anemia

Impaired cardiac
↓ Cardiac output
metabolism

Impaired oxygen
Beriberi ↓ SVR
delivery

Sepsis (septicemia)

Fever Tissue hypoxia

Excessive tissue
Hyperthyroidism ↑ Basal metabolic rate
oxygen demands

Catecholamines

↑ Heart rate and

stroke volume

↑ Cardiac output
FIGURE 23-40  High-Output Failure. SVR, Systemic vascular resistance.

efficient method of extracting energy from carbon bonds, and the cell
SHOCK
begins to use its stores of adenosine triphosphate (ATP) faster than
In shock the cardiovascular system fails to perfuse the tissues adequately, stores can be replaced. Without ATP, the cell cannot maintain an elec-
resulting in widespread impairment of cellular metabolism. Because tis- trochemical gradient across its selectively permeable membrane. Spe-
sue perfusion can be disrupted by any factor that alters heart function, cifically, the cell cannot operate the sodium-potassium pump. Sodium
blood volume, or blood pressure, shock has many causes and various and chloride accumulate inside the cell, and potassium exits the cell.
clinical manifestations. Ultimately, however, shock progresses to organ Cells of the nervous system and myocardium are profoundly and imme-
failure and death, unless compensatory mechanisms reverse the process diately affected. The resting potentials of these cells are reduced, and
or clinical intervention succeeds. Untreated severe shock overwhelms action potentials decrease in amplitude. Various clinical manifestations
the body’s compensatory mechanisms through positive feedback loops of impaired central nervous system and myocardial function result.
that initiate and maintain a downward physiologic spiral. As sodium moves into the cell, water follows. Throughout the body,
The term multiple organ dysfunction syndrome (MODS) describes the water drawn from the interstitium into the cells is “replaced” by
the failure of two or more organ systems after severe illness and injury water that is, in turn, drawn out of the vascular space. This decreases
and is a frequent complication of severe shock. The disease process circulatory volume. Within the cells, water causes cellular edema that
is initiated and perpetuated by uncontrolled inflammatory and stress disrupts cellular membranes, releasing lysosomal enzymes that injure
responses. It is progressive and is associated with significant mortality. the cells internally and then leak into the interstitium. Three positive
feedback loops further impair oxygen use: (1) activation of the clotting
Impairment of Cellular Metabolism cascade, (2) decreased circulatory volume, and (3) lysosomal enzyme
The final common pathway in shock of any type is impairment of release. The clotting cascade activates the inflammatory response and
cellular metabolism. Figure 23-41 illustrates the pathophysiology of also accounts for typical complications of shock, such as acute tubular
shock at the cellular level. necrosis (ATN), acute respiratory distress syndrome (ARDS), and dis-
seminated intravascular coagulation (DIC).126
Impairment of Oxygen Use Decreased circulatory volume causes the second positive feedback
In all types of shock, the cell either is not receiving an adequate amount loop and magnifies decreased tissue perfusion in all types of shock.
of oxygen or is unable to use oxygen. Without oxygen, the cell shifts Lysosomal enzymes, the third positive feedback loop, not only injure
from aerobic to anaerobic metabolism. Anaerobic metabolism is a less the cell that released them but also injure adjacent cells. By damaging
 628
CHAPTER 23  Alterations of Cardiovascular Function
Impaired cellular metabolism

↓ Tissue perfusion Impaired oxygen

Impaired glucose use
use

↓ Oxygen affinity for Catecholamines, cortisol,

Anaerobic metabolism ↑ Serum glucose
hemoglobin growth hormone

↓ ATP ↑ Lactate ↑ Pyruvate ↑ Lipolysis ↑ Gluconeogenesis ↑ Glycogenolysis

↓ Na+, K+ Metabolic acidosis ↑ Serum triglycerides,

pump ↓ Energy stores
free fatty acids

↑ Intracellular Na+ and

water ↓ Serum albumin ↑ Serum branched chain
amino acids

↓ Circulatory volume Cellular edema ↑ Serum alanine

↑ Urea, NH4 formation
and synthesis

↑Clotting cascade Inflammatory response Release of lysosomal

enzymes
FIGURE 23-41  Impaired Cellular Metabolism in Shock. ATP, Adenosine triphosphate.
 CHAPTER 23  Alterations of Cardiovascular Function 629

the mechanisms of surrounding cells, lysosomal enzymes extend areas vital organs have damage to cellular membranes, leakage of lysosomal
of impaired metabolism and cellular injury. enzymes, and ATP depletion, shock can be irreversible.
In addition to decreasing ATP stores, anaerobic metabolism affects
the pH of the cell, and metabolic acidosis develops. A compensatory Clinical Manifestations of Shock
mechanism enables cardiac and skeletal muscles to use lactic acid as a The clinical manifestations of shock are variable depending on the
fuel source, but only for a limited time. The decreasing pH of the cell type of shock, and observable and measurable signs and symptoms are
that is functioning anaerobically has serious consequences. Enzymes often conflicting in nature. Subjective complaints in shock are usu-
necessary for cellular function dissociate under acid conditions. Enzyme ally nonspecific. The individual may report feeling sick, weak, cold,
dissociation stops cell function, repair, and division. As lactic acid is hot, nauseated, dizzy, confused, afraid, thirsty, and short of breath.
released systemically, blood pH drops, reducing the oxygen-carrying Hypotension, characterized by a mean arterial pressure below 60 mm
capacity of the blood (see Chapter 4). Therefore less oxygen is deliv- Hg, is common to almost all shock states; however, it is a late sign
ered to the cells. Further acidosis triggers the release of more lysosomal of decreased tissue perfusion. Cardiac output and urinary output are
enzymes because the low pH disrupts lysosomal membrane integrity. usually variable early in shock states but generally become decreased as
the shock syndrome progresses. Respiratory rate is usually increased,
Impairment of Glucose Use and a respiratory alkalosis may be an important early indicator of
Impaired glucose use can be caused by either impaired glucose delivery impending shock. Other variable indicators of shock include altera-
or impaired glucose uptake by the cells (see Figure 23-43). The rea- tions of heart rate, core body temperature, skin temperature, systemic
sons for inadequate glucose delivery are the same as those enumerated vascular resistance (SVR), and skin color. Altered sensorium may be
for inadequate oxygen delivery. In addition, in septic and anaphylactic another indicator of poor tissue perfusion. A decreased, mixed venous
shock, glucose metabolism may be increased or disrupted because of oxygen saturation indicates poor tissue oxygenation and an alteration
fever or bacteria, and glucose uptake can be prevented by the presence in cellular oxygen extraction and can be used to monitor response to
of vasoactive toxins, endotoxins, histamine, and kinins. therapy.
Some compensatory mechanisms activated by shock contribute to
decreased glucose uptake by the cells. High serum levels of cortisol, Treatment for Shock
thyroid hormone, and catecholamines account for hyperglycemia and The first treatment for shock is to discover and correct or remove the
insulin resistance, tachycardia, increased SVR, and increased cardiac underlying cause. General supportive treatment includes intravenous
contractility. Cells shift to glycogenolysis, gluconeogenesis, and lipoly- fluid administered to expand intravascular volume, vasopressors, and
sis to generate fuel for survival (see Chapter 1). Except in the liver, supplemental oxygen. Further treatment depends on the cause and
kidneys, and muscles, the body’s cells have extremely limited stores severity of the shock syndrome, which is discussed with each type of
of glycogen. In fact, total body stores can fuel the metabolism for only shock. Once positive feedback loops are established, intervention in
about 10 hours. The depletion of fat and glycogen stores is not itself a shock is difficult. Prevention and very early treatment offer the best
cause of organ failure, but the energy costs of glycogenolysis and lipol- prognosis.
ysis are considerable and contribute to cell failure.
The depletion of protein also is a cause of organ failure. When glu- Types of Shock
coneogenesis causes proteins to be used for fuel, these proteins are no Shock is classified by cause as cardiogenic (caused by heart failure),
longer available to maintain cellular structure, function, repair, and hypovolemic (caused by insufficient intravascular fluid volume), neu-
replication. The breakdown of protein occurs in starvation states, rogenic (caused by neural alterations of vascular smooth muscle tone),
hyperdynamic metabolic states, and septic shock. The metabolism of anaphylactic (caused by immunologic processes), or septic (caused by
protein into amino acids that occurs with septicemia is called septic infection). As described previously, each of these share similar effects on
autocannibalism. During anaerobic metabolism, protein metabolism tissues and cells but can vary in their clinical manifestations and severity.
liberates alanine, which is converted to pyruvate. In sepsis, pyruvic acid
is changed into lactic acid, and a positive feedback loop is formed. Cardiogenic Shock
As proteins are broken down anaerobically, ammonia and urea are Cardiogenic shock is defined as decreased cardiac output and evidence
produced. Ammonia is toxic to living cells. Uremia develops, and uric of tissue hypoxia in the presence of adequate intravascular volume.
acid further disrupts cellular metabolism. Serum albumin and other Most cases of cardiogenic shock follow myocardial infarction, but
plasma proteins are consumed for fuel first. Serum protein consump- shock also can follow left heart failure, dysrhythmias, acute valvular
tion decreases capillary osmotic pressure and contributes to the devel- dysfunction, ventricular or septal rupture, myocardial or pericardial
opment of interstitial edema, creating another positive feedback loop infections, massive pulmonary embolism, cardiac tamponade, and
that decreases circulatory volume. In septic shock, plasma protein drug toxicity. The pathophysiology of cardiogenic shock is illustrated
breakdown includes metabolism of immunoglobulins, thereby impair- in Figure 23-42.
ing immune system function when it is most needed. The clinical manifestations of cardiogenic shock are caused by
Muscle wasting caused by protein breakdown weakens skeletal and widespread impairment of cellular metabolism. They include impaired
cardiac muscle. Skeletal muscle wasting impairs the muscles that facili- mentation, dyspnea and tachypnia, systemic venous and pulmonary
tate breathing. Muscle wasting therefore alters the actions of both the edema, dusky skin color, marked hypotension, oliguria, and ileus.
heart and the lungs. The delivery of oxygen and glucose to the cells is Management of cardiogenic shock includes careful fluid and pressor
directly reduced, as is the removal of waste products, forming another administration followed by early angiography, intra-aortic balloon
positive feedback loop. pump counterpulsation, ventricular assist devices, and early revascu-
A final outcome of impaired cellular metabolism is the buildup of larization (PCI or bypass surgery).127 Cardiogenic shock is often unre-
metabolic end products in the cell and interstitial spaces. Waste prod- sponsive to treatment, with a mortality of more than 70% reported.
ucts are toxic to the cells and further disrupt cellular function and New therapies being explored include anti-inflammatory drugs and
membrane integrity. Once a sufficiently large number of cells from nitric oxide synthetase inhibitors.127
630 CHAPTER 23  Alterations of Cardiovascular Function

Cardiac output

Compensatory renin- Adequate or Catecholamine

aldosterone, ADH SVR compensatory release
blood volume

Systemic and Preload, stroke volume,

pulmonary edema and heart rate

Dyspnea Myocardial oxygen requirements

FIGURE 23-42  Cardiogenic Shock. Shock becomes

life-threatening when compensatory mechanisms (in Cardiac output,
blue) cause increased myocardial oxygen require- Blood pressure
ejection fraction
ments. Renal and hypothalamic adaptive responses
(i.e., renin-angiotensin-aldosterone and antidiuretic
hormone [ADH]) maintain or increase blood volume.
The adrenal gland releases catecholamines (e.g., Tissue perfusion
mostly epinephrine, some norepinephrine), causing
vasoconstriction and increases in contractility and Ischemia
heart rate. These adaptive mechanisms, however, Impaired cellular
increase myocardial demands for oxygen and nutri- metabolism
ents. These demands further strain the heart, which
can no longer pump an adequate volume, resulting
in shock and impaired metabolism. SVR, Systemic Myocardial dysfunction
vascular resistance.

Decreased intravascular
volume

↓ Cardiac output

Shift of interstitial ↑ Heart rate, Catecholamine

fluid contractility release

↑ Volume ↑ SVR
Aldosterone, ADH

Splenic discharge
↑ Cardiac output

More volume loss

↓ Cardiac output ↓ Systemic and pulmonic

pressures

↓ Tissue perfusion FIGURE 23-43  Hypovolemic Shock. This type of

shock becomes life-threatening when compen-
satory mechanisms (in purple) are overwhelmed
by continued loss of intravascular volume. ADH,
Impaired cellular
metabolism Antidiuretic hormone; SVR, systemic vascular
resistance.
 CHAPTER 23  Alterations of Cardiovascular Function 631

Hypovolemic Shock
↓ Sympathetic
Hypovolemic shock is caused by loss of whole blood (hemorrhage),
and/or
plasma (burns), or interstitial fluid (diaphoresis, diabetes mellitus,
↑ parasympathetic
diabetes insipidus, emesis, diarrhea, or diuresis) in large amounts.
stimulation
Hypovolemic shock begins to develop when intravascular volume has
decreased by about 15%.
Hypovolemia is offset initially by compensatory mechanisms
(­Figure 23-43). Heart rate and SVR increase, boosting both cardiac ↓ Vascular tone
output and tissue perfusion pressures. Interstitial fluid moves into the
vascular compartment. The liver and spleen add to blood volume by
disgorging stored red blood cells and plasma. In the kidneys, renin Massive vasodilation
stimulates aldosterone release and the retention of sodium (and hence
water), whereas antidiuretic hormone (ADH) from the posterior pitu-
itary gland increases water retention. However, if the initial fluid or ↓ SVR
blood loss is great or if loss continues, compensation fails, resulting
in decreased tissue perfusion. As in cardiogenic shock, oxygen and
nutrient delivery to the cells is impaired and cellular metabolism fails. Inadequate cardiac output
Anaerobic metabolism and lactate production result in lactic acidosis
and serum and cellular electrolyte abnormalities.
The clinical manifestations of hypovolemic shock include high SVR,
poor skin turgor, thirst, oliguria, low systemic and pulmonary preloads, ↓ Tissue perfusion
rapid heart rate, thready pulse, and mental status deterioration. The dif-
ferences between the signs and symptoms of hypovolemic shock and those
of cardiogenic shock are mainly caused by differences in fluid volume and Impaired cellular
cardiac muscle health. Management begins with rapid fluid replacement metabolism
with crystalloids and blood products. For hemorrhagic hypovolemic
FIGURE 23-44  Neurogenic Shock. SVR, Systemic vascular
shock, the administration of pharmacologic doses of ADH can improve resistance.
blood pressure.128 Hypothermia and coagulopathies frequently compli-
cate treatment. If adequate tissue perfusion cannot be restored promptly,
systemic inflammation and multiple organ dysfunction are likely. are insect venoms, shellfish, peanuts, latex, and medications such as
penicillin. In genetically predisposed individuals, these allergens ini-
Neurogenic Shock tiate a vigorous humoral immune response (type I hypersensitivity)
Neurogenic shock (sometimes called vasogenic shock) is the result of that results in the production of large quantities of immunoglobulin E
widespread and massive vasodilation that results from parasympathetic (IgE) antibody (see Chapter 6). Allergen bound to IgE causes degran-
overstimulation and sympathetic understimulation (Figure 23-44) (see ulation of mast cells. Mast cells release a large number of vasoactive
Chapter 22). This type of shock can be caused by any factor that stimu- and inflammatory cytokines. This provokes an extensive immune and
lates parasympathetic or inhibits sympathetic stimulation of vascular inflammatory response, including vasodilation and increased vascu-
smooth muscle. Trauma to the spinal cord or medulla and conditions lar permeability, resulting in peripheral pooling and tissue edema.130
that interrupt the supply of oxygen or glucose to the medulla can cause Extravascular effects include constriction of extravascular smooth
neurogenic shock by interrupting sympathetic activity. Depressive drugs, muscle, often causing laryngospasm and bronchospasm (see Chapter
anesthetic agents, and severe emotional stress and pain are other causes. 26) and cramping abdominal pain with diarrhea.
The loss of vascular tone results in “relative hypovolemia,” in which The onset of anaphylactic shock is usually sudden, and progression to
blood volume has not changed but SVR decreases drastically so that the death can occur within minutes unless emergency treatment is given. The
amount of space containing the blood has increased. The pressure in the primary clinical manifestations of anaphylaxis include anxiety, dizziness,
vessels falls below that which is needed to drive nutrients across capillary difficulty breathing, stridor, wheezing, pruritus with hives (urticaria),
membranes to the cells. In addition, neurologic insult may cause brady- swollen lips and tongue, and abdominal cramping.130 A precipitous
cardia, which decreases cardiac output and further contributes to hypo- fall in blood pressure occurs, followed by impaired mentation. Other
tension and underperfusion of tissues. As with other types of shock, this signs include decreased SVR, with high or normal cardiac output, and
leads to impaired cellular metabolism. Management includes the careful oliguria. Treatment begins with removal of the antigen (if possible). Epi-
use of fluids and pressors until blood pressure stabilizes.129 nephrine is administered intramuscularly to cause vasoconstriction and
reverse airway constriction. Fluids are given intravenously to reverse the
Anaphylactic Shock relative hypovolemia, and antihistamines and corticosteroids are admin-
Anaphylactic shock results from a widespread hypersensitivity reac- istered to stop the inflammatory reaction. Vasopressors and inhaled
tion known as anaphylaxis. The lifetime prevalence of anaphylaxis is β-adrenergic agonist bronchodilators may also be necessary.130,131
0.5% to 2%.130 The basic physiologic alteration is the same as that of
neurogenic shock: vasodilation and relative hypovolemia, leading to
decreased tissue perfusion and impaired cellular metabolism (Figure
4 QUICK CHECK 23-11
1. Describe the mechanisms operative in shock.
23-45). Anaphylactic shock is characterized by other effects that rap- 2. Why does myocardial infarction often cause cardiogenic shock?
idly involve the entire body. 3. How is hypovolemic shock manifested?
Anaphylactic shock begins with exposure of a sensitized individ- 4. Why is anaphylactic shock considered a medical emergency?
ual to an allergen. Common allergens known to cause these reactions
632 CHAPTER 23  Alterations of Cardiovascular Function

Septic Shock Septic shock, a common cause of death in intensive care units, has
Septic shock begins with an infection that progresses to bacteremia, an overall mortality in the United States of 28% to 60% and can be
then systemic inflammatory response syndrome (SIRS) with sepsis, caused by any class of microorganism. Although 2 decades ago gram-
then severe sepsis, then septic shock, and finally multiple organ dys- negative bacteria were by far the microorganisms most often respon-
function syndrome (MODS). Consensus about definitions of each sible for causing septic shock, gram-positive bacteria now have become
component was achieved in 1992 and revised in 2001; these definitions the most common isolates. Septic shock also can be caused by fungi
are presented in Table 23-10.132 and viruses, and in almost one third of cases, the infectious organism is

Antigen (allergen)

Antibody (IgE)

Complement, histamine,
kinins, prostaglandins

↑ Capillary permeability Peripheral Constriction of extravascular

vasodilation smooth muscle (bronchoconstriction,
laryngospasm, gastrointestinal
cramps)

Extravasation of ↓ SVR
intravascular fluids

Edema Relative hypovolemia

↓ Cardiac output

↓ Tissue perfusion

Impaired cellular
metabolism
FIGURE 23-45  Anaphylactic Shock. IgE, Immunoglobulin E; SVR, systemic vascular resistance.

TABLE 23-10 CAUSES AND DEFINITIONS OF SEPTIC SHOCK

CAUSE DEFINITION
Infection Microbial phenomenon characterized by inflammatory response to presence of microorganisms or invasion of normally sterile
host tissue by those microorganisms
Bacteremia Presence of viable bacteria in blood
Systemic inflammatory Systemic inflammatory response to a variety of severe clinical insults manifested by two or more of following signs:
­response syndrome (SIRS) Temperature >38° C or <36° C
Heart rate >90 beats/min
Respiratory rate >20 breaths/min or arterial blood carbon dioxide level <32 mm Hg
White blood cell count >12,000 cells/mm3, <4000 cells/mm3, or containing <10% immature forms (bands)
Sepsis Systemic response to infection characterized by 2 or more of SIRS criteria
Severe sepsis Sepsis associated with organ dysfunction
Septic shock Severe sepsis complicated by persistent hypotension refractory to early fluid therapy
Multiple organ dysfunction Presence of altered organ function in an acutely ill individual such that homeostasis cannot be maintained without intervention
syndrome

Data adapted from American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Crit Care Med 20(6):864–874,
1992; Levy MM et al: SCCM/ES/CM/ACCP/ATS/SIS International Sepsis Definitions Conference, Crit Care Med 31(4):1250–1256, 2003.
 CHAPTER 23  Alterations of Cardiovascular Function 633

never identified. The most common sources of infection are the lungs, shock (hyperdynamic phase) (see Health Alert: The Role of Nitric
urinary tract, gastrointestinal tract, wounds, and indwelling vascular Oxide in Severe Sepsis).133 Later in the course of disease, inflamma-
catheters. The source and virulence of the infectious microorganism, tory mediators, such as complement and interleukins, depress myo-
as well as the underlying health of the affected individual, significantly cardial contractility such that cardiac output falls and tissue perfusion
affect prognosis. decreases.134 Tissue perfusion and cellular oxygen extraction also
Most septic shock begins when bacteria enter the bloodstream to are affected by activation of the clotting cascade through the action
produce bacteremia. These bacteria may directly stimulate an inflam- of platelet-activating factor and depletion of the endogenous antico-
matory response or they may release toxic substances into the blood- agulant protein C. Furthermore, unresponsiveness to or depletion of
stream. Gram-negative microorganisms release endotoxins, and vasoactive factors such as vasopressin contributes to hypotension and
gram-positive microorganisms release exotoxins, lipoteichoic acids, tissue hypoperfusion. The inflammatory response can become over-
and peptidoglycans. These substances trigger the septic syndrome whelming, leading to the systemic inflammatory response syndrome
by interacting with Toll-like receptors on macrophages and activate (SIRS), which can progress to widespread tissue hypoxia, necrosis, and
complement, coagulation, kinins, and inflammatory cells (Figure apoptosis, leading to septic shock and MODS. It has been determined
23-46).133 that there is a parallel release of anti-inflammatory mediators that
The release of inflammatory mediators triggers intense cellu- accompanies SIRS, causing a depression in the immune response to
lar responses and the subsequent release of secondary mediators, infection that contributes to the overall shock syndrome.133
including cytokines, complement fragments, prostaglandins, platelet-
activating factor, oxygen free radicals, nitric oxide, and proteolytic
enzymes. Chemotaxis, activation of granulocytes, and reactivation of
the phagocytic cells and inflammatory cascades result (see Risk Fac- RISK FACTORS
tors: Inflammatory Mediators Contributing to Septic Shock). Chap- Inflammatory Mediators Contributing to Septic
ter 5 discusses the description and function of inflammatory cells and Shock
mediators. This systemic inflammation, especially through the action
of nitric oxide, leads to widespread vasodilation with compensatory More than 100 inflammatory mediators have been implicated in the patho-
tachycardia and increased cardiac output in the early stages of septic genesis of septic shock. The following are some of the most important
contributors:

Interleukin-1β (IL-1β)
Gram-positive Gram-negative Released by macrophages and lymphocytes in septic shock in response to
organisms organisms bacterial toxins
Net effect: produces fever, vasodilation and hypotension, edema, myocardial
depression, and elevated white blood count
Exotoxins Endotoxins
Tumor Necrosis Factor-alpha (TNF-α)
TLR 2 receptor TLR 4 receptor Produced from macrophages, natural killer cells, and mast cells in response to
endotoxin and interleukins
Net effect: generates same symptoms of septic shock as those seen with
interleukins; thus is redundant
Macrophages
Platelet-Activating Factor (PAF)
Released from mononuclear phagocytes, platelets, and some endothelial cells
in response to endotoxin
Interleukin-1(IL-1), tumor necrosis factor- Net effect: contributes to widespread clotting, generates same symptoms of
alpha (TNF-), nitric oxide (NO) shock as those seen with interleukins and tumor necrosis factor-alpha, and
may initiate multiple organ failure

High-Mobility Group Box 1 (HMGB1)

SIRS (fever, tachycardia, tachypnea,
Released from mononuclear phagocytes, endothelial cells, neurons, and
leukocytosis) + bacteremia = sepsis
smooth muscle cells in response to endotoxin and exotoxins
Net effect: induces the release of interleukins and tumor necrosis factor

Vasodilation, hypotension, tissue

inflammation, tissue hypoperfusion (warm shock)
Clinical manifestations of septic shock are the result of inflamma-
tion, decreased perfusion of vital tissues attributable to low SVR from
Myocardial depression, worsening vasodilation, and an alteration in oxygen extraction by all cells. In early
tissue hypoperfusion (cold shock) shock, tachycardia causes cardiac output to remain normal or become
elevated, although myocardial contractility is reduced. Temperature
instability is present, ranging from hyperthermia to hypothermia.
Effects on other organ systems may result in deranged renal function,
Multiple organ dysfunction jaundice, clotting abnormalities with disseminated intravascular coag-
ulation (DIC), deterioration of mental status, and ARDS. Gastrointes-
FIGURE 23-46  Septic Shock. TLR, Toll-like receptor. tinal mucosa changes cause the translocation of bacteria from the gut
634 CHAPTER 23  Alterations of Cardiovascular Function

HEALTH ALERT HEALTH ALERT

The Role of Nitric Oxide in Severe Sepsis The Role of Activated Protein C in Sepsis and DIC
Nitric oxide (NO) is a free radical generated from l-arginine by a family of Activated protein C is an endogenous anticoagulant that regulates the activ-
enzymes known as NO synthetases. The most important enzyme in sepsis is ity of factors VIIIa and Va. It is also anti-inflammatory and inhibits nitric
called iNOS (inducible NOS), which responds to immune/inflammatory insult oxide–induced vascular dysfunction. In sepsis and disseminated intravascular
and mediates tissue damage. In sepsis, iNOS is activated, and NO and OONO− coagulation (DIC), activated protein C levels are decreased. The amount of
(peroxynitrite) are produced in large quantities. In septic shock, nitric oxide decrease is associated with mortality. Human recombinant activated protein C
has been shown to cause refractory peripheral vascular vasodilation, increase is effective for the treatment of sepsis-associated DIC. Controversies remain,
vascular permeability, and depress myocardial function. Nitric oxide contrib- however, about the use of this treatment for sepsis. Current evidence suggests
utes to the development of MODS because its effects include decreased cel- that administration of activated protein C improves outcomes in individuals
lular protein synthesis, oxidized cell membranes, damaged DNA, decreased with severe sepsis, and numerous trials continue to explore how best to use
glucose and glycogen production, and competition for cytochrome oxidase in this important new treatment.
the mitochondria, thus decreasing tissue oxygen utilization. Methylene blue,
Data from Levi M, Lowenberg E, Meijers JC: Sem Thromb Hemost
a selective inhibitor of guanylate cyclase (an enzyme involved in nitric oxide–
36(5):550–557, 2010; Lindenauer PK et al: Crit Care Med 38(4):1101–
mediated vasodilation), has shown promise in improving blood pressure in
1107, 2010; Neyrinck AP et al: Br J Pharmacol 158(4):1034–1047,
individuals with septic shock but has adverse effects on the pulmonary circu- 2009; Sanchez B et al: J Crit Care 25(2):343–347, 2010; Toussaint S,
lation. Studies are aimed at finding new treatments (such as antioxidants) to Gerlach H: N Engl J Med 361(27):2646–2652, 2009.
prevent the negative impact of this toxic free radical in sepsis.

Data from Azevedo LC: Mitochondrial dysfunction during sepsis,

Endocr Metab Immune Disord Drug Targets 10(3):214–223, 2010; For- Multiple Organ Dysfunction Syndrome
tin CF et al: Sepsis, leukocytes, and nitric oxide (NO): an intricate affair, Multiple organ dysfunction syndrome (MODS) is the progressive dys-
Shock 33(4):344–352, 2010; Paciullo CA et al: Methylene blue for the function of two or more organ systems resulting from an uncontrolled
treatment of septic shock, Pharmacother 30(7):702–715, 2010; Szabo
inflammatory response to a severe illness or injury. The organ dysfunc-
C, Modis K: Pathophysiological roles of peroxynitrite in circulatory
tion can progress to organ failure and death (Figure 23-47). Although
shock, Shock 34(suppl 1):4–14, 2010; Zhang T, Feng Q: Nitric oxide
and calcium signaling regulate myocardial tumor necrosis factor-α sepsis and septic shock are the most common causes, any severe injury
expression and cardiac function in sepsis, Can J Physiol Pharmacol or disease process that activates a massive systemic inflammatory
88(2):92–104, 2010. response in the host can initiate MODS. These triggers include severe
trauma, burns, acute pancreatitis, obstetric complications, major sur-
gery, circulatory shock, some drugs, and gangrenous or necrotic tissue.
into the bloodstream. Increased permeability of the gut also can lead to MODS is the most common cause of mortality in intensive care
increased inflammation and immune reactions attributable to toxins units. Mortality for individuals increases to 100% if there is failure of
carried by the intestinal lymphatics. five or more organs. People at greatest risk for developing MODS are
The diagnosis of septic shock rests on the recognition of the sys- elderly individuals and persons with significant tissue injury or preex-
temic manifestations of overwhelming inflammation (SIRS) in indi- isting disease (see Risk Factors: Development of Multiple Organ Dys-
viduals with suspected or documented infection. Determining the function Syndrome).
cause and severity of septic shock can be aided by measurement of
levels of serum lactate, C-reactive protein, and procalcitonin.135 The
management of septic shock following the “surviving sepsis guide- RISK FACTORS
lines” has improved outcomes.136 These guidelines include support of
the respiratory system (including mechanical ventilation if needed), Development of Multiple Organ Dysfunction
placement of a central venous catheter, the rapid administration of Syndrome
broad-spectrum antibiotics, removal of the source of infection if one Age >65 years
is found, administration of intravenous fluids and vasopressors, and Major trauma
careful monitoring.137 Selected individuals with severe refractory Baseline organ dysfunction (e.g., renal insufficiency, hepatic insufficiency)
hypotension are given systemic corticosteroids and vasopressin. Indi- Bowel infarction
viduals with refractory septic shock may respond to human recom- Acute pancreatitits
binant activated protein C138 (see Health Alert: The Role of Activated Coma on admission
Protein C in Sepsis and DIC). Control of hyperglycemia with insulin, Immunosuppression (e.g., corticosteroids)
treatment of complications associated with MODS, careful nutritional Inadequate, delayed resuscitation
support, and prevention of stress ulcers and deep venous thrombosis Malnutrition
are also essential. Because the septic syndrome is incompletely under- Multiple blood transfusions (>6 units/12 hr)
stood, recommended treatment continues to evolve. Persistent infectious focus
Preexisting chronic disease (e.g., cancer, diabetes)
4 QUICK CHECK 23-12
1. What are some of the important causes of septic shock?
2. What is the systemic inflammatory response syndrome?
3. Why is correction of the underlying problem the most important treatment PATHOPHYSIOLOGY  As a result of the initiating insult (sepsis, injury,
for all kinds of shock? or disease), the neuroendocrine system is activated with the release of
the stress hormones cortisol, epinephrine, and norepinephrine into the
 CHAPTER 23  Alterations of Cardiovascular Function 635

Injury
Sepsis
Disease

Endothelial damage
Neuroendocrine response
Release of inflammatory mediators

Activation of complement, coagulation,

and kallikrein/kinin systems

Vasodilation
↑ Capillary permeability Massive, systemic
immune/inflammatory Hypermetabolism
Selective vasoconstriction
Microvascular thrombi response

Maldistribution of systemic
and organ blood flow

O2 supply/demand ↑ O2 and substrate

Tissue hypoperfusion
imbalance demand

Supply-dependent
↓ Cardiac function
O2 consumption
Exhaustion of
fuel supply

Tissue hypoxia

Acidosis
Myocardial depression Impaired cellular Metabolic failure
function

Organ dysfunction

Multiple organ
dysfunction syndrome
(MODS)
FIGURE 23-47  Pathogenesis of Multiple Organ Dysfunction Syndrome.

bloodstream (see Chapter 8). Vascular endothelial damage occurs as a Because of the release of inflammatory mediators, three major
direct result of injury or from damage by bacterial toxins and inflam- plasma enzyme cascades are activated: complement, coagulation, and
matory mediators released into the circulation. The vascular endothe- kallikrein/kinin. The overall effect of the activation of these cascades
lium becomes permeable, allowing fluid and protein to leak into the is a hyperinflammatory and hypercoagulant state that maintains the
interstitial spaces, contributing to hypotension and hypoperfusion. interstitial edema formation, cardiovascular instability, endothelial
When the endothelium is damaged, platelets and tissue thromboplas- damage, and clotting abnormalities characteristic of MODS. A mas-
tin are activated, resulting in systemic microvascular coagulation that sive systemic immune/inflammatory response then develops involv-
may lead to DIC (see Chapter 20).133,139 ing neutrophils, macrophages, and mast cells (Table 23-11). The
636 CHAPTER 23  Alterations of Cardiovascular Function

TABLE 23-11 CELLS OF INFLAMMATION AND MULTIPLE ORGAN DYSFUNCTION

CELL ACTIVATORS CONTRIBUTION TO MULTIPLE ORGAN DYSFUNCTION
Neutrophils Complement, kinins, endotoxin, Release of phagocytic products: toxic oxygen free radicals, superoxide ion, hydrogen peroxide,
clotting factors hydroxyl radicals, proteases, platelet-activating factor (PAF), arachidonic acid metabolites
(­prostaglandins, thromboxane, leukotrienes)
Endothelial damage, vasodilation, vasopermeability, microvascular coagulation, selective
­vasoconstriction, hypotension, shock
Macrophages Complement, endotoxin, Release of same phagocytic products as neutrophils
­chemotactic factors Release of monokines: tumor necrosis factor (TNF), interleukin-1 (IL-1)
TNF produces fever, anorexia, hyperglycemia, weight loss
Mast cells Direct injury, endotoxin, Release of histamine, PAF, arachidonic acid metabolites
­complement Vasodilation, vasopermeability, hypotension, shock

inflammatory process initiated is the same as that described in septic Between 7 and 10 days, the hypermetabolic and hyperdynamic
shock and SIRS (see p. 632) and sets the stage for MODS. states intensify, bacteremia with enteric microorganisms is common,
The numerous inflammatory and clotting processes operating in and signs of liver and kidney failure appear. Liver failure, although
MODS cause maldistribution of blood flow and hypermetabolism. developing early, is not clinically detectable until later stages of MODS,
Oxygen delivery to the tissues decreases despite the supranormal sys- at which time jaundice, abdominal distention, liver tenderness, muscle
temic blood flow for several reasons: wasting, and hepatic encephalopathy appear. All facets of metabolism,
1. Shunting of blood past selected regional capillary beds is caused substance detoxification, and immune response are impaired; albumin
when inflammatory mediators override the normal vascular tone. and clotting factor synthesis decreases; protein wastes accumulate; and
2. Interstitial edema, resulting from microvascular changes in perme- liver tissue macrophages (Kupffer cells) no longer function effectively.
ability, contributes to decreased oxygen delivery by creating a rela- Progressive oliguria, azotemia, and edema mark the development of
tive hypovolemia and by increasing the distance oxygen must travel renal failure. Anuria, hyperkalemia, and metabolic acidosis may occur
to reach the cells.140 if renal shutdown is severe.
3. Capillary obstruction occurs because of formation of microvascular During days 14 to 24, renal and liver failure becomes more severe
thrombi and the aggregation of white blood cells. and the gastrointestinal system shows evidence of dysfunction. The
Hypermetabolism in MODS with accompanying alterations gastrointestinal system is sensitive to ischemic and inflammatory
in carbohydrate, fat, and lipid metabolism is initially a compensa- injury. Clinical manifestations of bowel involvement are hemorrhage,
tory measure to meet the body’s increased demands for energy. The ileus, malabsorption, diarrhea or constipation, vomiting, anorexia,
alterations in metabolism affect all aspects of substrate utilization. and abdominal pain. Compounding the damage caused by injury to
The net result of hypermetabolism is depletion of oxygen and fuel the bowel is the phenomenon of bacterial translocation. When media-
supplies. tors and severe ischemia injure the mucosal epithelium, bacteria and
Decreased oxygen delivery to the cells caused by the maldistri- toxins pass from the gut into the portal circulation. The overwhelmed
bution of blood flow, coagulation, myocardial depression, and the liver is unable to clear these products and they move into the sys-
hypermetabolic state combine to create an imbalance in oxygen temic circulation. Thus, whether infection or some other injury was
supply and demand. This imbalance is critical in the pathogenesis the precipitating cause of MODS, sepsis occurs once the gut barrier
of MODS because it results in a pathologic condition known as is damaged.
supply-dependent oxygen consumption.140 Ordinarily, the amount Hematologic failure and myocardial failure are usually later mani-
of oxygen consumed by the cells depends only on the demands of festations. The signs and symptoms of cardiac failure in the hyper-
the cells, because there is an adequate reserve of oxygen that can metabolic, hyperdynamic phase of MODS are similar to those of
be delivered if needed. The reserve, however, has been exhausted septic shock: tachycardia, bounding pulse, increased cardiac output,
in MODS, and the amount of oxygen consumed becomes depen- decreased systemic vascular resistance, and hypotension. In the ter-
dent on the amount the circulation is able to deliver; this amount is minal stages, hypodynamic circulation with bradycardia, profound
inadequate in MODS. Therefore tissue hypoxia with cellular acido- hypotension, and ventricular dysrhythmias may develop. Encepha-
sis and impaired cellular function ensue and result in the multiple lopathy, characterized by mental status changes ranging from confu-
organ failure. sion to deep coma, may occur at any time. Ischemia and inflammation
are responsible for the central nervous system manifestations, which
CLINICAL MANIFESTATIONS  There is often a predictable clinical include apprehension, confusion, disorientation, restlessness, agita-
pattern in the development of MODS, although there is certainly some tion, headache, decreased cognitive ability and memory, and decreased
individual variation. After the inciting event and aggressive resuscita- level of consciousness. When ischemia is severe, seizures and coma can
tion for approximately 24 hours, the individual develops a low-grade occur. Death may occur as early as 14 days or after a period of several
fever, tachycardia, dyspnea, altered mental status, and hyperdynamic weeks.
and hypermetabolic states. The lung is often the first organ to fail,
resulting in acute respiratory distress syndrome (ARDS) (see Chap- EVALUATION AND TREATMENT  Early detection of organ failure
ter 26). Respiratory failure is characterized by tachypnea, pulmonary is extremely important so that supportive measures can be initiated
edema with crackles and diminished breath sounds, use of accessory immediately. Frequent assessment of the clinical status of individuals
muscles, and hypoxemia. at known risk is essential. The Acute Physiology and Chronic Health
 CHAPTER 23  Alterations of Cardiovascular Function 637

Evaluation (APACHE) II and III systems assess for severity and pro-
HEALTH ALERT
gression of MODS. Once organ failure develops, monitoring of labora-
tory values and hemodynamic parameters also can be used to assess the Nutritional Support to Prevent and Treat MODS
degree of impairment. Critical illness is associated with overgrowth of bacteria in the gut and
Therapeutic management of MODS consists of prevention and increased permeability of the gut for microorganisms and toxins. These factors
support. First, if the initial insult is known, it is aggressively treated and contribute to endotoxemia, sepsis, multiple organ failure, and death. The liver
sources of infection are removed. The second priority is restoration is also affected and contributes to metabolic, nutritional, and hemostatic dys-
and maintenance of tissue oxygenation and cardiovascular function. function. Maintaining the integrity of the gastrointestinal tract is an important
Third, nutritional support must be provided (see Health Alert: Nutri- step in preventing and managing sepsis and multiple organ dysfunction. Nutri-
tional Support to Prevent and Treat MODS). Last, individual organs tional support not only prevents malnutrition but also helps maintain adequate
must be supported. Activated protein C (drotrecogin alfa) has been functioning of the gut and improves immunity. Enteral nutrition (EN) has advan-
shown to improve outcomes in those with DIC and may be useful for tages over parenteral nutrition (PN) for postoperative/post-trauma individuals.
the general management of septic shock with multiple organ dysfunc- Immediate and early EN improves mucosal blood flow, reduces intramucosal
tion syndrome.138,141 acidosis and permeability problems, and decreases the need for stress ulcer
prophylaxis. EN also maintains the protective role of the gut by decreasing
inflammatory cytokine production and improving mucosal IgA levels, which

4 QUICK CHECK 23-13

helps prevent infection. EN should be given as soon as is practical. Jejunal
tube feedings have advantages over gastric tube feedings, including faster
1. Why can MODS be initiated by either a septic or a nonseptic insult? metabolic recovery, less vomiting, and less risk of regurgitation and aspiration.
2. Why are inflammation and clotting triggered when the vascular endothe-
lium is injured? Data from Marla R, Dahn MS, Lange MP: Surg Infect 5(4):357–363,
3. Describe the mechanisms that result in decreased oxygen delivery to the 2004; McClave SA, Heyland DK: Nutr Clin Pract 24(3):305–315, 2009;
tissues in MODS. Moore FA, Moore EE: Nutr Clin Pract 24(3):297–304, 2009; Oz HS,
Chen TS, Neuman M: JPEN J Parenter Enteral Nutr 33(4):380–389, 2009.

DID YOU UNDERSTAND?

Diseases of the Veins and Arteries 10. Clinical manifestations of hypertension result from damage of organs and
1. Varicosities are areas of veins in which blood has pooled, usually in the tissues outside the vascular system. These include retinal changes, heart
saphenous veins. Varicosities may be caused by damaged valves as a result disease, renal disease, and central nervous system problems, such as
of trauma to the valve or by chronic venous distention involving gravity and stroke and dementia.
venous constriction. 11. Hypertension is managed with both pharmacologic and nonpharmacologic
2. Chronic venous insufficiency is inadequate venous return over a long period methods that lower the blood volume and the total peripheral resistance.
of time that causes pathologic ischemic changes in the vasculature, skin, 12. Orthostatic hypotension is a drop in blood pressure that occurs on standing.
and supporting tissues. The compensatory vasoconstriction response to standing is replaced by a
3. Venous stasis ulcers follow the development of chronic venous insuffi- marked vasodilation and blood pooling in the muscle vasculature.
ciency and probably develop as a result of the borderline metabolic state of 13. The clinical manifestations of orthostatic hypotension include fainting and
the cells in the affected extremities. may involve cardiovascular symptoms, as well as impotence and bowel and
4. Deep venous thrombosis results from stasis of blood flow, endothelial dam- bladder dysfunction.
age, or hypercoagulability. The most serious complication of deep venous 14. An aneurysm is a localized dilation of a vessel wall; the aorta is particularly
thrombosis is pulmonary embolism. susceptible.
5. Superior vena cava syndrome is a progressive occlusion of the superior 15. A thrombus is a clot that remains attached to a vascular wall. An embolus
vena cava that leads to venous distention in the upper extremities and is a mobile aggregate of a variety of substances that occludes the vascula-
head. Because this syndrome is usually caused by bronchogenic cancer, ture. Sources of emboli include clots, air, amniotic fluid, bacteria, fat, and
it is generally considered an oncologic emergency rather than a vascular foreign matter. These emboli cause ischemia and necrosis when a vessel is
emergency. totally blocked.
6. Hypertension is the elevation of systemic arterial blood pressure resulting 16. The most common source of arterial thrombotic emboli is the heart as a
from increases in cardiac output (blood volume), total peripheral resistance, result of mitral and aortic valvular disease and atrial fibrillation, followed
or both. by myxomas. Tissues affected include the lower extremities, the brain, and
7. Hypertension can be primary, without a known cause, or secondary, caused the heart.
by an underlying disease. 17. Emboli to the central organs cause tissue death in lungs, kidneys, and
8. The risk factors for hypertension include a positive family history; male mesentery.
gender; advancing age; black race; obesity; high sodium intake; low mag- 18. Peripheral vascular diseases include Buerger disease and Raynaud disease,
nesium, potassium, or calcium intake; diabetes mellitus; cigarette smoking; involving arterioles of the extremities.
and heavy alcohol consumption. 19. Atherosclerosis is a form of arteriosclerosis and is the leading contributor
9. The exact cause of primary hypertension is unknown, although several to coronary artery disease (CAD) and cerebrovascular disease (CVD).
hypotheses are proposed, including overactivity of the sympathetic nervous 20. Atherosclerosis is an inflammatory disease that begins with endothelial
system; overactivity of the renin-angiotensin-aldosterone system; sodium injury.
and water retention by the kidneys; hormonal inhibition of sodium-potas- 21. Important steps in atherogenesis include vasoconstriction, adherence of
sium transport across cell walls; and complex interactions involving insulin macrophages, release of inflammatory mediators, oxidation of LDL, forma-
resistance, inflammation, and endothelial function. tion of foam cells and fatty streaks, and development of fibrous plaque.

Continued
638 CHAPTER 23  Alterations of Cardiovascular Function

DID YOU UNDERSTAND?—cont’d

22. Once a plaque has formed, it can rupture, resulting in clot formation and 4. The hemodynamic integrity of the cardiovascular system depends to a great
instability and vasoconstriction, which lead to obstruction of the lumen and extent on properly functioning cardiac valves. Congenital or acquired disorders
inadequate oxygen delivery to tissues. that result in stenosis, regurgitation, or both can structurally alter the valves.
23. Peripheral artery disease is the result of atherosclerotic plaque formation 5. Characteristic heart sounds, cardiac murmurs, and systemic complaints
in the arteries that supply the extremities, and it causes pain and ischemic assist in identification of an abnormal valve. If severely compromised func-
changes in the nerves, muscles, and skin of the affected limb. tion exists, a prosthetic heart valve may be surgically implanted to replace
24. Coronary artery disease (CAD) is the result of an atherosclerotic plaque that the faulty one.
gradually narrows the coronary arteries or that ruptures and causes sudden 6. Mitral valve prolapse (MVP) describes the condition in which the mitral
thrombus formation. valve leaflets do not position themselves properly during systole. Mitral
25. Many risk factors contribute to the onset and escalation of CAD, includ- valve prolapse may be a completely asymptomatic condition or can result in
ing traditional risk factors such as dyslipidemia, smoking, hypertension, unpredictable symptoms. Afflicted valves are at greater risk for developing
diabetes mellitus (insulin resistance), and obesity/sedentary lifestyle and infective endocarditis.
nontraditional risk factors such as elevated C-reactive protein levels, hyper- 7. Rheumatic fever is an inflammatory disease that results from a delayed
homocysteinemia, and changes in adipokines. immune response to a streptococcal infection in genetically predisposed
26. Ischemic heart disease is most commonly the result of coronary artery dis- individuals. The disorder usually resolves without sequelae if treated early.
ease and the ensuing decrease in myocardial blood supply. 8. Severe or untreated cases of rheumatic fever may progress to rheumatic
27. Atherosclerotic plaque progression can be gradual and cause stable angina heart disease, a potentially disabling cardiovascular disorder.
pectoris, which is predictable chest pain caused by myocardial ischemia in 9. Infective endocarditis is a general term for infection and inflammation of
response to increased demand (e.g., exercise) without infarction. the endocardium, especially the cardiac valves. In the mildest cases, val-
28. Prinzmetal angina results from coronary artery vasospasm. vular function may be slightly impaired by vegetations that collect on the
29. Myocardial ischemia may be asymptomatic, which is called silent ischemia, valve leaflets. If left unchecked, severe valve abnormalities, chronic bacte-
and is a risk factor for the development of the acute coronary syndromes. remia, and systemic emboli may occur as vegetations detach from the valve
30. Sudden coronary obstruction due to thrombus formation causes the acute surface and travel through the bloodstream. Antibiotic therapy can limit the
coronary syndromes. These include unstable angina, non-ST elevation extension of this disease.
myocardial infarction (non-STEMI), and ST elevation myocardial infarction 10. Human immunodeficiency virus (HIV) infection and AIDS are associated
(STEMI). with cardiac abnormalities, including myocarditis, endocarditis, pericardi-
31. Unstable angina results in reversible myocardial ischemia. tis, and cardiomyopathy.
32. Myocardial infarction is caused by prolonged, unrelieved ischemia that
interrupts blood supply to the myocardium. After about 20 minutes of myo- Manifestations of Heart Disease
cardial ischemia, irreversible hypoxic injury causes cellular death and tis- 1. A dysrhythmia (arrhythmia) is a disturbance of heart rhythm. Dysrhythmias
sue necrosis. range in severity from occasional missed beats or rapid beats to distur-
33. Myocardial infarction is clinically classified as non-STEMI or STEMI based bances that impair myocardial contractility and are life-threatening.
on electrocardiographic findings that suggest the extent of myocardial dam- 2. Dysrhythmias can occur because of an abnormal rate of impulse generation
age (subendocardial versus transmural). or an abnormal conduction of impulses.
34. An increase in plasma enzyme levels is used to diagnose the occurrence of 3. Heart failure (HF) is an inability of the heart to supply the metabolism with
myocardial infarction as well as indicate its severity. Elevations of the iso- adequate circulatory volume and pressure.
enzymes creatine kinase-myocardial bound (CK-MB), troponins, and lactate 4. Left heart failure (congestive heart failure) can be divided into systolic and
dehydrogenase (LDH-1) are most predictive of a myocardial infarction. diastolic heart failure.
35. Treatment of a myocardial infarction includes revascularization (thrombo- 5. The most common causes of left ventricular failure are myocardial infarc-
lytics or PCI) and administration of antithrombotics, ACE inhibitors, and tion and hypertension.
beta-blockers. Pain relief and fluid management also are key components 6. Systolic heart failure is caused by increased preload, decreased contractility,
of care. Dysrhythmias and cardiac failure are the most common complica- or increased afterload. These processes result in an increased left ventricular
tions of acute myocardial infarction. end-diastolic volume and an increased left ventricular end-diastolic pressure
that cause increased pulmonary venous pressures and pulmonary edema.
Disorders of the Heart Wall 7. In addition to the hemodynamic changes of left ventricular failure, there
1. Inflammation of the pericardium, or pericarditis, may result from several is a neuroendocrine response that tends to exacerbate and perpetuate the
sources (infection, drug therapy, tumors). Pericarditis presents with symp- condition.
toms that are physically troublesome, but in and of themselves they are not 8. The neuroendocrine mediators of HF include the sympathetic nervous sys-
life-threatening. tem and the renin-angiotensin-aldosterone system; thus diuretics, beta-
2. Fluid may collect within the pericardial sac (pericardial effusion). Cardiac blockers, and angiotensin-converting enzyme (ACE) inhibitors are important
function may be severely impaired if the accumulation of fluid occurs rap- components of the pharmacologic therapy.
idly and involves a large volume. 9. Diastolic heart failure is a clinical syndrome characterized by the symptoms
3. Cardiomyopathies are a diverse group of primary myocardial disorders that and signs of heart failure, a preserved ejection fraction, and abnormal dia-
are usually the result of remodeling, neurohumoral responses, and hyperten- stolic function.
sion. The cardiomyopathies are categorized as dilated (congestive), restric- 10. Diastolic dysfunction means that the left ventricular end-diastolic pressure
tive (rigid and noncompliant), and hypertrophic (asymmetric). The size of the is increased, even if volume and cardiac output are normal.
cardiac muscle walls and chambers may increase or decrease depending on 11. Right heart failure can result from left heart failure or pulmonary
the type of cardiomyopathy, thereby altering contractile activity. disease.
 CHAPTER 23  Alterations of Cardiovascular Function 639

DID YOU UNDERSTAND?—cont’d

Shock 9. Hypovolemic shock is caused by loss of blood or fluid in large amounts. The
1. Shock is a widespread impairment of cellular metabolism involving positive use of compensatory mechanisms may be vigorous, but tissue perfusion
feedback loops that places the individual on a downward physiologic spiral ultimately decreases and results in impaired cellular metabolism.
leading to multiple organ dysfunction syndrome. 10. Neurogenic shock results from massive vasodilation, causing a rela-
2. Types of shock are cardiogenic, hypovolemic, neurogenic, anaphylactic, and tive hypovolemia even though cardiac output may be high, and leads to
septic. Multiple organ dysfunction syndrome can develop from all types of impaired cellular metabolism.
shock. 11. Anaphylactic shock is caused by physiologic recognition of a foreign sub-
3. The final common pathway in all types of shock is impaired cellular metabo- stance. The inflammatory response is triggered, and a massive vasodilation
lism—cells switch from aerobic to anaerobic metabolism. Energy stores with fluid shift into the interstitium follows. The relative hypovolemia leads
drop, and cellular mechanisms relative to membrane permeability, action to impaired cellular metabolism.
potentials, and lysozyme release fail. 12. Septic shock begins with impaired cellular metabolism caused by uncon-
4. Anaerobic metabolism results in activation of the inflammatory response, trolled septicemia. The infecting agent triggers the inflammatory and
decreased circulatory volume, and decreasing pH. immune responses. This inflammatory response is accompanied by wide-
5. Impaired cellular metabolism results in cellular inability to use glucose spread changes in tissue and cellular function.
because of impaired glucose delivery or impaired glucose intake, result- 13. Multiple organ dysfunction syndrome (MODS) is the progressive failure of
ing in a shift to glycogenolysis, gluconeogenesis, and lipolysis for fuel two or more organ systems after a severe illness or injury. It can be trig-
generation. gered by chronic inflammation, necrotic tissue, severe trauma, burns, adult
6. Glycogenolysis is effective for about 10 hours. Gluconeogenesis results in respiratory distress syndrome, acute pancreatitis, and other severe injuries.
the use of proteins necessary for structure, function, repair, and replication 14. MODS involves the stress response; changes in the vascular endothelium
that leads to more impaired cellular metabolism. resulting in microvascular coagulation; release of complement, coagulation,
7. Gluconeogenesis contributes to lactic acid, uric acid, and ammonia buildup, and kinin proteins; and numerous inflammatory processes. Consequences
interstitial edema, and impairment of the immune system, as well as gen- of all these mediators are a maldistribution of blood flow, hypermetabo-
eral muscle weakness, leading to decreased respiratory function and car- lism, hypoxic injury, and myocardial depression.
diac output. 15. Clinical manifestations of MODS include inflammation, tissue hypoxia, and
8. Cardiogenic shock is decreased cardiac output, tissue hypoxia, and the hypermetabolism. All organs can be affected including the kidney, lung,
presence of adequate intravascular volume. liver, gastrointestinal tract, and central nervous system.

 KEY TERMS
•  cute coronary syndrome  598
A •  atty streak  595
F •  etabolic syndrome  599
M
• Acute pericarditis  609 • Fibrous plaque  595 • Mitral regurgitation  615
• Anaphylactic shock  631 • Foam cell  595 • Mitral stenosis  614
• Anaphylaxis  631 • Heart failure  622 • Mitral valve prolapse syndrome
• Aneurysm  591 • Hibernating myocardium  606 (MVPS)  615
• Aortic regurgitation  614 • High-density lipoprotein (HDL)  590 • Multiple organ dysfunction syndrome
• Aortic stenosis  613 • Highly-sensitive C-reactive protein (MODS)  634
• Arteriosclerosis  594 (hs-CRP)  599 • Myocardial infarction (MI)  604
• Atherosclerosis  594 • High-output failure  626 • Myocardial remodeling  606
• Bacterial translocation • Hyperhomocysteinemia  599 • Myocardial stunning  606
• Cardiogenic shock  629 • Hypertension  587 • Myocarditis  617
• Cardiomyopathy  611 • Hypertensive hypertrophic • Neurogenic shock (vasogenic shock)  631
• Chronic left heart failure  625 cardiomyopathy  612 • Nonbacterial thrombotic endocarditis  618
• Chronic orthostatic hypotension  591 • Hypertrophic cardiomyopathy  612 • Non-ST elevation MI (non-STEMI)  604
• Chronic venous insufficiency (CVI)  586 • Hypertrophic obstructive • Orthostatic (postural) hypotension  591
• Chylomicron  598 cardiomyopathy  612 • Percutaneous coronary intervention
• Complicated plaque  595 • Hypovolemic shock  631 (PCI)  604
• Constrictive pericarditis (restrictive peri- • Infarction  598 • Pericardial effusion  610
carditis [chronic pericarditis])  611 • Infective endocarditis  617 • Peripheral artery disease (PAD)  597
• Coronary artery disease (CAD)  597 • Intermittent claudication  597 • Peripheral pooling  631
• Deep venous thrombosis (DVT)  586 • Ischemia  597 • Plaque  594
• Diastolic heart failure  625 • Isolated systolic hypertension (ISH)  587 • Pressure-natriuresis relationship  588
• Dilated cardiomyopathy  611 • Left heart failure  623 • Primary hypertension (essen-
• Dyslipidemia (dyslipoproteinemia)  598 • Lipoprotein  598 tial ­hypertension, idiopathic
• Dysrhythmia (arrhythmia)  619 • Lipoprotein(a) (Lp[a])  599 hypertension)  587
• Embolism  593 • Low-density lipoprotein (LDL)  594 • Prinzmetal angina  601
• Embolus  593 • Malignant hypertension  590 • Raynaud disease  594
• False aneurysm  592 • Mental stress–induced ischemia  601 • Raynaud phenomenon  594
Continued
640 CHAPTER 23  Alterations of Cardiovascular Function

 KEY TERMS—cont’d
•  estrictive cardiomyopathy  612
R • S upply-dependent oxygen • T rue aneurysm  591
• Rheumatic fever  616 consumption  636 • Unstable angina  604
• Rheumatic heart disease (RHD)  616 • Systemic inflammatory response • Valvular hypertrophic
• Right heart failure  626 ­syndrome (SIRS)  632 cardiomyopathy  612
• Secondary hypertension  590 • Systolic heart failure  623 • Valvular regurgitation (valvular ­insufficiency
• Septic shock  632 • Tamponade  610 or valvular incompetence)  612
• Shock  627 • Thromboangiitis obliterans • Valvular stenosis  612
• Silent ischemia  601 (Buerger disease)  593 • Varicose vein  585
• Stable angina pectoris  601 • Thromboembolus  586 • Venous stasis ulcer  586
• ST elevation MI (STEMI)  604 • Thrombus  586 • Ventricular remodeling  623
• Superior vena cava syndrome (SVCS)  586 • Transmural myocardial infarction  605 • Very-low-density lipoprotein
• Tricuspid regurgitation  615 (VLDL)  598

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 CHAPTER

24
Alterations of Cardiovascular
Function in Children
Nancy L. McDaniel and Valentina L. Brashers

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Congenital Heart Disease, 643 Acquired Cardiovascular Disorders, 654
Obstructive Defects, 644 Kawasaki Disease, 654
Defects With Increased Pulmonary Blood Flow, 647 Systemic Hypertension, 655
Defects With Decreased Pulmonary Blood Flow, 649
Mixing Defects, 651
Congestive Heart Failure, 653

Cardiovascular disorders in children are classified as congenital or The incidence of CHD is three to four times higher in siblings of
acquired. Congenital heart disease is the most common. The diag- affected children, and chromosomal defects account for about 6%
nosis and management of congenital heart disease continues to of all cases of CHD. Down syndrome, trisomies 13 and 18, Turner
improve with the use of fetal echocardiography and early interven- syndrome, and cri du chat syndrome (chromosome 5p deletion syn-
tional catheterization or surgical repair. Acquired heart disease in drome) have been associated with a relatively high incidence of heart
children continues to present challenges to the practitioner. Although defects. Only a small percentage of cases of CHD are clearly linked
guidelines for diagnosing acquired diseases are available, work is still solely to genetic or environmental factors. The cause of most defects
needed in developing standards of treatment and long-term follow- is multifactorial.1,2
up protocols. Congenital heart defects can be categorized according to (1)
whether they cause cyanosis, (2) whether they increase or decrease
blood flow into the pulmonary circulation, and (3) whether they
CONGENITAL HEART DISEASE obstruct blood flow from the ventricles (Figure 24-1). The normal
The incidence of congenital heart disease (CHD) varies from 4 to 8 movement of blood through the right side of the heart and into the
per 1000 live births and is the major cause of death in the first year pulmonary system is separate from the blood flow through the left
of life other than prematurity. Several environmental and genetic risk side of the heart into the systemic circulation (Figure 24-2, A). Abnor-
factors are associated with the incidence of different types of CHD. mal movement from one side of the heart to the other is termed a
Among the environmental factors are (1) maternal conditions, such shunt. Shunting of blood flow from the left heart into the right heart
as intrauterine viral infections (especially rubella), diabetes mellitus, is called a left-to-right shunt and occurs in conditions such as atrial
phenylketonuria, alcoholism, hypercalcemia, drugs (e.g., thalidomide, septal defect and ventricular septal defect (see Figure 24-2, B). This
phenytoin), and complications of increased age; (2) antepartal bleed- increases blood flow into the pulmonary circulation. Because blood
ing; and (3) prematurity (Table 24-1).1,2 continues to flow through the lungs before passing into the systemic
Genetic factors also have been implicated in the incidence of CHD, circulation, there is no decrease in tissue oxygenation or cyanosis.
although the mechanism of causation is often unknown (Table 24-2). Thus defects that cause left-to-right shunt are termed acyanotic heart

643
644 CHAPTER 24  Alterations of Cardiovascular Function in Children

TABLE 24-1 MATERNAL CONDITIONS TABLE 24-2 CONGENITAL HEART

AND ENVIRONMENTAL DISEASE IN SELECTED
EXPOSURES AND THE FETAL CHROMOSOMAL
ASSOCIATED CONGENITAL ABERRATIONS
HEART DEFECTS COMMON DEFECTS
TYPE OF CONGENITAL (IN DECREASING
CAUSE HEART DEFECT INCIDENCE ORDER OF
CONDITIONS OF CHD (%) FREQUENCY)
Infection
Intrauterine Patent ductus arteriosus (PDA), pulmonary 5p (cri du chat syndrome) 25 VSD, PDA, ASD
stenosis, coarctation of aorta Trisomy 13 syndrome 90 VSD, PDA, dextrocardia
Systemic viral PDA, pulmonary stenosis, coarctation of Trisomy 18 syndrome 99 VSD, PDA, PS
aorta Trisomy 21 50 AVSD, VSD
Rubella PDA, pulmonary stenosis, coarctation of (Down syndrome)
aorta Turner syndrome (XO) 35 COA, AS, ASD
Coxsackie B5 Endocardial fibroelastosis Klinefelter variant (XXXXY) 15 PDA, ASD
Radiation Specific cardiovascular effect not known From Park MK: Pediatric cardiology for practitioners, ed 5, St Louis,
2008, Mosby.
Metabolic Disorders AS, Aortic stenosis; ASD, atrial septal defect; AVSD, atrioventricular
Diabetes Ventricular septal defect (VSD), septal defect; COA, coarctation of the aorta; PDA, patent ductus arte-
­cardiomegaly, transposition of the great riosus; PS, pulmonary stenosis; VSD, ventricular septal defect.
vessels
Phenylketonuria (PKU) Coarctation of aorta, PDA
Hypercalcemia Supravalvular aortic stenosis, pulmonic Obstructive Defects
stenosis; aortic hyperplasia Coarctation of the Aorta
Drugs PATHOPHYSIOLOGY  Coarctation of the aorta (COA) is an abnor-
Thalidomide No specific lesion mal localized narrowing of the aorta just proximal to the insertion of
Dextroamphetamine One case of reported transposition the ductus arteriosus. Before birth, the ductus arteriosus bypasses this
Alcohol Tetralogy of Fallot, atrial septal defect, VSD obstruction and allows for blood to flow from the pulmonary artery
into the distal aorta. However, once the ductus closes after birth, blood
Peripheral Conditions flow to the lower extremities is restricted by the coarctation. Clinically,
Increased maternal age VSD, tetralogy of Fallot (relationship there is increased blood pressure proximal to the defect (head and
unclear) upper extremities, right greater than left) and decreased blood pressure
Antepartal bleeding Various defects (relationship unclear) distal to the obstruction (torso and lower extremities) (Figure 24-3).
Prematurity PDA, VSD
High altitude PDA, atrial septal defect (increased CLINICAL MANIFESTATIONS  The location and severity of the COA
incidence) determine whether an infant will become symptomatic after the ductus
arteriosus closes. If the COA is severe, infants will present with low car-
diac output, poor tissue perfusion, acidosis, and hypotension. Physical
examination of the infant will reveal weak or absent femoral pulses.
defects. Other types of acyanotic heart defects obstruct blood flow Some infants with COA will remain asymptomatic after the closure
from the ventricles but do not cause shunting. Cyanotic heart defects of the ductus arteriosus. As they age, children with undiagnosed COA
frequently cause shunting of blood from the right side of the heart will present with unexplained upper extremity hypertension. Chil-
directly into the left side of the heart (right-to-left shunt). This type dren may complain of leg pain or cramping with exercise. They also
of shunt decreases blood flow through the pulmonary system, causing may rarely experience dizziness, headaches, fainting, or epistaxis from
less than normal oxygen delivery to the tissues and resultant cyanosis hypertension.1,2
(see Chapter 26). The most common cyanotic heart defect is tetralogy
of Fallot (TOF); in this condition, narrowing of the pulmonary out- EVALUATION AND TREATMENT  Physical examination and mea-
flow tract increases right heart pressures, thus forcing blood through surement of upper and lower extremity blood pressures will often
a defect in the ventricular septum into the left heart (see Figure 24-2, suggest the diagnosis. Echocardiography, magnetic resonance imag-
C). Cyanosis, a bluish discoloration of the skin indicating that tissues ing (MRI), and cardiac catheterization may be needed to confirm the
are not receiving normal amounts of oxygen, also can be caused by diagnosis. Initial treatment in the symptomatic newborn consists of
other types of heart defects that result in the mixing of venous and continuous intravenous infusion of prostaglandin E1 to maintain the
arterial blood. patency of the ductus arteriosus. Once the symptomatic newborn is
Most congenital heart defects are named to describe the underly- stabilized, surgical correction is indicated.3
ing defect (for example, valvular abnormalities; abnormal openings Surgical correction consists of either resection of the narrowed por-
in the septa, including persistence of the foramen ovale; continued tion of the aorta with an end-to-end anastomosis or enlargement of the
patency of the ductus arteriosus; and malformation or abnormal constricted section using a graft taken from a portion of the left sub-
placement of the great vessels). A description of the most common clavian artery. Because this defect is outside the heart and pericardium,
defects follows. cardiopulmonary bypass usually is not required and a thoracotomy
 CHAPTER 24  Alterations of Cardiovascular Function in Children 645

Acyanotic Cyanotic

↑ Pulmonary Obstruction ↓ Pulmonary blood flow Mixed blood flow

blood flow to blood flow
from ventricles

Atrial septal defect Coarctation of aorta Tetralogy of Fallot Transposition of great arteries
Ventricular septal defect Aortic stenosis Tricuspid atresia Total anomalous pulmonary venous return
Patent ductus arteriosus Pulmonic stenosis Truncus arteriosus
Atrioventricular canal Hypoplastic left heart syndrome
FIGURE 24-1  Comparison of Acyanotic-Cyanotic and Hemodynamic Classification Systems of
Congenital Heart Disease. (From Hockenberry MJ et al: Wong’s nursing care of infants and children,
ed 9, St Louis, 2011, Mosby.)

NORMAL ASD/VSD TETRALOGY OF FALLOT

RA LA RA LA RA LA

RV LV RV LV RV LV

PV AV PV AV PV AV
A B C
FIGURE 24-2  Shunting of Blood in Congenital Heart Disease. A, Normal. B, Acyanotic defect.
C, Cyanotic defect. ASD, Atrial septal defect; AV, aortic valve; LA, left atrium; LV, left ventricle;
PV, pulmonic valve; RA, right atrium; RV, right ventricle; VSD, ventricular septal defect. (Modified from
Hockenberry MJ et al: Wong’s nursing care of infants and children, ed 8, St Louis, 2009, Mosby.)

Coarctation
of the aorta

Ao

Ao
A
B
FIGURE 24-3  Postductal and Preductal Coarctation of the Aorta. A, Postductal coarctation occurs
distal to (“after”) the insertion of the closed ductus arteriosus into the aortic arch. Preductal coarctation
occurs proximal to (“before”) the insertion of the patent ductus arteriosus. The coarctation consists of
a flap of tissue that protrudes from the tunica media of the aortic wall. B, Coarctation of the aorta with
typical indentation of the aortic wall (arrow) opposite the ductal arterial ligament (asterisk). Ao, Aorta.
(A from Hockenberry MJ et al: Wong’s essentials of pediatric nursing, ed 8, St Louis, 2009, Mosby;
B from Damjanov I, Linder J, editors: Anderson’s pathology, ed 10, St Louis, 1996, Mosby.)
646 CHAPTER 24  Alterations of Cardiovascular Function in Children

incision is used. However, coarctation repair may be part of a more heart disease in which strenuous physical activity may be curtailed
complex operation, which might require a sternotomy incision and because of the cardiac condition.1,2
cardiopulmonary bypass. Postoperative hypertension is treated with Subvalvular AS is a stricture caused by a fibrous ring below a nor-
intravenous medication, often a short-acting beta-blocker, followed by mal valve. It can also be caused by a narrowed left ventricular outflow
oral medications, such as an angiotensin-converting enzyme inhibitor. tract in combination with a small aortic valve annulus. Supravalvular
Residual hypertension after repair of COA seems to be related to age AS, a narrowing of the aorta just above the valve, occurs infrequently. It
and time of repair. can occur as a single defect (familial supravalvular stenosis syndrome)
Studies have shown that percutaneous balloon angioplasty has been or as a part of Williams-Beuren syndrome, which also is characterized
effective in reducing residual postoperative coarctation in most chil- by unusual facial appearance and mental disability.5
dren.1,2 Balloon angioplasty of COA as an initial intervention can also
be considered. However, in infants younger than 7 months of age, most CLINICAL MANIFESTATIONS  Infants with significant AS demon-
will experience recoarctation in only a short period of time after pri- strate signs of decreased cardiac output with faint pulses, hypotension,
mary angioplasty. Other complications include aneurysm formation tachycardia, and poor feeding. A loud, harsh systolic ejection murmur
and blood vessel injury from arterial access. Data exist that support is expected. Older children also may have complaints of exercise intol-
balloon angioplasty as an effective therapy in selected infants older erance and, rarely, chest pain. Children are at risk for bacterial endo-
than 7 months of age with a decreased risk of aneurysm formation as carditis, although prophylaxis with antibiotics is no longer routinely
compared to younger infants.4 recommended (see Health Alert: Endocarditis Risk). Aortic stenosis,
when severe, also can be complicated by coronary insufficiency, ven-
Aortic Stenosis tricular dysfunction, and, rarely, sudden death.
PATHOPHYSIOLOGY  Aortic stenosis (AS) is a narrowing or stric-
ture of the left ventricular outlet, causing resistance of blood flow from
the left ventricle into the aorta (Figure 24-4). The physiologic conse-
HEALTH ALERT
quence of severe AS is hypertrophy of the left ventricular wall, which Endocarditis Risk
eventually leads to increased end-diastolic pressure, resulting in pul-
Children with congenital heart disease are at risk for developing endocardi-
monary venous and pulmonary arterial hypertension. If severe, there
tis. Although the risk is low, a transient bacteremia has been noted to fol-
may be decreased cardiac output and pulmonary vascular congestion.
low dental and surgical procedures and instrumentation involving mucosal
Left ventricular hypertrophy impedes coronary artery perfusion and
surfaces. A blood-borne pathogen can inhabit areas of the heart where there
may result in subendocardial ischemia and associated papillary muscle
is high turbulence (such as an abnormal valve or vessel) or reside on artificial
dysfunction that cause mitral insufficiency.
material (such as a valve or homograft). Streptococcus viridans (α-hemolytic
There are three types of AS. Valvular AS occurs as a consequence of
streptococci) is the most commonly found pathogen following dental or oral
malformed or fused cusps, resulting in a unicuspid or bicuspid valve.
procedures. Enterococcus faecalis (enterococci) is the most common bacte-
Valvular AS is a serious defect because (1) the obstruction tends to
rium found following genitourinary and gastrointestinal tract surgery or instru-
be progressive; (2) there may be sudden episodes of myocardial isch-
mentation. The American Heart Association has provided updated guidelines
emia or low cardiac output that, on rare occasions, can result in sud-
for the prevention of bacterial endocarditis. The type and dose of antibiotic
den death in late childhood or adolescence; and (3) surgical repair will
prophylaxis recommended depend on the procedure and the cardiac classi-
not result in a normal valve. This is one of the rare forms of ­congenital
fication of risk for endocarditis. Good dental hygiene with daily brushing and
flossing is critically important.
Data from the American Heart Association: available at
www.americanheart.org.

EVALUATION AND TREATMENT

Valvular aortic stenosis. Valvular AS diagnosis is confirmed by
echocardiography. Mild to moderate valvular AS does not usually
require intervention or restriction of activity. Treatment of severe valvu-
lar AS varies, with nonsurgical palliation the initial treatment of choice
by many interventional cardiologists. Dilation of the stenotic valve with
Aortic stenosis balloon angioplasty, which is performed in the cardiac catheterization
laboratory, still carries a high morbidity and mortality in the critically
ill neonate; however, in older infants and children it compares favorably
with surgical valvotomy.4,6 Balloon angioplasty is, however, associated
with the risk of aortic regurgitation (insufficiency). Children undergo-
ing this procedure almost always require surgical intervention at some
time to relieve recurrent narrowing or worsening regurgitation.4,6
Surgical treatment for valvular AS depends on the severity of the
stenosis, previous interventions, and age of the child. Aortic valve com-
FIGURE 24-4  Aortic Stenosis (AS). Narrowing of the aortic valve missurotomy or valvotomy may be used as an early intervention. Aor-
causing resistance to blood flow in the left ventricle, decreased car- tic valve replacement may be required if the valve is severely dysplastic.
diac output, left ventricular hypertrophy, and pulmonary congestion. The Ross procedure, which involves moving the native pulmonary
(From Hockenberry MJ et al: Wong’s essentials of pediatric nurs- valve into the aortic position and replacing the pulmonary valve with a
ing, ed 8, St Louis, 2009, Mosby.) graft, has become an option. The advantage of the Ross procedure over
 CHAPTER 24  Alterations of Cardiovascular Function in Children 647

Catheter

Pulmonary
artery

Pulmonary
valve

Balloon

Pulmonic stenosis
A B
FIGURE 24-5  Pulmonic Stenosis (PS). A, The pulmonary valve narrows at the entrance of the pulmo-
nary artery. B, Balloon angioplasty is used to dilate the valve. A catheter is inserted across the stenotic
pulmonic valve into the pulmonary artery, and a balloon at the end of the catheter is inflated while it
is positioned across the narrowed valve opening. (A from James SR, Ashwill JW: Nursing care of chil-
dren: principles and practice, ed 3, St Louis, 2007, Saunders.)

mechanical valve replacement, especially in a young child, is that there systolic murmur is expected with PS. Pulmonary atresia produces a
is no requirement for long-term anticoagulation therapy; however, continuous murmur.
the valve may fail with time. Mechanical valve replacement is usually
deferred as long as possible. Aortic stenosis requires lifelong evaluation EVALUATION AND TREATMENT  Echocardiography confirms the
and treatment. Multiple surgical or catheterization interventions are diagnosis and determines the severity of the PS. The treatment of
expected. Mortality for sick infants and young children is higher than choice for infants with moderate to severe pulmonary stenosis is bal-
that for older children. loon angioplasty (see Figure 24-5, B). A catheter with a special bal-
Subvalvular aortic stenosis. Surgical correction for subvalvular AS loon device is used to dilate the area of narrowing. The procedure has
involves incising the constricting fibromuscular ring. If the obstruc- proved highly effective, with a 50% to 75% reduction in pressure gradi-
tion results from a narrow left ventricular outflow tract and a small ent across the pulmonic valve and a low rate of complications.6 In rare
aortic valve annulus, a patch may be required to enlarge the entire left cases, surgical valvotomy may be required. Pulmonary blood flood is
ventricular outflow tract and annulus and replace the aortic valve, an supported with prostaglandin E1 infusion to maintain the patency of
approach known as the Konno procedure. An aortic homograft with a the ductus arteriosus in cases of pulmonary atresia in the neonatal
valve also may be used (extended aortic root replacement). period until surgery is performed to supply pulmonary blood flow.3,4
Supravalvular aortic stenosis. Surgery is usually required for man- Both balloon dilation and surgical valvotomy leave the pulmonary
agement of moderate-to-severe supravalvular aortic stenoses. Balloon valve incompetent (insufficient); however, children are usually able to
angioplasty and stent insertion have been successful but carry a higher tolerate pulmonary valve incompetence and are asymptomatic. Long-
risk of rupture.5 An extended graft with coronary reimplantation may term problems with restenosis or clinically significant valve incom-
be needed if narrowing is severe. petence may occur, but reintervention for uncomplicated PS is rarely
necessary.1,2
Pulmonic Stenosis
PATHOPHYSIOLOGY  Pulmonic stenosis (PS) is a narrowing or Defects With Increased Pulmonary Blood Flow
stricture of the pulmonary valve that causes resistance to blood flow Patent Ductus Arteriosus
from the right ventricle to the pulmonary artery (Figure 24-5). Gener- PATHOPHYSIOLOGY  Patent ductus arteriosus (PDA) is failure of
ally moderate to severe stenosis causes right ventricular hypertrophy. the fetal ductus arteriosus (artery connecting the aorta and pulmo-
Pulmonary atresia is an extreme form of PS with total fusion of the nary artery) to close within the first weeks of life (Figure 24-6). The
valve leaflets (blood cannot flow to the lungs); the right ventricle may continued patency of this vessel allows blood to flow from the higher-
be hypoplastic. In some cases of right ventricular outflow obstruction, pressure aorta to the lower-pressure pulmonary artery, causing a left-
the narrowing is below the valve (infundibular or subvalve PS). to-right shunt.

CLINICAL MANIFESTATIONS  Most infants are asymptomatic if the CLINICAL MANIFESTATIONS  Infants may be asymptomatic or
PS is mild to moderate. Newborns with severe PS or pulmonary atre- show signs of pulmonary overcirculation, such as dyspnea, fatigue,
sia will be cyanotic (from a right-to-left shunt through an atrial septal and poor feeding. There is a characteristic machinery-like murmur in
defect [ASD]) and may have signs of decreased cardiac output. A harsh both systole and diastole. Aortic flow (run-off) into the lower pressure
648 CHAPTER 24  Alterations of Cardiovascular Function in Children

Patent ductus
arteriosus

Ao
SCV

LPA
RPA
Ao

PT

B
A
FIGURE 24-6  Patent Ductus Arteriosus (PDA). A, PDA with left-to-right shunt. B, PDA in an adult with
pulmonary hypertension. Ao, Aorta; LPA, left pulmonary artery; RPA, right pulmonary artery; SCV, sub-
clavian vein. (A from Hockenberry MJ et al: Wong’s essentials of pediatric nursing, ed 8, St Louis, 2009,
Mosby; B from Damjanov I, Linder J, editors: Anderson’s pathology, ed 10, St Louis, 1996, Mosby.)

pulmonary circulation produces low diastolic blood pressure, widened surgery with cardiopulmonary bypass. Interventional catheterization
pulse pressure, and bounding pulses. Children are at risk for bacterial closure involves placement of a closure device.8 All options have low
endocarditis and, rarely, may develop pulmonary hypertension in later morbidity and mortality. Atrial dysrhythmias persist in about 10% of
life from chronic excessive pulmonary blood flow. individuals in both groups after closure.

EVALUATION AND TREATMENT  Diagnosis is confirmed with Ventricular Septal Defect

echocardiography. Administration of indomethacin (a prostaglan- PATHOPHYSIOLOGY  A ventricular septal defect (VSD) is an open-
din inhibitor) has proved successful in closing a PDA in premature ing of the septal wall between the ventricles. VSDs are the most com-
infants and some newborns. Surgical division of the PDA through a mon type of congenital heart defect. VSDs are classified by location.
left thoracotomy also may be done; in some cases the procedure can be Perimembranous VSDs are located high in the septal wall of the ven-
performed with thoracoscopy. Closure with an occlusion device dur- tricle underneath the aortic valve. Muscular VSDs are located low in
ing cardiac catheterization is performed for most older children. Both the septal wall. VSDs also can be located in the inlet or outlet portion
surgical and nonsurgical procedures can be considered low risk.6 of the ventricle. VSDs are similar to ASDs in that blood will shunt from
left to right. Left-to-right shunting of blood can occur with a large
Atrial Septal Defect VSD. Depending on the size and location, many VSDs close spontane-
PATHOPHYSIOLOGY  An atrial septal defect (ASD) is an opening in ously, most often within the first 2 years of life.
the septal wall between the two atria. This opening allows blood to
shunt from the left atrium to the right atrium. There are three types CLINICAL MANIFESTATIONS  Depending on the size, location,
of ASDs. An ostium primum ASD is an opening low in the atrial sep- and degree of shunting and pulmonary vascular resistance, children
tum and may be associated with abnormalities of the mitral valve. An may have no symptoms or have clinical effects from excessive pul-
ostium secundum ASD is an opening in the middle of the atrial sep- monary blood flow. In the infant, excessive pulmonary blood flow
tum and is the most common type. A sinus venosus ASD is an open- from left-to-right shunting causes dyspnea and tachypnea and is
ing usually high in the atrial wall and may be associated with partial commonly called congestive heart failure (CHF), although the heart
anomalous pulmonary venous connection.7 Left-to-right shunting of muscle functions well in VSD. A holosystolic (pansystolic) murmur
blood can occur with a large ASD. is expected.
If the degree of shunting is significant and not corrected, the child
CLINICAL MANIFESTATIONS  Children with an ASD are usually is at risk for developing pulmonary hypertension. Irreversible pulmo-
asymptomatic. Infants with a large ASD may, in rare cases, develop nary hypertension can result in Eisenmenger syndrome, a condition
pulmonary overcirculation and slow growth. Some older children and in which shunting of blood is reversed because of high pulmonary
adults will experience shortness of breath with activity as the right ven- pressure and resistance (right-to-left shunt with cyanosis). Children
tricle becomes less compliant with age. Pulmonary hypertension and with VSD are at risk for endocarditis.
stroke are associated rare complications. A systolic ejection murmur
and a widely split second heart sound are the expected findings on EVALUATION AND TREATMENT  Diagnosis is confirmed by echo-
physical exam. cardiogram. Cardiac catheterization may be needed to calculate the
degree of shunting and to directly measure the pressures in the heart.
EVALUATION AND TREATMENT  Diagnosis is confirmed by echo- Smaller VSDs require minimal treatment and may close completely or
cardiography. The ASD may be closed surgically with primary repair become small enough that surgical closure is not required. If the infant
(sutured closed) or with a patch. Surgical repair involves open-heart has severe CHF or failure to thrive that is unmanageable with medical
 CHAPTER 24  Alterations of Cardiovascular Function in Children 649

(either repair of the mitral valve cleft or fashioning of two AV valves).

If the mitral valve defect is severe, valve replacement may be needed.
A potential problem following repair is mitral regurgitation, which
may later require valve replacement.

Defects With Decreased Pulmonary Blood Flow

Tetralogy of Fallot
PATHOPHYSIOLOGY  The classic form of tetralogy of Fallot (TOF)
includes four defects: (1) ventricular septal defect, (2) pulmonic ste-
Atrioventricular nosis, (3) overriding aorta, and (4) right ventricular hypertrophy
canal defect (Figure 24-8). The pathophysiology varies widely, depending not only
on the degree of pulmonary stenosis but also on the pulmonary and
systemic vascular resistance to flow. If total resistance to pulmonary
flow is greater than systemic resistance, the shunt is from right to left.
If systemic resistance is more than pulmonary resistance, the shunt is
from left to right. Pulmonic stenosis decreases blood flow to the lungs
and, consequently, the amount of oxygenated blood that returns to
the left heart. Physiologic compensation to chronic, severe hypoxia
FIGURE 24-7  Atrioventricular Canal (AVC) Defect. (From
includes production of more red blood cells (polycythemia), develop-
­Hockenberry MJ et al: Wong’s essentials of pediatric nursing, ed 8,
St Louis, 2009, Mosby.)
ment of collateral bronchial vessels, and enlargement of the nail beds
(clubbing).

therapy, early surgical repair is performed. Surgical repair involves CLINICAL MANIFESTATIONS  Some infants may be acutely cyanotic
open-heart surgery with cardiopulmonary bypass. The opening is at birth. In others, progression of hypoxia and cyanosis may be more
sutured closed primarily or with a patch. Nonsurgical intervention is gradual over the first year of life as the pulmonary stenosis worsens.
available but only under restricted conditions.6,9-11 Acute episodes of cyanosis and hypoxia can occur, called hypercya-
notic spells, blue spells, or “tet” spells. These spells (increased right-to-
Atrioventricular Canal Defect left shunt) may occur during crying or after feeding. If prolonged or
PATHOPHYSIOLOGY  Atrioventricular canal (AVC) defect, also frequent, these spells are an indication for emergent evaluation and
known as atrioventricular septal defect (AVSD) or by the traditional surgical treatment.
term endocardial cushion defect (ECD), is the result of incomplete Chronic cyanosis may cause clubbing of the fingers and poor
fusion of endocardial cushions (Figure 24-7). AVC defect consists of growth in children. Squatting can help with cyanosis in these children
an ostium primum ASD and inlet VSD with associated abnormali- because it increases peripheral resistance in the systemic circulation,
ties of the atrioventricular valve tissue. These valve abnormalities which causes an increase in pressures in the left heart and consequent
range from a cleft in the mitral valve to a common mitral and tri- reduction in right-to-left shunting and improvement in pulmonary
cuspid valve. The directions and pathways of flow are determined by perfusion. Children with unrepaired TOF are at risk for emboli, stroke,
pulmonary and systemic resistance, left and right ventricular pres- brain abscess, seizures, and loss of consciousness or sudden death fol-
sures, and the compliance of each chamber. Flow is generally from lowing a tet spell.
left to right. AVC is a common cardiac defect in children with Down
syndrome. However, most children with this defect have normal EVALUATION AND TREATMENT  Diagnosis is confirmed with echo-
karyotype. cardiography. Elective surgical repair is usually performed in the first
year of life. Indications for earlier repair include increasing cyanosis
CLINICAL MANIFESTATIONS  Infants with this defect often display or the development of hypercyanotic spells. Complete repair involves
moderate to severe heart failure attributable to left-to-right shunting closure of the VSD, resection of the infundibular stenosis, and enlarge-
and pulmonary overcirculation. Infants with pulmonary hyperten- ment of the right ventricular outflow tract.
sion and high pulmonary resistance have less shunting and therefore In very small infants who cannot undergo primary repair, a pal-
minimal signs of CHF. There may be mild cyanosis that increases with liative procedure to increase pulmonary blood flow and increase oxy-
crying. Those with a large left-to-right shunt will have a murmur, and gen saturation may be performed. This systemic artery to pulmonary
those with minimal shunt may not have a murmur. Children with artery anastomosis is the Blalock-Taussig or modified Blalock-Taussig
AVC are at risk for developing irreversible pulmonary hypertension if shunt, which provides blood flow to the pulmonary arteries.
left surgically untreated.
Tricuspid Atresia
EVALUATION AND TREATMENT  AVC is one of the most frequent PATHOPHYSIOLOGY  Tricuspid atresia is failure of the tricuspid
diagnoses made with fetal echocardiography. Cardiac catheterization valve to develop; consequently, there is no communication from right
usually is not needed. Initial treatment goals include aggressive medi- atrium to right ventricle (Figure 24-9). Blood flows through an atrial
cal management of CHF and nutritional supplementation. Infants are septal defect or a patent foramen ovale to the left atrium and through
followed closely for signs or symptoms of failure to thrive. Complete a ventricular septal defect to the right ventricle. This condition is often
surgical repair is performed between 3 and 6 months of age to prevent associated with pulmonic stenosis or transposition of the great arter-
irreversible pulmonary hypertension. This procedure consists of patch ies. There is complete mixing of unoxygenated and oxygenated blood
closure of the septal defects and reconstruction of the AV valve tissue in the left side of the heart, resulting in systemic desaturation and mild
650 CHAPTER 24  Alterations of Cardiovascular Function in Children

Ao PT

Pulmonic Overriding
stenosis aorta

Ventricular
septal defect

LV
RV
Right ventricular
A hypertrophy

B
FIGURE 24-8  Tetralogy of Fallot (TOF). A, TOF hemodynamics. B, Right ventricular (RV) hypertrophy
and AO. (A from Hockenberry MJ et al: Wong’s essentials of pediatric nursing, ed 8, St Louis, 2009,
Mosby; B from Damjanov I, Linder J, editors: Anderson’s pathology, ed 10, St Louis, 1996, Mosby.)

LA

RA

Tricuspid
atresia
LV

RV

B
A
FIGURE 24-9  Tricuspid Atresia. A, Tricuspid atresia hemodynamics. B, Small right ventricle (RV) slit
of VSD; left ventricle (LV) is enlarged. (A from Hockenberry MJ et al: Wong’s essentials of pediatric
nursing, ed 8, St Louis, 2009, Mosby; B from Damjanov I, Linder J, editors: Anderson’s pathology,
ed 10, St Louis, 1996, Mosby.)
 CHAPTER 24  Alterations of Cardiovascular Function in Children 651

cyanosis. The physiologic process that causes lesion development is

variable, depending on the great vessel anatomy and amount of pul- Mixing Defects
monary stenosis. Transposition of the Great Arteries or Transposition
of the Great Vessels
CLINICAL MANIFESTATIONS  A murmur is noted, and cyanosis is PATHOPHYSIOLOGY  In transposition of the great arteries (TGA)
usually seen in the newborn period. Tachycardia, dyspnea, fatigue, and or transposition of the great vessels (TGV), the pulmonary artery
poor feeding may be noted with excessive pulmonary blood flow. Older leaves the left ventricle and the aorta exits the right ventricle (Figure
children may have signs of chronic hypoxemia with clubbing. Children 24-10). Associated defects, such as ASD, VSD, or PDA, permit mixing
are at risk for bacterial endocarditis, brain abscess, and stroke. of saturated and desaturated blood, which maintains adequate tissue
oxygenation for a limited time.
EVALUATION AND TREATMENT  After diagnosis is confirmed by
echocardiography, the neonate with decreased pulmonary blood CLINICAL MANIFESTATIONS  Clinical manifestations depend on the
flow is treated with a continuous infusion of prostaglandin E1 to type and size of the associated defects. Children with limited communi-
maintain the patency of the ductus arteriosus until surgical interven- cation between cardiac chambers are severely cyanotic, acidotic, and ill at
tion. If the ASD is restrictive, an atrial septostomy is done during birth. Those with large septal defects or a patent ductus arteriosus may be
cardiac catheterization.10 Treatment is accomplished in staged pro- less severely cyanotic but may have symptoms of pulmonary overcircula-
cedures. Once the infant is stabilized, a Blalock-Taussig shunt (sys- tion. Classically no murmur is heard unless there is an associated VSD.
temic to pulmonary artery anastomosis) is placed to increase blood
flow to the lungs. EVALUATION AND TREATMENT  Diagnosis is suspected by physical
Further surgery is undertaken between 6 months and 2 years of examination and confirmed with echocardiography. Administration
age, depending on the child’s growth and degree of pulmonary blood of intravenous prostaglandin E1 to maintain the patency of the duc-
flow. The next step is usually a Glenn shunt in which the superior tus arteriosis may be initiated to temporarily increase oxygen delivery.
vena cava is anastomosed to the pulmonary artery. At that time, Enlargement of the patent foramen ovale by balloon atrial septostomy
the pulmonary artery may be ligated or the Blalock-Taussig shunt may be performed during cardiac catheterization to increase mixing
may be removed. The final separation of the pulmonary circulation and maintain cardiac output.9,10
from the systemic circulation is the Fontan procedure. In this stage, The most preferred type of surgical repair for TGA performed in
the inferior vena caval blood flow is routed to the pulmonary artery the first weeks of life is the arterial switch procedure. It involves tran-
using a tube graft or baffle. The infant must have normal ventricular secting the great arteries and anastomosing the main pulmonary artery
function and low pulmonary vascular resistance for the procedure to to the native proximal aorta (just above the aortic valve) and anasto-
be successful. mosing the ascending aorta to the native proximal pulmonary artery.
Postoperative complications that increase hospital stay include The coronary arteries are moved with a “button” of tissue from the
pleural and pericardial effusions, elevated pulmonary vascular resis- proximal aorta to the proximal pulmonary artery, creating a new aorta.
tance, and ventricular dysfunction. Exercise tolerance is limited in Reimplantation of the coronary arteries is critical to the infant’s sur-
many children with the Fontan procedure, but general health is con- vival, and the arteries must be reattached without torsion or kinking
sidered good. to provide the heart with its supply of oxygen. The advantage of the

Circulation of unoxygenated blood

Pulmonary artery

RA RV Ao Body

Mixing of
blood via ASD VSD PDA
Aorta defects

LA LV PA Lungs

A
Circulation of oxygenated blood B
FIGURE 24-10  Hemodynamics in Transposition of the Great Vessels (TGV). A, Complete transpo-
sition of the great vessels with an intact interventricular septum. The aorta arises from the right ven-
tricle and the pulmonary artery from the left ventricle. B, Oxygen saturation in the two, parallel circuits.
Ao, Aorta; ASD, atrial septal defect; LA, left atrium; LV, left ventricle; PA, pulmonary artery; PDA, patent
ductus arteriosus; RA, right atrium; RV, right ventricle; VSD, ventricular septal defect. (A from Hocken-
berry MJ et al: Wong’s essentials of pediatric nursing, ed 8, St Louis, 2009, Mosby.)
652 CHAPTER 24  Alterations of Cardiovascular Function in Children

arterial switch procedure is the reestablishment of normal circulation CLINICAL MANIFESTATIONS  Most infants develop cyanosis early
with the left ventricle acting as the systemic pump. Potential complica- in life. The degree of cyanosis is inversely related to the amount of
tions of the arterial switch include narrowing at the great artery anas- pulmonary blood flow. Children with unobstructed TAPVC may be
tomoses or coronary artery insufficiency. Long-term results for the asymptomatic until pulmonary vascular resistance decreases dur-
arterial switch operation are usually good. ing infancy, increasing pulmonary blood flow, with resulting signs of
pulmonary overcirculation. Cyanosis becomes worse with pulmonary
Total Anomalous Pulmonary Venous Connection vein obstruction; once obstruction occurs, the infant’s condition usu-
PATHOPHYSIOLOGY  Total anomalous pulmonary venous con- ally deteriorates rapidly. Without intervention, cardiac failure will
nection (TAPVC) is a rare defect characterized by failure of the pulmo- progress to death. Murmur is not a common feature of TAPVC.
nary veins to join the left atrium during cardiac development. TAPVC
is also called total anomalous pulmonary venous return (TAPVR) or EVALUATION AND TREATMENT  Diagnosis is suspected with echo-
total anomalous pulmonary venous drainage (TAPVD) (Figure 24-11). cardiography but may require confirmative angiography. Corrective
The pulmonary venous return is connected to the right side of the cir- repair is usually required in early infancy. The surgical approach varies
culation rather than to the left atrium. The type of TAPVC is classified with the anatomic defect. In general, however, the common pulmo-
according to the pulmonary venous point of attachment: nary vein (venous confluence) is sutured to the left atrium, the ASD
• Supracardiac: Attachment above the diaphragm, usually to the is closed, and the anomalous pulmonary venous connection may be
superior vena cava (most common form) ligated.
• Cardiac: Direct attachment to the heart, usually to the right atrium
or coronary sinus Truncus Arteriosus
• Infracardiac: Attachment below the diaphragm, such as to the infe- PATHOPHYSIOLOGY  Truncus arteriosus (TA) is failure of normal
rior vena cava (most severe and least common form) septation and division of the embryonic outflow track into a pulmo-
The right atrium receives all the blood that normally would flow nary artery and an aorta, resulting in a single vessel that exits the heart.
into the left atrium. As a result, the right side of the heart is enlarged There is always an associated VSD with mixing of the systemic and
and the left side, especially the left atrium, is smaller than normal. An arterial circulations (Figure 24-12) causing some degree of cyanosis.
associated ASD or patent foramen ovale allows systemic venous blood Blood ejected from the heart flows preferentially to the lower-pressure
to shunt from the right atrium to the left side of the heart. As a result, pulmonary arteries, causing increased pulmonary blood flow. The
the oxygen saturation of the blood in both sides of the heart (and, ulti- three types are as follows:
mately, in the systemic arterial circulation) is the same. If the pulmo- • Type I: A single pulmonary trunk arises near the base of the truncus
nary blood flow is increased, pulmonary venous return is also large, and divides into the left and right pulmonary arteries.
and the amount of saturated blood is relatively high. However, if there • Type II: The left and right pulmonary arteries arise separately from
is obstruction to pulmonary venous drainage, the infant has severe the posterior aspect of the truncus.
cyanosis and low cardiac output. Infracardiac TAPVC often is associ- • Type III: The pulmonary arteries arise independently and from the
ated with obstruction of pulmonary venous drainage and is a surgical lateral aspect of the truncus.
emergency with high mortality.
CLINICAL MANIFESTATIONS  Most infants are symptomatic with
moderate heart failure and variable cyanosis, poor growth, and activ-
Total anomalous ity intolerance. Children are at risk for brain abscess and bacterial
pulmonary venous endocarditis.
connection

Superior
vena cava

Pulmonary
Pulmonary artery
vein

Atrial
septal Pulmonary
defect vein
Truncus
arteriosus

FIGURE 24-12  Truncus Arteriosus (TA). (From James SR, Ashwill

FIGURE 24-11  Total Anomalous Pulmonary Venous Connec- JW: Nursing care of children: principles and practice, ed 3, St Louis,
tion (TAPVC). 2007, Saunders.)
 CHAPTER 24  Alterations of Cardiovascular Function in Children 653

EVALUATION AND TREATMENT  Diagnosis is made by echocar- (Norwood, Glenn, Fontan). Disadvantages of neonatal transplantation
diography. Corrective repair is a modification of the Rastelli procedure include shortage of newborn organ donors, risk of rejection, long-term
and is performed in the first few weeks or months of life. It involves problems with chronic immunosuppression, and infection.
closing the VSD so that the truncus arteriosus receives the outflow Long-term (>10 years) outcome from both procedures has
from the left ventricle, excising the pulmonary arteries from the aorta improved. The survival continues to improve and quality of life for the
and attaching them to the right ventricle by means of a homograft. children is generally good.7,9,10,12-14 No treatment is recommended for
These children require additional procedures to replace the conduit as infants with little hope of surgical survival. The family is then offered
its size becomes inadequate in relation to growth. palliative care.

Hypoplastic Left Heart Syndrome

PATHOPHYSIOLOGY  Hypoplastic left heart syndrome (HLHS) is 4 QUICK CHECK 24-1
underdevelopment of the left side of the heart. Features include small 1. What are the three principal classifications of congenital heart disease?
left atrium, small or absent mitral valve, small or absent left ventricle, 2. Describe the different characteristics that determine whether the defects
and a small or absent aortic valve. Coarctation also is expected (Figure are cyanotic or acyanotic.
24-13). Most blood from the left atrium flows across the patent fora- 3. What is the most common type of congenital heart defect?
men ovale to the right atrium, to the right ventricle, and out the pul-
monary artery. The descending aorta receives blood from the patent
ductus arteriosus supplying systemic blood flow and filling the aorta Congestive Heart Failure
and coronary arteries as well. Congestive heart failure (CHF) is a common complication of many con-
genital heart defects. CHF occurs when the heart is unable to maintain
CLINICAL MANIFESTATIONS  HLHS presents in the early new- sufficient cardiac output to meet the metabolic demands of the body. The
born period as mild cyanosis, tachypnea, and low cardiac output if not most common congenital causes of CHF in infancy and childhood are
already detected by fetal echocardiogram. Support of the systemic cir- listed in Table 24-3. Classic CHF in children also can be acquired, usually
culation is accomplished with prostaglandin E1 infusion. If HLHS is not resulting from cardiomyopathies. Pulmonary overcirculation from large
suspected and the patent ductus arteriosus closes, there is progressive left-to-right shunt is often called CHF but is not usually associated with
deterioration with cyanosis and decreased cardiac output, leading to
cardiovascular collapse. If untreated, HLHS is usually fatal in the first
months of life. TABLE 24-3 CAUSES OF CONGESTIVE
HEART FAILURE RESULTING
EVALUATION AND TREATMENT  Echocardiography shows all of the FROM CONGENITAL HEART
features of HLHS. Cardiac catheterization is rarely required. A multi- DISEASE
stage repair approach is used. The first stage is the Norwood procedure,
which is anastomosis of the main pulmonary artery to the aorta to cre- AGE OF ONSET CAUSE
ate a new aorta, construction of a shunt to provide pulmonary blood At birth HLHS
flow, creation of a large atrial septal defect, and repair of the coarctation. Volume overload lesions
The second stage is a bidirectional Glenn shunt done at 6 to 9 months of Severe tricuspid or pulmonary insufficiency
age to relieve cyanosis and reduce the volume load on the right ventri- Large systemic AV fistula
cle. The final repair is a Fontan procedure. Some centers perform heart First week TGA
transplantation in the newborn period rather than the staged procedure PDA in small premature infants
HLHS (with more favorable anatomy)
TAPVR, particularly those with pulmonary venous
Hypoplastic Coarctation obstruction
ascending aorta of aorta Others
Systemic AV fistula
Critical AS or PS
1-4 weeks COA with associated anomalies
Critical AS
Large left-to-right shunt lesions (VSD, PDA) in
premature infants
All other lesions previously listed
4-6 weeks Some left-to-right shunt lesions, such as AVSD
Hypoplastic 6 weeks to 4 months Large VSD
left ventricle
Large PDA
Others, such as anomalous left coronary artery from PA

From Park MK: Pediatric cardiology for practitioners, ed 5, St Louis,

2008, Mosby.
AS, Aortic stenosis; AVSD, atrioventricular septal defect; AV, atrioven-
tricular; COA, coarctation of the aorta; HLHS, hypoplastic left heart
FIGURE 24-13  Hypoplastic Left Heart Syndrome (HLHS). (From syndrome; PA, pulmonary artery; PDA, patent ductus arteriosus; PS,
Hockenberry MJ et al: Wong’s essentials of pediatric nursing, ed 8, pulmonic stenosis; TAPVR, total anomalous pulmonary venous return;
St Louis, 2009, Mosby.) TGA, transposition of great arteries; VSD, ventricular septal defect.
654 CHAPTER 24  Alterations of Cardiovascular Function in Children

decreased ventricular function and failure to meet metabolic demands. Treatment is aimed at decreasing cardiac workload and increas-
However, the clinical manifestations are similar, such as failure to thrive, ing the efficiency of heart function. Severe congenital heart disease is
tachypnea, tachycardia, and respiratory tract infections.2 managed with surgical repair. Medical management initially consists of
In general, the pathophysiologic mechanisms of CHF in infants diuretics, such as furosemide. Depending on the degree of CHF, other
and children are similar to those in adults. It is most often a result of diuretics can be used in combination with furosemide to counteract
decreased left ventricular systolic function and the associated left atrial potassium losses. Agents that reduce afterload, such as captopril or enal-
and pulmonary venous hypertension and pulmonary venous conges- april and beta-blockers, are employed to further manage severe CHF.1,2
tion. The same compensatory mechanisms are activated in the face of
inadequate cardiac output (see Figure 23-38). Right ventricular failure
ACQUIRED CARDIOVASCULAR DISORDERS
is rare in childhood.
Left heart failure in infants is manifested as poor feeding and suck- Acquired heart diseases refer to disease processes or abnormalities that
ing, often leading to failure to thrive. In left heart failure, dyspnea, tachy- occur after birth. They result from various causes, such as infection,
pnea, and diaphoresis may be accompanied by retractions, grunting, genetic disorders, autoimmune processes in response to infection,
and nasal flaring. Wheezing, coughing, and rales are rare in childhood environmental factors, or autoimmune diseases. Examples of acquired
CHF.1,12,13 Common skin changes, such as pallor or mottling, are often heart diseases include Kawasaki disease, myocarditis, rheumatic heart
present (Box 24-1). Systemic venous congestion is rare in childhood. disease, cardiomyopathy, and systemic hypertension. This chapter dis-
The presence of peripheral edema and weight gain suggests renal dis- cusses Kawasaki disease and systemic hypertension. Myocarditis, rheu-
ease or nutritional disease much more often than cardiac dysfunction. matic heart disease, and cardiomyopathy are discussed in Chapter 23.
A thorough physical examination with emphasis on cardiac and
pulmonary findings will often reveal the degree of CHF. Plotting a Kawasaki Disease
child’s growth (height, weight, head circumference) is an important Kawasaki disease (KD), formerly known as mucocutaneous lymph
method of assessing a child’s health. Infants with CHF or pulmonary node syndrome, is an acute, usually self-limiting systemic vasculi-
overcirculation usually have low weight with normal length and head tis that may result in cardiac sequelae. It was first identified in 1967.
circumference measurements. The failure to thrive is usually the result Although KD occurs throughout the world, the greatest number of
of increased metabolic expenditure relative to caloric intake. An elec- cases are seen in Japan.1,2 This reflects the genetic component of KD,
trocardiogram (ECG) also should be performed to determine the pres- with the case rate being highest among Asians, less among white chil-
ence of dysrhythmia or hypertrophy. A chest x-ray is useful in assessing dren, and rare in black children.
the presence of cardiomegaly and signs of increased pulmonary circu- Kawasaki disease is primarily a condition of young children. Eighty
lation or pulmonary edema. percent of cases are seen in children younger than 5 years of age, with the
incidence peaking in the toddler age group. Males are affected slightly
more than females. The peak incidence is in the winter and spring.1,2
BOX 24-1 CLINICAL MANIFESTATIONS OF The etiology of Kawasaki disease remains unknown. Current eti-
CONGESTIVE HEART FAILURE ologic theories center on an immunologic response to an infectious,
toxic, or antigenic substance.14
Impaired Myocardial Function
Tachycardia PATHOPHYSIOLOGY  Kawasaki disease progresses pathologically
Sweating (inappropriate) and clinically in the following stages. In the early or acute phase, small
Decreased urinary output capillaries, arterioles, and venules become inflamed, as does the heart
Fatigue itself. In the subacute state, inflammation spreads to larger vessels and
Weakness aneurysms of the coronary arteries may develop. In the convalescent
Restlessness stage, medium-sized arteries begin the granulation process and may
Anorexia cause coronary artery thickening with increased risk for thrombosis.
Pale, cool extremities After the convalescent stage, inflammation wanes with potential scar-
Weak peripheral pulses ring of the affected vessels, calcification, and stenosis.
Decreased blood pressure
Gallop rhythm CLINICAL MANIFESTATIONS  The clinical course of the disease pro-
Cardiomegaly gresses in three stages: acute, subacute, and convalescent. In the acute
phase, the child with classic or typical KD has fever, conjunctivitis, oral
Pulmonary Congestion
changes (“strawberry” tongue), rash, and lymphadenopathy and is often
Tachypnea
irritable. During this phase, myocarditis may develop. The subacute phase
Dyspnea
begins when the fever ends and continues until the clinical signs have
Retractions (infants)
resolved. It is at this time that the child is most at risk for coronary artery
Flaring nares
aneurysm development. Desquamation of the palms and soles occurs
Exercise intolerance
at this time, as well as marked thrombocytosis. The convalescent phase
Orthopnea
is marked by the elevation of the erythrocyte sedimentation rate and
Cough, hoarseness
C-reactive protein level, as well as by an increased platelet count. Arthritis
Cyanosis
may be present. This phase continues until all laboratory values return
Wheezing
to normal—usually about 6 to 8 weeks after onset.1 Atypical KD is now
Grunting
described with the presentation of infants as young as 6 weeks who have
Excerpted from Hockenberry MJ et al: Wong’s nursing care of infants fever and coronary aneurysms without the “classic” physical findings or
and children, ed 9, St Louis, 2011, Mosby. typical time course. Recognition is difficult and may delay treatment.14
 CHAPTER 24  Alterations of Cardiovascular Function in Children 655

EVALUATION AND TREATMENT  The diagnosis is based on the Hypertension is classified into two categories: primary, or essential,
diagnostic criteria for Kawasaki disease, which state that the child must hypertension, in which a specific cause cannot be identified, and sec-
exhibit five of six criteria, including fever (Box 24-2). These children ondary hypertension, in which a cause can be identified (see Box 24-3).
usually have leukocytosis, increased erythrocyte sedimentation rates, Hypertension (HTN) in children differs from adult hypertension in
thrombocytosis, and elevated levels of liver enzymes. An echocardio- etiology and presentation. Children, when diagnosed with HTN, are
gram is obtained at the time of diagnosis as a baseline measurement often found to have secondary hypertension caused by some underly-
to assess for coronary aneurysms or inflammation. Serial echocardio- ing disease, such as renal disease or coarctation of the aorta (see Box
grams are obtained after treatment to assess for development of coro- 24-3). An increased prevalence of primary HTN in older children has
nary aneurysms or regression of those present early in the course of the been noted. Researchers are now focusing on primary HTN in older
disease. Treatment includes oral administration of aspirin and intrave- children in relation to morbidity and the presence of early athero-
nous infusion of gamma globulin (most often only one dose). Aspirin sclerotic disease. Certain factors influence blood pressure in children.
is continued until the manifestations of inflammation are resolved. Children who are overweight are often hypertensive (see Health Alert:
Treatment with aspirin and intravenous immunoglobulin during U.S. Childhood Obesity and Its Association With Cardiovascular Dis-
the acute phase has decreased the morbidity of Kawasaki disease and ease). Smoking also is associated with an increased risk for HTN.16-18
has reduced the incidence of coronary abnormalities from approxi-
mately 20% to less than 10% at 6 to 8 weeks after initiation of therapy.
Most children recover completely from Kawasaki disease, including HEALTH ALERT
regression of aneurysms. The most common cardiovascular sequela is
U.S. Childhood Obesity and Its Association
coronary thrombosis.14
With Cardiovascular Disease
Systemic Hypertension Childhood obesity is epidemic in the United States. The number of overweight
Systemic hypertension in children is defined as systolic and diastolic children has doubled since the 1970s, and obesity has been called the most seri-
blood pressure levels greater than the 95th percentile for age and gen- ous and prevalent nutritional disorder in the United States. Obesity is linked to
der on at least three occasions (Tables 24-4 and 24-5). The Fourth Task insulin resistance and diabetes and increases cardiovascular risk, especially ath-
Force on Blood Pressure Control in Children uses height as an addi- erosclerosis, hypertension, and lipid abnormalities. The mechanisms by which
tional criterion to the blood pressure guidelines.1,15 insulin resistance and diabetes cause cardiovascular diseases include endothe-
lial dysfunction, structural changes in arterial walls, abnormal vasoconstriction,
BOX 24-2 DIAGNOSTIC CRITERIA and changes in renal function and salt transport. Research into genetics and
FOR KAWASAKI DISEASE insulin-regulated transcription factors suggests that obesity, insulin resistance,
diabetes, and cardiovascular disease share important molecular etiologies and
The child must exhibit five of the following six criteria, including fever: processes. These findings may lead investigators to important new treatments.
1. Fever for 5 or more days (often diagnosed with shorter duration of fever if For now, helping children develop good exercise and dietary habits has been
other symptoms are present) shown to significantly improve arterial function and reduce cardiovascular risk.
2. Bilateral conjunctival infection without exudation
3. Changes in the oral mucous membranes, such as erythema, dryness, and Content and update references and statistics can be found at www.
fissuring of the lips; oropharyngeal reddening; or “strawberry tongue” cdc.gov/obesity/childhood/index.html.
4. Changes in the extremities, such as peripheral edema, peripheral ery-
thema, and desquamation of palms and soles, particularly periungual peeling
5. Polymorphous rash, often accentuated in the perineal area TABLE 24-5 SUGGESTED NORMAL
6. Cervical lymphadenopathy BP VALUES (MM HG) BY
Data from Hockenberry MJ et al: Wong’s nursing care of infants and AUSCULTATORY METHOD
children, ed 9, St Louis, 2011, Mosby. (SYSTOLIC/DIASTOLIC K5)
MEAN 90TH 95TH
TABLE 24-4 NORMATIVE BLOOD AGE (YR) BP LEVELS PERCENTILE PERCENTILE
PRESSURE LEVELS 6-7 104/55 114/73 117/78
(SYSTOLIC/DIASTOLIC 8-9 106/58 117/76 120/82
[MEAN]) BY DINAMAP 10-11* 108/60 120/77 124/82
MONITOR IN CHILDREN 12-13* 112/62 124/78 128/83
5 YEARS OLD AND YOUNGER 14-15
Boys 116/66 132/80 138/86
MEAN BP LEVELS 90TH 95TH
Girls 112/68 126/80 130/83
AGE (mm Hg) PERCENTILE PERCENTILE
16-18
1-3 days 64/41 (50) 75/49 (50) 78/52 (62) Boys 121/70 136/82 140/86
1 month to 95/58 (72) 106/68 (83) 110/71 (86) Girls 110/68 125/81 127/84
2 years
2-5 years 101/57 (74) 112/66 (82) 115/68 (85) From Park MK: Pediatric cardiology for practitioners, ed 4, St Louis,
2002, Mosby; modified from Goldring D et al: J Pediatr 91:884, 1977;
Data from Park MK: Pediatric cardiology for practitioners, ed 5, St Prineas RJ et al: Hypertension 1(suppl):18, 1980.
Louis, 2008, Mosby; modified from Park MK, Menard SM: Am J Dis BP, Blood pressure; K5, phase V of Korotkoff sound.
Children 143:860, 1989. *Values for ages 10 to 13 years have been extrapolated from these
BP, Blood pressure. two studies using age-related increments from other studies.
656 CHAPTER 24  Alterations of Cardiovascular Function in Children

BOX 24-3 CONDITIONS ASSOCIATED WITH SECONDARY HYPERTENSION IN CHILDREN

Renal Disorders Cushing syndrome
Congenital defects Adrenogenital syndrome
Polycystic kidney, ectopic kidney, horseshoe kidney, etc. Hyperthyroidism
Obstructive anomalies Aldosteronism
Hydronephrosis Hypercalcemia
Renal tumor Diabetes mellitus
Wilms tumor
Renovascular disease Neurologic Disorders
Abnormalities of renal arteries Space-occupying lesions of cranium (increased intracranial pressure)
Renal vein thrombosis Tumors
Acquired disorders Cysts
Glomerulonephritis—acute or chronic Hematoma
Pyelonephritis Cerebral edema
Nephritis associated with collagen disease Encephalitis (including Guillain-Barré and Reye syndromes)

Cardiovascular Disease Miscellaneous Causes

Coarctation of aorta Drugs (corticosteroids, oral contraceptives, pressor agents, amphetamines)
Arteriovenous fistulae Burns
Patent ductus arteriosus Genitourinary surgery
Aortic or mitral insufficiency Trauma (e.g., stretching of femoral nerve with leg traction)
Insect bites (e.g., scorpion)
Metabolic and Endocrine Diseases Intravascular overload (blood, fluid)
Adrenal tumors Hypernatremia
Adenoma Toxemia of pregnancy
Pheochromocytoma Heavy metal poisoning
Neuroblastoma

Modified from Hockenberry MJ et al: Wong’s nursing care of infants and children, ed 9, St Louis, 2011, Mosby.

PATHOPHYSIOLOGY  In infants and children, a cause of HTN is TABLE 24-6 MOST COMMON CAUSES
almost always found. In general, the younger the child with significant OF CHRONIC SUSTAINED
hypertension, the more likely a correctable cause can be determined. HYPERTENSION
Therefore a thorough evaluation needs to be performed.2,16
AGE GROUP CAUSES
The pathophysiology of primary HTN in children is not clearly
understood but may result from a complex interaction of a strong Newborn Renal artery thrombosis, renal artery stenosis, congenital
predisposing genetic component with disturbances in sympathetic renal malformation, COA, bronchopulmonary dysplasia
vascular smooth muscle tone, humoral agents (angiotensin, catechol- <6 yr Renal parenchymal disease, COA, renal artery stenosis
amines), renal sodium excretion, and cardiac output. Ultimately these 6-10 yr Renal artery stenosis, renal parenchymal disease,
factors impair the ability of the peripheral vascular bed to relax. primary hypertension
>10 yr Primary hypertension, renal parenchymal disease
CLINICAL MANIFESTATIONS  Most children with systemic HTN COA, Coarctation of the aorta.
are asymptomatic. It is necessary that a thorough history and physical From Park MK: Pediatric cardiology for practitioners, ed 5, St Louis,
examination be obtained. The examination should include an accu- 2008, Mosby.
rate blood pressure measurement on three separate occasions using an
appropriate-size cuff.16-18 Medication therapy is controversial in children with primary
hypertension; however, when nonpharmacologic therapy fails, the
EVALUATION AND TREATMENT  In children, the history and physi- approach is similar to the treatment of hypertension in adults with the
cal examination should be directed at determining the etiology of use of angiotensin-converting enzyme inhibitors or angiotensin recep-
HTN, such as coarctation of the aorta or renal disease (Table 24-6). tor blocker medications.2 The current emphasis on preventive cardiol-
A complete blood count, serum chemistry levels, urinalysis, urine cul- ogy, especially for children, is significant because many investigators
ture, lipid profile, and renal ultrasound are part of the routine evalua- believe signs of atherosclerosis are present during childhood.1,18
tion for renal disease (Table 24-7). If coarctation of the aorta is found,
surgical correction is initiated. If HTN is determined to be essential,
or primary, in nature, nonpharmacologic therapy is used initially.
4 QUICK CHECK 24-2
Moderate weight loss and exercise can decrease systolic and diastolic 1. Why are the infant’s height and weight important in the assessment of
pressures in many children. Appropriate diet, regular physical activity, congestive heart failure?
and avoidance of smoking have been shown to be effective in reducing 2. Why is it of critical importance to recognize and treat children during the
blood pressure.18 Ambulatory blood pressure monitoring (ABPM) has acute phase of Kawasaki disease?
the potential to become an important tool in the evaluation and man- 3. Discuss the causes of the recent epidemic of obesity in children and the
agement of childhood hypertension.19 cardiovascular effects.
 CHAPTER 24  Alterations of Cardiovascular Function in Children 657

TABLE 24-7 ROUTINE AND SPECIAL LABORATORY TESTS FOR HYPERTENSION

LABORATORY TESTS SIGNIFICANCE OF ABNORMAL RESULTS
Urinalysis, urine culture, blood urea nitrogen, and creatinine levels Renal parenchymal disease
Serum electrolyte levels ­(hypokalemia) Hyperaldosteronism, primary or secondary
Adrenogenital syndrome
Renin-producing tumors
ECG, chest x-ray studies Cardiac cause of hypertension, also baseline function
Intravenous pyelography (or ­ultrasonography, radionuclide studies, computed Renal parenchymal diseases
tomography of kidneys) Renovascular hypertension
Tumors (neuroblastoma, Wilms tumor)
Plasma renin activity, peripheral High-renin hypertension
Renovascular hypertension
Renin-producing tumors
Some caused by Cushing syndrome
Some caused by essential hypertension
Low-renin hypertension
Adrenogenital syndrome
Primary hyperaldosteronism
24-hr urine collection for ­17-ketosteroids and 17-hydroxycorticosteroids Cushing syndrome
Adrenogenital syndrome
24-hr urine collection for ­catecholamine levels and ­vanillylmandelic acid Pheochromocytoma
Neuroblastoma
Aldosterone Hyperaldosteronism, primary or secondary
Renovascular hypertension
Renin-producing tumors
Renal vein plasma renin activity Unilateral renal parenchymal disease
Renovascular hypertension
Abdominal aortogram Renovascular hypertension
Abdominal COA
Unilateral renal parenchymal diseases
Pheochromocytoma

From Park MK: Pediatric cardiology for practitioners, ed 6, St Louis, 2008, Mosby.
COA, Coarctation of the aorta; ECG, electrocardiogram.

DID YOU UNDERSTAND?

Congenital Heart Disease 6. Congenital defects that maintain or create direct communication between
1. Most congenital heart defects have begun to develop by the eighth week the pulmonary and systemic circulatory systems cause blood to shunt from
of gestation, and some have associated causes, both environmental and one system to another, mixing oxygenated and unoxygenated blood and
genetic. increasing blood volume and, occasionally, pressure on the receiving side
2. Environmental risk factors associated with the incidence of congenital heart of the shunt.
defects typically are maternal conditions. Maternal conditions include viral 7. The direction of shunting through an abnormal communication depends on
infections, diabetes, drug intake, and advanced maternal age. differences in pressure and resistance between the two systems. Flow is
3. Genetic factors associated with congenital heart defects include but are always from an area of high pressure to an area of low pressure.
not limited to Down syndrome, trisomy 13, trisomy 18, cri du chat syn- 8. Obstruction of ventricular outflow is commonly caused by pulmonary steno-
drome, and Turner syndrome. sis (right ventricle) or aortic stenosis (left ventricle).
4. Classification of congenital heart defects is based on (a) whether they 9. In less severe obstruction, ventricular outflow remains normal because of
cause blood flow to the lungs to increase, decrease, or remain normal; (b) compensatory ventricular hypertrophy stimulated by increased afterload
whether they cause cyanosis; and (c) whether they cause obstruction to and, in postductal coarctation of the aorta, development of collateral circu-
flow. lation around the coarctation.
5. Cyanosis, a bluish discoloration of the skin, indicates that the tissues are 10. Acyanotic congenital defects that increase pulmonary blood flow consist
not receiving normal amounts of oxygenated blood. Cyanosis can be caused of abnormal openings (atrial septal defect, ventricular septal defect, pat-
by defects that (a) restrict blood flow into the pulmonary circulation; (b) ent ductus arteriosus, or atrioventricular septal defect) that permit blood to
overload the pulmonary circulation, causing pulmonary overcirculation, shunt from left (systemic circulation) to right (pulmonary circulation). Cya-
pulmonary edema, and respiratory difficulty; or (c) cause large amounts nosis does not occur because the left-to-right shunt does not interfere with
of unoxygenated blood to shunt from the pulmonary to the systemic the flow of oxygenated blood through the systemic circulation.
circulation.

Continued
658 CHAPTER 24  Alterations of Cardiovascular Function in Children

DID YOU UNDERSTAND?—cont’d

11. If the abnormal communication between the left and right circuits is large, 15. Congestive heart failure is usually the result of congenital heart defects
volume and pressure overload in the pulmonary circulation lead to left heart that increase blood volume in the pulmonary circulation. A clinical manifes-
failure. tation of CHF unique to children is failure to thrive.
12. Cyanotic congenital defects in which saturated and desaturated blood mix
within the heart or great arteries include truncus arteriosus, tricuspid atre- Acquired Cardiovascular Disorders in Children
sia, tetralogy of Fallot, transposition of the great vessels, total anomalous 1. Two examples of acquired heart disease in children are Kawasaki disease
pulmonary venous connection, and hypoplastic left heart syndrome. and systemic hypertension.
13. In cyanotic heart defects that decrease pulmonary blood flow (tetralogy of 2. Kawasaki disease is an acute systemic vasculitis that also may result in the
Fallot), myocardial hypertrophy cannot compensate for restricted right ven- development of coronary artery aneurysms and thrombosis.
tricular outflow. Flow to the lungs decreases, and cyanosis is caused by an 3. Systemic hypertension in children differs from HTN in adults in etiology
insufficient volume of oxygenated blood and right-to-left shunt. and presentation. When significant hypertension is found in a child, the
14. Initial treatment for congenital heart disease, depending on the defect, is examiner should evaluate for the presence of renal disease or coarctation.
aimed at controlling the level of congestive heart failure or cyanosis. Inter-
ventional procedures in the cardiac catheterization laboratory and surgical
palliation or repair are performed to restore circulation to as normal as
possible.

 KEY TERMS
•  cyanotic heart defect  643
A •  awasaki disease (KD)  654
K • S ystemic hypertension  655
• Aortic stenosis (AS)  646 • Left-to-right shunt  643 • Tetralogy of Fallot (TOF)  649
• Atrial septal defect (ASD)  648 • Muscular VSD  648 • Total anomalous pulmonary venous con-
• Atrioventricular canal (AVC) defect • Ostium primum ASD  648 nection (TAPVC)  652
(atrioventricular septal defect [AVSD], • Ostium secundum ASD  648 • Transposition of the great arteries
endocardial cushion defect [ECD])  649 • Patent ductus arteriosus (PDA)  647 (TGA; transposition of the great vessels
• Coarctation of the aorta (COA)  644 • Perimembranous VSD  648 [TGV])  651
• Congenital heart disease (CHD)  643 • Pulmonary atresia  647 • Tricuspid atresia  649
• Congestive heart failure (CHF)  653 • Pulmonic stenosis (PS)  647 • Truncus arteriosus (TA)  652
• Cyanosis  644 • Right-to-left shunt  644 • Valvular AS  646
• Cyanotic heart defect  644 • Shunt  643 • Ventricular septal defect (VSD)  648
• Eisenmenger syndrome  648 • Sinus venosus ASD  648
• Hypoplastic left heart syndrome • Subvalvular AS  646
(HLHS)  653 • Supravalvular AS  646

REFERENCES 12. Federspiel MC: Cardiac assessment in the neonatal population, Neonatal
Netw 29(3):135–142, 2010.
1. Allen HD, editor: Moss and Adams’ heart disease in infants, children, and 13. Hartas GA, Emmanouil T, Gupta-Malhotra M: Approach to diagnosing
adolescents including the fetus and young adults, ed 7, Philadelphia, 2008, congenital cardiac disorders, Crit Care Nurs Clin North Am 21:27–36,
Lippincott Williams & Wilkins. 2009.
2. Park MK: Pediatric cardiology for practitioners, ed 5, St Louis, 2008, Mosby. 14. Newberger JW, et al: Diagnosis, treatment and long-term management
Available at http://mdconsult/book. of Kawasaki disease: a statement for health professionals from The Com-
3. Sadowski SL: Congenital cardiac disease in the newborn infant: past, pres- mittee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council
ent, and future, Crit Care Nurs Clin North Am 21:7–48, 2009. on Cardiovascular Disease in the Young, American Heart Association,
4. Hijazi ZM, Awad SM: Pediatric cardiac interventions, JACC Cardiovasc Circulation 110:2747–2771, 2004.
Interv 1(6):603–611, 2008. 15. National High Blood Pressure Education Program Working Group on
5. Pober BR: Williams-Beuren syndrome, N Engl J Med 362(3):239–252, High Blood Pressure in Children and Adolescents: The fourth report on
2010. the diagnosis, evaluation and treatment of high blood pressure in children
6. Hollinger I, Mittnacht A: Cardiac catheterization, interventional cardiol- and adolescents, Pediatrics 114(suppl 2, 4th rep):555–576, 2004.
ogy, and ablation techniques for children, Int Anesthesiol Clin 47(3):63–99, 16. Brady TM, Feld LG: Pediatric approach to hypertension, Semin Nephrol
2009. 29(4):379–388, 2009.
7. Wong D, et al: Whaley and Wong’s nursing care of infants and children, ed 17. Nguyen M: Mitsnefes: Evaluation of hypertension by the general pediatri-
7, St Louis, 2003, Mosby. cian, Curr Opin Pediatr 19(2):165–169, 2007.
8. Gervasi L, Basu S: Atrial septal defect devices used in the cardiac catheter- 18. Seikaly MG: Hypertension in children; an update on treatment strategies,
ization laboratory, Prog Cardiovasc Nurs 24(3):86–89, 2009. Curr Opin Pediatr 19(2):170–177, 2007.
9. Barron DJ, et al: Hypoplastic left heart syndrome, Lancet 374(9589):551– 19. Urbina E, et al: Ambulatory blood pressure monitoring in children and
564, 2009. adolescents: recommendations for standard assessment: a scientific state-
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genital heart disease, Catheter Cardiovasc Interv 72(5):663–674, 2008. sion and Obesity in Youth Committee of the Council on Cardiovascular
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 CHAPTER

25
Structure and Function of the
Pulmonary System
Valentina L. Brashers

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
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CHAPTER OUTLINE
Structures of the Pulmonary System, 659 Mechanics of Breathing, 667
Conducting Airways, 659 Gas Transport, 669
Gas-Exchange Airways, 663 Control of the Pulmonary Circulation, 675
Pulmonary and Bronchial Circulation, 663 GERIATRIC CONSIDERATIONS: Aging & the Pulmonary ­
Chest Wall and Pleura, 663 System, 675
Function of the Pulmonary System, 663
Ventilation, 664
Neurochemical Control of Ventilation, 665

The pulmonary system consists of the lungs, airways, chest wall, and lung. The lung tissue that surrounds the airways supports them, prevent-
pulmonary circulation. Its primary function is the exchange of gases ing their distortion or collapse as gas moves in and out during ventilation.
between the environmental air and the blood. The three steps in this The lungs are protected from exogenous contaminants by a series
process are (1) ventilation, the movement of air into and out of the of mechanical barriers (Table 25-1). These defense mechanisms are so
lungs; (2) diffusion, the movement of gases between air spaces in the effective that contamination of the lung tissue itself, particularly by
lungs and the bloodstream; and (3) perfusion, the movement of blood infectious agents, is rare.
into and out of the capillary beds of the lungs to body organs and tis-
sues. The first two functions are carried out by the pulmonary system Conducting Airways
and the third by the cardiovascular system (see Chapter 22). Normally The conducting airways allow air into and out of the gas-exchange struc-
the pulmonary system functions efficiently under a variety of condi- tures of the lung. The nasopharynx, oropharynx, and related struc-
tions and with little energy expenditure. tures are often called the upper airway (Figure 25-2). These structures
are lined with a ciliated mucosa that warms and humidifies inspired air
and removes foreign particles from it. The mouth and oropharynx are
STRUCTURES OF THE PULMONARY SYSTEM used for ventilation when the nose is obstructed or when increased flow
The pulmonary system consists of two lungs and their airways, the blood is required, for example, during exercise. Filtering and humidifying are
vessels that serve these structures (Figure 25-1), and the chest wall, or tho- not as efficient with mouth breathing.
racic cage. The lungs are divided into lobes: three in the right lung (upper, The larynx connects the upper and lower airways and consists of
middle, lower) and two in the left lung (upper, lower). Each lobe is further the endolarynx and its surrounding triangular-shaped bony and car-
divided into segments and lobules. The space between the lungs, which tilaginous structures. The endolarynx encompasses two pairs of folds:
contains the heart, great vessels, and esophagus, is called the mediastinum. the false vocal cords (supraglottis) and the true vocal cords. The slit-
A set of conducting airways, or bronchi, delivers air to each section of the shaped space between the true cords forms the glottis (see Figure 25-2).

659
660 CHAPTER 25  Structure and Function of the Pulmonary System

Nasal cavity

Nasopharynx
Upper Oropharynx Pharynx
respiratory Laryngopharynx
tract
Larynx

Left and
right Trachea
primary
bronchi
Lower
respiratory
tract

Alveoli

Bronchioles Alveolar
duct

Capillary

Alveolar
sac

FIGURE 25-1  Structure of the Pulmonary System. The enlargement in the circle depicts the acinus,
where oxygen and carbon dioxide are exchanged. (From Patton KT, Thibodeau GA: Anatomy & physiol-
ogy, ed 7, St Louis, 2010, Mosby.)

The vestibule is the space above the false vocal cords. The laryngeal
TABLE 25-1 PULMONARY DEFENSE box is formed of three large cartilages (epiglottis, thyroid, cricoid) and
MECHANISMS three smaller cartilages (arytenoid, corniculate, cuneiform) connected
STRUCTURE OR by ligaments. The supporting cartilages prevent collapse of the larynx
SUBSTANCE MECHANISM OF DEFENSE during inspiration and swallowing. The internal laryngeal muscles
Upper respiratory Maintains constant temperature and humidification control vocal cord length and tension, and the external laryngeal mus-
tract mucosa of gas entering lungs; traps and removes foreign cles move the larynx as a whole. Both sets of muscles are important to
particles, some bacteria, and noxious gases from swallowing, ventilation, and vocalization.1 The internal muscles con-
inspired air tract during swallowing to prevent aspiration into the trachea. These
Nasal hairs and Trap and remove foreign particles, some bacteria, and muscles also contribute to voice pitch.
turbinates noxious gases from inspired air The trachea, which is supported by U-shaped cartilage, connects the
Mucous blanket Protects trachea and bronchi from injury; traps most larynx to the bronchi, the conducting airways of the lungs. The tra-
foreign particles and bacteria that reach lower chea branches into two main airways, or bronchi (sing., bronchus), at
airways the carina (see Figure 25-1). The right and left main bronchi enter the
Cilia Propel mucous blanket and entrapped particles lungs at the hila (sing., hilum), or “roots” of the lungs, along with the
toward oropharynx, where they can be swallowed pulmonary blood and lymphatic vessels. From the hila the main bron-
or expectorated chi branch farther, as shown in Figure 25-3.
Alveolar Ingest and remove bacteria and other foreign material The bronchial walls have three layers: an epithelial lining, a smooth
­macrophages from alveoli by phagocytosis (see Chapters 5 and 6) muscle layer, and a connective tissue layer. The epithelial lining of the
Irritant receptors in Stimulation by chemical or mechanical irritants trig- bronchi contains single-celled exocrine glands—the mucus-secreting
nares (nostrils) gers sneeze reflex, which results in rapid removal of goblet cells—and ciliated cells. The goblet cells produce a mucous
irritants from nasal passages blanket that protects the airway epithelium, and the ciliated epithe-
Irritant receptors in Stimulation by chemical or mechanical irritants lial cells rhythmically beat this mucous blanket toward the trachea and
trachea and large triggers cough reflex, which results in removal of pharynx where it can be swallowed or expectorated by coughing. The
airways irritants from lower airways layers of epithelium that line the bronchi become thinner with each
successive branching (Figure 25-4).
 CHAPTER 25  Structure and Function of the Pulmonary System 661

NASAL WALL PHARYNX

Nasal conchae Nasopharynx

Oropharynx
Laryngeal pharynx

Vestibule
Hard palate
Soft palate
Cilia
Epiglottis

Thyroid cartilage
Epiglottis
Tracheal Vocal
Elastic fibers cords
cartilage
False
cord
Corniculate Cuneiform
cartilage tubercle
Corniculate
Arytenoid tubercle
Cilia
cartilage
Cricoid
cartilage

Tracheal cartilage Trachealis Trachea

muscle
Intercartilaginous
ligaments

TRACHEA LARYNX
FIGURE 25-2  Structures of the Upper Airway. (Redrawn from Thompson JM et al: Mosby’s clinical
nursing, ed 5, St Louis, 2002, Mosby.)
662 CHAPTER 25  Structure and Function of the Pulmonary System

CONDUCTING AIRWAYS RESPIRATORY UNIT

SUBSEGMENTAL BRONCHI
SEGMENTAL (BRONCHIOLES) ALVEOLAR
TRACHEA
BRONCHI DUCTS
Nonrespiratory Respiratory

GENERATIONS 8 16 24 26
FIGURE 25-3  Structures of the Lower Airway. (Redrawn from Thompson JM et al: Mosby’s clinical
nursing, ed 5, St Louis, 2002, Mosby.)

Lower airways Cellular structures

Mucous layer
Serous cell
Goblet cell
Ciliated cell
Basal cell
Basement membrane
Trachea and bronchus Lamina propria

Mucous layer
Ciliated cell
Clara cell
Basal cell
Basement membrane
Lamina propria
Bronchiole

Mucous layer
Clara cell
Ciliated cell
Nerve
Basement membrane
Lamina propria
Respiratory bronchiole

Capillary lumen
Type II alveolar cell
Basement membrane
Surfactant
Alveolar macrophage
Type I alveolar cell

Alveoli
FIGURE 25-4  Changes in the Bronchial Wall With Progressive Branching. (From Wilson SF,
Thompson JM: Respiratory disorders, St Louis, 1990, Mosby.)
 CHAPTER 25  Structure and Function of the Pulmonary System 663

Gas-Exchange Airways Terminal

The conducting airways terminate in the respiratory bronchioles, bronchiole
Pulmonary
alveolar ducts, and alveoli (sing., alveolus). These thin-walled struc- arteriole
Pulmonary
tures together are sometimes called the acinus (see Figures 25-1 and
venule
25-3), and all of them participate in gas exchange.2
The alveoli are the primary gas-exchange units of the lung, where
oxygen enters the blood and carbon dioxide is removed (Figure 25-5).
Tiny passages called pores of Kohn permit some air to pass through the Alveolar Alveolar sac
septa from alveolus to alveolus, promoting collateral ventilation and duct
even distribution of air among the alveoli. The lungs contain approxi-
mately 25 million alveoli at birth and 300 million by adulthood.
Two major types of epithelial cells appear in the alveolus. Type I
alveolar cells provide structure, and type II alveolar cells secrete sur-
factant, a lipoprotein that coats the inner surface of the alveolus and
lowers alveolar surface tension at end-expiration, thereby preventing
lung collapse.1-4
Like the bronchi, alveoli contain cellular components of inflamma-
tion and immunity, particularly the mononuclear phagocytes (called
alveolar macrophages). These cells ingest foreign material that reaches
the alveolus and prepare it for removal through the lymphatics.
(Phagocytosis and the mononuclear phagocyte system are described Alveoli
in Chapters 5 and 6.)
FIGURE 25-5  Alveoli. Bronchioles subdivide to form tiny tubes
called alveolar ducts, which end in clusters of alveoli called alveolar
4 QUICK CHECK 25-1
sacs. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 7,
St Louis, 2010, Mosby.)
1. List the major components of the pulmonary system.
2. What are conducting airways?
3. Describe an alveolus. The bronchial circulation is part of the systemic circulation, and it
supplies nutrients to the conducting airways, large pulmonary vessels,
and membranes (pleurae) that surround the lungs. Not all of its capil-
Pulmonary and Bronchial Circulation laries drain into its own venous system. Some empty into the pulmo-
The pulmonary circulation facilitates gas exchange, delivers nutrients to nary vein and contribute to the normal venous mixture of oxygenated
lung tissues, acts as a reservoir for the left ventricle, and serves as a filter- and deoxygenated blood or right-to-left shunt (right-to-left shunts are
ing system that removes clots, air, and other debris from the circulation. described in Chapter 26). The bronchial circulation does not partici-
Although the entire cardiac output from the right ventricle goes into pate in gas exchange.1
the lungs, the pulmonary circulation has a lower pressure and resis- Lung vasculature also includes deep and superficial lymphatic cap-
tance than the systemic circulation. Pulmonary arteries are exposed to illaries. Fluid and alveolar macrophages migrate from the alveoli to
about one fifth the pressure of the systemic circulation. Usually about the terminal bronchioles, where they enter the lymphatic system. Both
one third of the pulmonary vessels are filled with blood (perfused) at deep and superficial lymphatic vessels leave the lung at the hilum. The
any given time. More vessels become perfused when right ventricular lymphatic system plays an important role in keeping the lung free of
cardiac output increases. Therefore increased delivery of blood to the fluid. (The lymphatic system is described in Chapter 22.)
lungs does not normally increase mean pulmonary artery pressure.
The pulmonary artery divides and enters the lung at the hila, Chest Wall and Pleura
branching with each main bronchus and with all bronchi at every divi- The chest wall (skin, ribs, intercostal muscles) protects the lungs from
sion. Therefore every bronchus and bronchiole has an accompanying injury, and its muscles, along with the diaphragm, perform the mus-
artery or arteriole. The arterioles divide at the terminal bronchioles to cular work of breathing. The thoracic cavity is contained by the chest
form a network of pulmonary capillaries around the acinus. Capillary wall and encases the lungs (Figure 25-7). A serous membrane called the
walls consist of an endothelial layer and a thin basement membrane, pleura adheres firmly to the lungs and then folds over itself and attaches
which often fuses with the basement membrane of the alveolar septum. firmly to the chest wall. The membrane covering the lungs is the vis-
Consequently, very little separation exists between blood in the capil- ceral pleura; that lining the thoracic cavity is the parietal pleura. The area
lary and gas in the alveolus. between the two pleurae is called the pleural space, or pleural cavity.
The shared alveolar and capillary walls compose the alveolocapil- Normally, only a thin layer of fluid secreted by the pleura (pleural fluid)
lary membrane (Figure 25-6). Gas exchange occurs across this mem- fills the pleural space, lubricating the pleural surfaces and allowing the
brane. With normal perfusion, approximately 100 ml of blood in the two layers to slide over each other without separating. Pressure in the
pulmonary capillary bed is spread very thinly over 70 to 100 m2 of alve- pleural space is usually negative or subatmospheric (−4 to −10 mm Hg).
olar surface area. Any disorder that thickens the membrane impairs gas
exchange.
Each pulmonary vein drains several pulmonary capillaries. Unlike
FUNCTION OF THE PULMONARY SYSTEM
the pulmonary arteries, pulmonary veins are dispersed randomly The pulmonary system (1) ventilates the alveoli, (2) diffuses gases into
throughout the lung and then leave the lung at the hila and enter the and out of the blood, and (3) perfuses the lungs so that the organs
left atrium. They have no valves. and tissues of the body receive blood that is rich in oxygen and low in
664 CHAPTER 25  Structure and Function of the Pulmonary System

Type II Surfactant Interstitial Connective

layer cell tissue Alveolar
alveolar cell epithelium
Capillary
Capillary Surfactant endothelium
endothelium layer

Alveolus
Red blood
cell

O2
Alveolar Alveolus
epithelium

CO2
Basement
membrane

Type I
alveolar cell

Alveolar Basement Interstitial

macrophage membrane space

FIGURE 25-6  Section Through the Alveolar Septum (Gas-Exchange Membrane). Inset shows a
magnified view of the respiratory membrane composed of the alveolar wall (fluid coating, epithelial cells,
basement membrane), interstitial fluid, and wall of a pulmonary capillary (basement membrane, endo-
thelial cells). The gases CO2 (carbon dioxide) and O2 (oxygen) diffuse across the respiratory membrane.

Trachea Thyroid Neurochemical Control of Ventilation

Right primary cartilage Larynx (respiratory center, central and peripheral chemoreceptors)
bronchus Cricoid
cartilage
Mechanics of Breathing
Aorta
Left (major and accessory muscles, lung elasticity, airway resistance,
primary alveolar surface tension, work of breathing)
Right
bronchus
lung
Mediastinum
Parietal Gas Transport
pleura (distribution of ventilation and perfusion, oxygen transport,
Visceral carbon dioxide transport)
pleura Left lung
Control of the Pulmonary Circulation
Pleural space (distribution of pulmonary blood flow)
Diaphragm FIGURE 25-8  Functional Components of the Respiratory Sys-
Esophagus tem. The central nervous system responds to neurochemical stimu-
lation of ventilation and sends signals to the chest wall musculature.
FIGURE 25-7  Thoracic (Chest) Cavity and Related Structures.
The response of the respiratory system to these impulses is influ-
The thoracic (chest) cavity is divided into three subdivisions (left and
enced by several factors that impact the mechanisms of breath-
right pleural divisions and mediastinum) by a partition formed by a
ing and, therefore, affect the adequacy of ventilation. Gas transport
serous membrane called the pleura. (From Thibodeau GA, Patton
between the alveoli and pulmonary capillary blood depends on a
KT: Anatomy & physiology, ed 3, St Louis, 1996, Mosby.)
variety of physical and chemical activities. Finally, the control of the
pulmonary circulation plays a role in the appropriate distribution of
carbon dioxide. Each component of the pulmonary system contributes blood flow.
to one or more of these functions (Figure 25-8).

Ventilation times gas is inspired and expired per minute. The amount of effective
Ventilation is the mechanical movement of gas or air into and out ventilation is calculated by multiplying the ventilatory rate (breaths per
of the lungs. It is often misnamed respiration, which is actually the minute) by the volume or amount of air per breath (liters per breath
exchange of oxygen and carbon dioxide during cellular metabolism. or tidal volume). This is called the minute volume (or minute ventila-
“Respiratory rate” is actually the ventilatory rate, or the number of tion) and is expressed in liters per minute.
 CHAPTER 25  Structure and Function of the Pulmonary System 665

Blood-brain
barrier

Voluntary and Capillary HCO3

higher centers
H
H2O + CO2 CO2
H
H2CO3

Control centers H + HCO3

Pneumotaxic center
(inspiration)
Chemosensitive center
(sensitive to H, O2, and CO2)
Apneustic center
(inspiration and expiration)
Dorsal respiratory group
Stretch
(inspiration)
Ventral respiratory group Irritant
(inspiration and expiration) Vagus
nerve J-receptors

Vagus
nerve

Carotid
body

Inter-
costal
Aortic nerve
bodies
↓ PO2

Phrenic
nerve
(to diaphragm)
FIGURE 25-9  Neurochemical Respiratory Control System.

Carbon dioxide (CO2), the gaseous form of carbonic acid (H2CO3), Neurochemical Control of Ventilation
is produced by cellular metabolism. The lung eliminates about 10,000 Breathing is usually involuntary, because homeostatic changes in
milliequivalents (mEq) of carbonic acid per day in the form of CO2, ventilatory rate and volume are adjusted automatically by the ner-
which is produced at the rate of approximately 200 ml/min. Carbon vous system to maintain normal gas exchange. Voluntary breathing
dioxide is eliminated to maintain a normal arterial CO2 pressure is necessary for talking, singing, laughing, and deliberately holding
(Paco2) of 40 mm Hg and normal acid-base balance. Adequate venti- one’s breath. The mechanisms that control respiration are complex
lation is necessary to maintain normal Paco2 levels. Diseases that limit (Figure 25-9).
ventilation result in CO2 retention. The adequacy of alveolar venti- The respiratory center in the brain stem controls respiration by
lation cannot be accurately determined by observation of ventilatory transmitting impulses to the respiratory muscles, causing them to con-
rate, pattern, or effort. If a healthcare professional needs to determine tract and relax. The respiratory center is composed of several groups of
the adequacy of ventilation, an arterial blood gas analysis must be per- neurons: the dorsal respiratory group (DRG), the ventral respiratory
formed to measure Paco2. group (VRG), the pneumotaxic center, and the apneustic center.1-4
The basic automatic rhythm of respiration is set by the DRG, which
receives afferent input from peripheral chemoreceptors in the carotid
4 QUICK CHECK 25-2 and aortic bodies and from several different types of receptors in the
lungs. The VRG contains both inspiratory and expiratory neurons and
1. List the major components of the pulmonary circulation.
2. What are the visceral and parietal pleurae? is almost inactive during normal, quiet respiration, becoming active
when increased ventilatory effort is required. The pneumotaxic center
666 CHAPTER 25  Structure and Function of the Pulmonary System

and apneustic center, situated in the pons, do not generate primary and CSF reach equilibrium. As the central chemoreceptors sense the
rhythm but, rather, act as modifiers of the rhythm established by the resulting decrease in pH (increase in hydrogen ion concentration),
medullary centers. The pattern of breathing can be influenced by emo- they stimulate the respiratory center to increase the depth and rate of
tion, pain, and disease. ventilation. Increased ventilation causes the Pco2 of arterial blood to
decrease below that of the CSF, and carbon dioxide diffuses back out
Lung Receptors of the CSF, returning its pH to normal.
Three types of lung receptors send impulses from the lungs to the dor- The central chemoreceptors are sensitive to very small changes in
sal respiratory group: the pH of CSF (equivalent to a 1 to 2 mm Hg change in Pco2) and
1. Irritant receptors (C-fibers) are found in the epithelium of all con- can maintain a normal Paco2 under many different conditions, includ-
ducting airways. They are sensitive to noxious aerosols (vapors), ing strenuous exercise.6 If inadequate ventilation, or hypoventilation,
gases, and particulate matter (e.g., inhaled dusts), which cause is long term (e.g., in chronic obstructive pulmonary disease), these
them to initiate the cough reflex.5 When stimulated, irritant recep- receptors become insensitive to small changes in Paco2 (“reset”) and
tors also cause bronchoconstriction and increased ventilatory rate. regulate ventilation poorly (see Health Alert: Changes in the Chemical
2. Stretch receptors are located in the smooth muscles of airways Control of Breathing During Sleep).
and are sensitive to increases in the size or volume of the lungs.
They decrease ventilatory rate and volume when stimulated, an
occurrence sometimes referred to as the Hering-Breuer expiratory HEALTH ALERT
reflex. This reflex is active in newborns and assists with ventilation. Changes in the Chemical Control of Breathing
In adults, this reflex is active only at high tidal volumes (such as During Sleep
with exercise) and may protect against excess lung inflation. Stretch
receptors called rapidly adapting receptors (RARs) have been found There are multiple sites of central carbon dioxide chemosensitivity in the brain
to be an important mediator of cough.5 stem, and there are specialized chemosensory sites that function only during
3. J-receptors (juxtapulmonary capillary receptors) are located near certain sleep states. Chemical control of ventilation, related to both hypercap-
the capillaries in the alveolar septa. They are sensitive to increased nia and hypoxia, appears to be blunted during sleep. The orexins are neurohor-
pulmonary capillary pressure, which stimulates them to initiate mones that control feeding, vigilance, and sleep. It is postulated that changes
rapid, shallow breathing, hypotension, and bradycardia.4 in orexin activity contribute to the blunting of chemoreceptor sensitivity seen
The lung is innervated by the autonomic nervous system (ANS). in many states, including obesity and sleep apnea. Congestive heart failure,
Fibers of the sympathetic division in the lung branch from the upper chronic obstructive pulmonary disease, and hypertension also are associated
thoracic and cervical ganglia of the spinal cord. Fibers of the para- with abnormal breathing responses during sleep. Changes in the chemical
sympathetic division of the ANS travel in the vagus nerve to the lung. control of breathing during sleep may contribute to morbidity and mortality
(Structures and function of the ANS are discussed in detail in Chapter seen in individuals with these disorders.
12.) The parasympathetic and sympathetic divisions control airway cal-
Data from Brown LK: Hypoventilation syndromes, Clin Chest Med
iber (interior diameter of the airway lumen) by stimulating bronchial 31(2):249–270, 2010; Kuwaki T, Li A, Nattie E: State-dependent central
smooth muscle to contract or relax. The parasympathetic receptors chemoreception: a role of orexin, Respir Physiol Neurobiol 173(3):223–
cause smooth muscle to contract, whereas sympathetic receptors cause 229, 2010; Nattie E, Li A: Central chemoreception in wakefulness and
it to relax. Bronchial smooth muscle tone depends on equilibrium— sleep: evidence for a distributed network and a role for orexin, J Appl
that is, equal stimulation of contraction and relaxation. The parasym- Physiol 108(5):1417–1424, 2010; Pacchia CF: Sleep apnea and hyper-
pathetic division of the ANS is the main controller of airway caliber tension: role of chemoreflexes in humans, Exp Physiol 92(1):45–50,
under normal conditions. Constriction occurs if the irritant receptors 2007; Pinna GD et al: Long-term time-course of nocturnal breathing
in the airway epithelium are stimulated by irritants in inspired air, by disorders in heart failure patients, Eur Respir J 35(2):361–367, 2010;
Piper AJ: The highs and lows of gas exchange during sleep, Respirol-
inflammatory mediators (e.g., histamine, serotonin, prostaglandins,
ogy 15(2):191–193, 2010.
leukotrienes), by many drugs, and by humoral substances.

Chemoreceptors The peripheral chemoreceptors are somewhat sensitive to changes

Chemoreceptors monitor the pH, Paco2, and Pao2 (arterial pressure in Paco2 and pH but are sensitive primarily to oxygen levels in arterial
of oxygen) of arterial blood.6 Central chemoreceptors monitor arte- blood (Pao2).7 As Pao2 and pH decrease, peripheral chemoreceptors,
rial blood indirectly by sensing changes in the pH of cerebrospinal particularly in the carotid bodies, send signals to the respiratory center
fluid (CSF) (see Figure 25-9, p. 665). They are located near the respi- to increase ventilation. However, the Pao2 must drop well below nor-
ratory center and are sensitive to hydrogen ion concentration in the mal (to approximately 60 mm Hg) before the peripheral chemorecep-
CSF. (Chapter 4 describes the relationship between ions and the pH, tors have much influence on ventilation. If Paco2 is elevated as well,
or acid-base status, of body fluids.) The pH of the CSF reflects arte- ventilation increases much more than it would in response to either
rial pH because carbon dioxide in arterial blood can diffuse across the abnormality alone. The peripheral chemoreceptors become the major
blood-brain barrier (the capillary wall separating blood from cells of stimulus to ventilation when the central chemoreceptors are reset by
the central nervous system) into the CSF until the partial pressure of chronic hypoventilation.8
carbon dioxide (Pco2) is equal on both sides. Carbon dioxide that has
entered the CSF combines with H2O to form carbonic acid, which sub-
sequently dissociates into hydrogen ions that are capable of stimulat-
ing the central chemoreceptors. In this way, Paco2 regulates ventilation
4 QUICK CHECK 25-3
1. Describe three functions of the respiratory center in the brain stem.
through its impact on the pH (hydrogen ion content) of the CSF.1-4,6 2. What are the three types of lung receptors?
If alveolar ventilation is inadequate, Paco2 increases. Carbon diox- 3. How do the functions of central and peripheral chemoreceptors differ?
ide diffuses across the blood-brain barrier until Pco2 values in blood
 CHAPTER 25  Structure and Function of the Pulmonary System 667

Mechanics of Breathing external intercostals may contract during quiet breathing, inspiration
The mechanical aspects of inspiration and expiration are known col- at rest is usually assisted by the diaphragm only.
lectively as the mechanics of breathing and involve (1) major and The accessory muscles of inspiration are the sternocleidomastoid
accessory muscles of inspiration and expiration, (2) elastic properties and scalene muscles. Like the external intercostals, these muscles
of the lungs and chest wall, and (3) resistance to airflow through the enlarge the thorax by increasing its AP diameter. The accessory mus-
conducting airways. Alterations in any of these properties increase the cles assist inspiration when minute volume (volume of air inspired
work of breathing or the metabolic energy needed to achieve adequate and expired per minute) is high, as during strenuous exercise, or when
ventilation and oxygenation of the blood. the work of breathing is increased because of disease. The accessory
muscles do not increase the volume of the thorax as efficiently as the
Major and Accessory Muscles diaphragm does.
The major muscles of inspiration are the diaphragm and the external There are no major muscles of expiration because normal, relaxed
intercostal muscles (muscles between the ribs) (Figure 25-10). The dia- expiration is passive and requires no muscular effort. The accessory
phragm is a dome-shaped muscle that separates the abdominal and muscles of expiration, the abdominal and internal intercostal muscles,
thoracic cavities. When it contracts and flattens downward, it increases assist expiration when minute volume is high, during coughing, or when
the volume of the thoracic cavity, creating a negative pressure that airway obstruction is present. When the abdominal muscles contract,
draws gas into the lungs through the upper airways and trachea. Con- intra-abdominal pressure increases, pushing up the diaphragm and
traction of external intercostal muscles elevates the anterior portion decreasing the volume of the thorax. The internal intercostal muscles
of the ribs and increases the volume of the thoracic cavity by increas- pull down the anterior ribs, decreasing the AP diameter of the thorax.
ing its front-to-back (anterior-posterior [AP]) diameter. Although the
Alveolar Surface Tension
Surface tension occurs at any gas-liquid interface and refers to the
tendency for liquid molecules that are exposed to air to adhere to one
Scalenus another. This phenomenon can be seen in the way liquids “bead” when
muscles
Sternocleidomastoid splashed on a waterproof surface.
Intercostal Within a sphere, such as an alveolus, surface tension tends to make
muscles
expansion difficult. According to the law of Laplace, the pressure
(P) required to inflate a sphere is equal to two times the surface ten-
sion (2T) divided by the radius (r) of the sphere, or P = 2T/r. As the
Pectoralis radius of the sphere (or alveolus) decreases, more and more pressure
minor is required to inflate it. If the alveoli were lined only with a water-like
fluid, taking breaths would be extremely difficult.
Serratus Alveolar ventilation, or distention, is made possible by surfac-
anterior tant, which lowers surface tension by coating the air-liquid interface
in the alveoli. Surfactant, a lipoprotein produced by type II alveolar
cells, includes two groups of surfactant proteins. One group consists
of small hydrophobic molecules that have a detergent-like effect that
Rectus separates the liquid molecules, thereby decreasing alveolar surface ten-
abdominis sion.2,9 As the radius of a surfactant-lined sphere (alveolus) shrinks the
A surface tension decreases, and as the radius expands the surface ten-
sion increases. This occurs because the smaller radius causes surfac-
tant molecules to crowd together and then repel one another strongly.
Serratus A larger radius spreads them apart, decreasing their mutual repellence.
posterior
Intercostal superior Therefore normal alveoli are much easier to inflate at low lung volumes
muscles (i.e., after expiration) than at high volumes (i.e., after inspiration). The
decrease in surface tension caused by surfactant also is responsible
for keeping the alveoli free of fluid. If surfactant is not produced in
adequate quantities, alveolar surface tension increases, causing alveolar
collapse, decreased lung expansion, increased work of breathing, and
severe gas-exchange abnormalities. The second group of surfactant
proteins consists of large hydrophilic molecules called collectins that
are capable of inhibiting foreign pathogens (see Chapter 5).9

Elastic Properties of the Lung and Chest Wall

Diaphragm The lung and chest wall have elastic properties that permit expansion
Serratus during inspiration and return to resting volume during expiration.
Transversus posterior Elastin fibers in the alveolar walls and surrounding the small airways
thoracis interior and pulmonary capillaries, as well as surface tension at the alveolar air-
B liquid interface, produce this effect. The elasticity of the chest wall is
FIGURE 25-10  Muscles of Ventilation. A, Anterior view. B, Pos- the result of the configuration of its bones and musculature.
terior view. (Modified from Thompson JM et  al: Mosby’s clinical Elastic recoil is the tendency of the lungs to return to the resting
nursing, ed 5, St Louis, 2002, Mosby.) state after inspiration. Normal elastic recoil permits passive expiration,
668 CHAPTER 25  Structure and Function of the Pulmonary System

eliminating the need for major muscles of expiration. Passive elastic the relative ease with which these structures can be stretched and is,
recoil may be insufficient during labored breathing (high minute vol- therefore, the opposite of elasticity. Compliance is determined by alve-
ume), when the accessory muscles of expiration may be needed. The olar surface tension and the elastic recoil of the lung and chest wall.
accessory muscles are used also if disease compromises elastic recoil Increased compliance indicates that the lungs or chest wall is
(e.g., in emphysema) or blocks the conducting airways. abnormally easy to inflate and has lost some elastic recoil. A decrease
Normal elastic recoil depends on an equilibrium between opposing indicates that the lungs or chest wall is abnormally stiff or difficult to
forces of recoil in the lungs and chest wall. Under normal conditions, inflate. Compliance increases with normal aging and with disorders
the chest wall tends to recoil by expanding outward. The tendency of the such as emphysema; it decreases in individuals with acute respira-
chest wall to recoil by expanding is balanced by the tendency of the lungs tory distress syndrome, pneumonia, pulmonary edema, and fibrosis.
to recoil or inward collapse around the hila. The opposing forces of the (These disorders are described in Chapter 26.)
chest wall and lungs create the small negative intrapleural pressure.
Balance between the outward recoil of the chest wall and inward Airway Resistance
recoil of the lungs occurs at the resting level, the end of expiration, Airway resistance, which is similar to resistance to blood flow
where the functional residual capacity (FRC) is reached. During inspi- (described in Chapter 22), is determined by the length, radius, and
ration, the diaphragm and intercostal muscles contract, air flows into cross-sectional area of the airways and by the density, viscosity, and
the lungs, and the chest wall expands. Muscular effort is needed to velocity of the gas (Poiseuille law). Resistance (R) is computed by
overcome the resistance of the lungs to expansion. During expiration, dividing change in pressure (P) by rate of flow (F), or R = P/F (Ohm
the muscles relax and the elastic recoil of the lungs causes the thorax law). Airway resistance is normally very low. One half to two thirds of
to decrease in volume until, once again, balance between the chest wall total airway resistance occurs in the nose. The next highest resistance is
and lung recoil forces is reached (Figure 25-11). in the oropharynx and larynx. There is very little resistance in the con-
Compliance is the measure of lung and chest wall distensibility and ducting airways of the lungs because of their large cross-sectional area.
is defined as volume change per unit of pressure change. It represents Airway resistance increases when the diameter of the airways decreases.

Airflow

Chest wall Chest wall

recoil
Chest wall
Pleural recoil
space Muscular
Lung contraction
recoil Lung dominates
Lungs recoil

Diaphragm
Diaphragm Diaphragm
A relaxed contracting B
End of expiration Inspiration

Airflow

Chest wall Chest wall

fully recoiled recoil

Lung Muscular Lung recoil

recoil contraction dominates
maintains
inflation
Diaphragm Diaphragm
C contracted relaxing D
End of inspiration Expiration
FIGURE 25-11  Interaction of Forces During Inspiration and Expiration. A, Outward recoil of the
chest wall equals inward recoil of the lungs at the end of expiration. B, During inspiration, contraction
of respiratory muscles, assisted by chest wall recoil, overcomes the tendency of lungs to recoil. C, At
the end of inspiration, respiratory muscle contraction maintains lung expansion. D, During expiration,
respiratory muscles relax, allowing elastic recoil of the lungs to deflate the lungs.
 CHAPTER 25  Structure and Function of the Pulmonary System 669

Bronchoconstriction, which increases airway resistance, can be caused

by stimulation of parasympathetic receptors in the bronchial smooth
4 QUICK CHECK 25-4
1. Describe the work of the diaphragm in ventilation.
muscle and by numerous irritants and inflammatory mediators.2 Air-
2. What is surfactant? What is its function?
way resistance can also be increased by edema of the bronchial mucosa
3. How is elastic recoil related to compliance?
and by airway obstructions such as mucus, tumors, or foreign bodies.
4. Where is airway resistance found?
Bronchodilation, which decreases resistance to airflow, is caused by
β2-adrenergic receptor stimulation.

Work of Breathing
The work of breathing is determined by the muscular effort (and Gas Transport
therefore oxygen and energy) required for ventilation. Normally very Gas transport, the delivery of oxygen to the cells of the body and the
low, the work of breathing may increase considerably in diseases that removal of carbon dioxide, has four steps: (1) ventilation of the lungs,
disrupt the equilibrium between forces exerted by the lung and chest (2) diffusion of oxygen from the alveoli into the capillary blood, (3)
wall. More muscular effort is required when lung compliance decreases perfusion of systemic capillaries with oxygenated blood, and (4) dif-
(e.g., in pulmonary edema), chest wall compliance decreases (e.g., in fusion of oxygen from systemic capillaries into the cells. Steps in the
spinal deformity or obesity), or airways are obstructed by broncho- transport of carbon dioxide occur in reverse order: (1) diffusion of car-
spasm or mucous plugging (e.g., in asthma or bronchitis). Pulmonary bon dioxide from the cells into the systemic capillaries, (2) perfusion of
function tests (PFTs) measure lung volumes and flow rates and can be the pulmonary capillary bed by venous blood, (3) diffusion of carbon
used to diagnose lung disease (Figure 25-12). dioxide into the alveoli, and (4) removal of carbon dioxide from the
An increase in the work of breathing can result in a marked lung by ventilation. If any step in gas transport is impaired by a respi-
increase in oxygen consumption and an inability to maintain adequate ratory or cardiovascular disorder, gas exchange at the cellular level is
ventilation. compromised.

Greater activity
Resting state (forceful inspiration
(normal breathing) plus forceful expiration)

Respiratory
reserve volume
diminishes

(4500-5000 ml, theoretical)

Inspiratory

Vital capacity (VC)

reserve volume (IRV)
(3000-3300 ml)
Total lung capacity (TLC)
(5700-6200 ml)

Tidal volume (TV) (500 ml) (Volume of

exhaled air after normal inspiration)

Expiratory
Expiratory
reserve volume (ERV) reserve volume
(1000-1200 ml) diminishes

Residual volume (RV)

(1200 ml)

Time
Anatomic dead space
Residual
volume
Expiratory Total
reserve volume lung
Vital capacity
Tidal volume capacity
Inspiratory
reserve volume
FIGURE 25-12  Spirogram. During normal, quiet respirations, the atmosphere and lungs exchange
about 500 ml of air (VT). With a forcible inspiration, about 3300 ml more air can be inhaled (IRV). After
a normal inspiration and normal expiration, approximately 1000 ml more air can be forcibly expired
(ERV). Vital capacity (VC) is the amount of air that can be forcibly expired after a maximal inspiration
and indicates, therefore, the largest amount of air that can enter and leave the lungs during respiration.
Residual volume (RV) is the air that remains trapped in the alveoli. (From Patton KT, Thibodeau GA:
Anatomy & physiology, ed 7, St Louis, 2010, Mosby.)
670 CHAPTER 25  Structure and Function of the Pulmonary System

A B C

O2 blue
N2 black

FIGURE 25-13  Relationship Between Number of Gas Molecules and Pressure Exerted by the Gas
in an Enclosed Space. A, Theoretically, 10 molecules of the same gas exert a total pressure of 10
within the space. B, If the number of molecules is increased to 20, total pressure is 20. C, If there are
different gases in the space, each gas exerts a partial pressure: here the partial pressure of nitrogen
(N2) is 20, that of oxygen (O2) is 6, and the total pressure is 26.

Measurement of Gas Pressure

A gas is composed of millions of molecules moving randomly and col- TABLE 25-2 COMMON PULMONARY
liding with each other and with the wall of the space in which they ABBREVIATIONS
are contained. These collisions exert pressure. If the same number of SYMBOL DEFINITION
gas molecules is contained in a small and a large container, the pres- V Volume or amount of gas
sure is greater in the small container because more collisions occur Q Perfusion or blood flow
in the smaller space (Figure 25-13). Heat increases the speed of the P Pressure (usually partial pressure) of a gas
molecules, which also increases the number of collisions and therefore Pao2 Partial pressure of oxygen in arterial blood
the pressure. PAo2 Partial pressure of oxygen in alveolar gas
Barometric pressure (PB) (atmospheric pressure) is the pressure Paco2 Partial pressure of carbon dioxide in arterial blood
exerted by gas molecules in air at specific altitudes. At sea level, baro- Pvo2 Partial pressure of oxygen in mixed venous or pulmonary
metric pressure is 760 mm Hg and is the sum of the pressure exerted by artery blood
each gas in the air at sea level. The portion of the total pressure exerted P(A−a)o2 Difference between alveolar and arterial partial pressure of
by any individual gas is its partial pressure (see Figure 25-13). At sea oxygen (A−a gradient)
level the air consists of oxygen (20.9%), nitrogen (78.1%), and a few PB Barometric or atmospheric pressure
other trace gases. The partial pressure of oxygen is equal to the percent- Sao2 Saturation of hemoglobin (in arterial blood) with oxygen
age of oxygen in the air (20.9%) times the total pressure (760 mm Hg), Svo2 Saturation of hemoglobin (in mixed venous blood) with oxygen
or 159 mm Hg (760 × 0.209 = 158.84 mm Hg). (Symbols used in the VA Alveolar ventilation
measurement of gas pressures and pulmonary ventilation are defined VD Dead-space ventilation
in Table 25-2.) VE Minute capacity
The amount of water vapor contained in a gas mixture is deter- VT Tidal volume or average breath
mined by the temperature of the gas and is unrelated to baromet- V̇ / Q̇ * Ratio of ventilation to perfusion
ric pressure. Gas that enters the lungs becomes saturated with Fio2 Fraction of inspired oxygen
water vapor (humidified) as it passes through the upper airway. FRC Functional residual capacity
At body temperature (37° C), water vapor exerts a pressure of 47 FVC Forced vital capacity
mm Hg regardless of total (barometric) pressure. The partial pres- FEV1 Forced expiratory volume in 1 second
sure of water vapor must be subtracted from the barometric pres-
sure before the partial pressure of other gases in the mixture can *An overhead dot means measurement over time, usually 1 minute.
be determined. In saturated air at sea level, the partial pressure of
oxygen is therefore (760 − 47) × 0.209 = 149 mm Hg. All pressure
and volume measurements made in pulmonary function laborato- barometric pressure is considered zero, and pressure varies up or down
ries specify the temperature and humidity of a gas at the time of from zero. Physiologic pressure measurements that involve fluids,
measurement. rather than gases, are measured as variations from barometric pres-
Many pressure measurements are stated as variations from sure. For example, a systolic blood pressure of 120 mm Hg indicates
barometric pressure, rather than percentages of it. On such scales, that systolic pressure is 120 mm Hg above barometric pressure.
 CHAPTER 25  Structure and Function of the Pulmonary System 671

Standing
or
sitting

Side-lying

Supine

FIGURE 25-14  Pulmonary Blood Flow and Gravity. The greatest volume of pulmonary blood flow
normally will occur in the gravity-dependent areas of the lung. Body position has a significant effect on
the distribution of pulmonary blood flow.

Distribution of Ventilation and Perfusion Distribution of perfusion in the pulmonary circulation also is
Effective gas exchange depends on an approximately even distribution affected by alveolar pressure (gas pressure in the alveoli). The pulmo-
of gas (ventilation) and blood (perfusion) in all portions of the lungs.1 nary capillary bed differs from the systemic capillary bed in that it is
The lungs are suspended from the hila in the thoracic cavity. When an surrounded by gas-containing alveoli. If the gas pressure in the alveoli
individual is in an upright position (sitting or standing), gravity pulls exceeds the blood pressure in the capillary, the capillary collapses and
the lungs down toward the diaphragm and compresses their lower por- flow ceases. This is most likely to occur in portions of the lung where
tions or bases. The alveoli in the upper portions, or apices, of the lungs blood pressure is lowest and alveolar gas pressure is greatest—that is,
contain a greater residual volume of gas and are larger and less numer- at the apex of the lung.
ous than those in the lower portions. Because surface tension increases The lungs are divided into three zones on the basis of relationships
as the alveoli become larger, the larger alveoli in the upper portions of among all the factors affecting pulmonary blood flow. Alveolar pres-
the lung are more difficult to inflate (less compliant) than the smaller sure and the forces of gravity, arterial blood pressure, and venous blood
alveoli in the lower portions of the lung. Therefore, during ventilation pressure affect the distribution of perfusion, as shown in Figure 25-15.
most of the tidal volume is distributed to the bases of the lungs, where In zone I, alveolar pressure exceeds pulmonary arterial and venous
compliance is greater. pressures. The capillary bed collapses, and normal blood flow ceases.
The heart pumps against gravity to perfuse the pulmonary circula- Normally zone I is a very small part of the lung at the apex. In zone II,
tion. As blood is pumped into the lung apices of a sitting or standing alveolar pressure is greater than venous pressure but not arterial pres-
individual, some blood pressure is dissipated in overcoming gravity. sure. Blood flows through zone II, but it is impeded to a certain extent
As a result, blood pressure at the apices is lower than that at the bases. by alveolar pressure. Zone II is normally above the level of the left
Because greater pressure causes greater perfusion, the bases of the atrium. In zone III, both arterial and venous pressures are greater than
lungs are better perfused than the apices (Figure 25-14). Thus ventila- alveolar pressure and blood flow is not affected by alveolar pressure.
tion and perfusion are greatest in the same lung portions—the lower Zone III is in the base of the lung. Blood flow through the pulmonary
lobes—and depend on body position. If a standing individual assumes capillary bed increases in regular increments from the apex to the base.
a supine or side-lying position, the areas of the lungs that are then most Although both blood flow and ventilation are greater at the base of
dependent become the best ventilated and perfused. the lungs than at the apices, they are not perfectly matched in any zone.
672 CHAPTER 25  Structure and Function of the Pulmonary System

Apex
Alveolus
Capillary Zone I
Arteriole Venule P A  P a  PV

Zone II
Alveolus Pa  PA  PV

Pulmonary Pulmonary
artery vein

Alveolus Zone III

Pa  PV  PA

FIGURE 25-15  Gravity and Alveolar Pressure. Effects of gravity and alveolar pressure on pulmonary
blood flow in the three lung zones. In zone I, alveolar pressure (PA) is greater than arterial and venous
pressures, and no blood flow occurs. In zone II, arterial pressure (Pa) exceeds alveolar pressure, but
alveolar pressure exceeds venous pressure (PV). Blood flow occurs in this zone, but alveolar pressure
compresses the venules (venous ends of the capillaries). In zone III, both arterial and venous pressures
are greater than alveolar pressure and blood flow fluctuates depending on the difference between
­­arterial pressure and venous pressure.

Perfusion exceeds ventilation in the bases, and ventilation exceeds per- oxygen has ample time to diffuse into the blood, even during increased
fusion in the apices of the lung. The relationship between ventilation cardiac output, which speeds blood flow and shortens the time the
and perfusion is expressed as a ratio called the ventilation-perfusion blood remains in the capillary.
  1 The normal V̇ / Q̇ ratio is 0.8. This is the amount by
ratio ( V/Q). Determinants of arterial oxygenation. As oxygen diffuses across the
which perfusion exceeds ventilation under normal conditions. alveolocapillary membrane, it dissolves in the plasma, where it exerts
pressure (the partial pressure of oxygen in arterial blood, or Pao2). As
Oxygen Transport the Pao2 increases, oxygen moves from the plasma into the red blood
Approximately 1000 ml (1 L) of oxygen is transported to the cells of the cells (erythrocytes) and binds with hemoglobin molecules. Oxygen
body each minute. Oxygen is transported in the blood in two forms: a continues to bind with hemoglobin until the hemoglobin-binding
small amount dissolves in plasma, and the remainder binds to hemo- sites are filled or saturated. Oxygen then continues to diffuse across
globin molecules. Without hemoglobin, oxygen would not reach the the alveolocapillary membrane until the Pao2 (oxygen dissolved in
cells in amounts sufficient to maintain normal metabolic function. plasma) and PAo2 (oxygen in the alveolus) equilibrate, eliminating the
(Hemoglobin is discussed in detail in Chapter 19, and cellular metabo- pressure gradient across the alveolocapillary membrane. At this point,
lism is explored in Chapter 1.) diffusion ceases (see Figure 25-16).
Diffusion across the alveolocapillary membrane. The alveolocapil- The majority (97%) of the oxygen that enters the blood is bound to
lary membrane is ideal for oxygen diffusion because it has a large total hemoglobin. The remaining 3% stays in the plasma and creates the par-
surface area (70 to 100 m2) and is very thin (0.5 micrometer [μm]). tial pressure of oxygen (Pao2). The Pao2 can be measured in the blood
In addition, the partial pressure of oxygen molecules in alveolar gas by obtaining an arterial blood gas measurement. The oxygen satura-
(PAo2) is much greater than that in capillary blood, a condition that tion (Sao2) is the percentage of the available hemoglobin that is bound
promotes rapid diffusion down the concentration gradient from the to oxygen and can be measured using a device called an oximeter.
alveolus into the capillary. The partial pressure of oxygen (oxygen ten- Because hemoglobin transports all but a small fraction of the oxy-
sion) in mixed venous or pulmonary artery blood (Pvo2) is approxi- gen carried in arterial blood, changes in hemoglobin concentration
mately 40 mm Hg as it enters the capillary, and alveolar oxygen tension affect the oxygen content of the blood. Decreases in hemoglobin con-
(PAo2) is approximately 100 mm Hg at sea level. Therefore, a pres- centration below the normal value of 15 g/dl of blood reduce oxygen
sure gradient of 60 mm Hg facilitates the diffusion of oxygen from the content, and increases in hemoglobin concentration may increase oxy-
alveolus into the capillary (Figure 25-16). gen content, minimizing the impact of impaired gas exchange. In fact,
Blood remains in the pulmonary capillary for about 0.75 second, increased hemoglobin concentration is a major compensatory mecha-
but only 0.25 second is required for oxygen concentration to equili- nism in pulmonary diseases that impair gas exchange. For this reason,
brate (equalize) across the alveolocapillary membrane. Therefore measurement of hemoglobin concentration is important in assessing
 CHAPTER 25  Structure and Function of the Pulmonary System 673

Inspired air Expired air

PO2 = 159 mmHg PO2 = 127 mmHg

PCO2 = 0.3 mmHg PCO2 = 28 mmHg
PH2O = 3.7 mmHg PH2O = 21 mmHg
PN2 = 597 mmHg PN2 = 584 mmHg

Pulmonary Pulmonary vein

From heart and artery To heart and
systemic systemic
circulation PO2 = 104 mmHg circulation
values PCO2 = 40 mmHg values
PH2O = 47 mmHg
PO2 = 40 mmHg PN2 = 569 mmHg PO2 = 100 mmHg
PCO2 = 46 mmHg PCO2 = 40 mmHg
PH2O = 47 mmHg CO2 PH2O = 47 mmHg
PN2 = 573 mmHg PN2 = 573 mmHg
O2

Tissues

PO2 = 40 mmHg
PCO2 = 46 mmHg
PH2O = 47 mmHg
PN2 = 573 mmHg

FIGURE 25-16  Partial Pressure of Respiratory Gases in Normal Respiration. The numbers shown
are average values near sea level. The values of Po2, Pco2, and Pn2 fluctuate from breath to breath.
(Modified from Thompson JM et al: Mosby’s clinical nursing, ed 5, St Louis, 2002, Mosby.)

individuals with pulmonary disease. If cardiovascular function is nor- blood into the alveoli, the blood carbon dioxide level is reduced and
mal, the body’s initial response to low oxygen content is to accelerate the affinity of hemoglobin for oxygen is increased. The shift in the oxy-
cardiac output. In individuals who also have cardiovascular disease, this hemoglobin dissociation curve caused by changes in carbon dioxide
compensatory mechanism is ineffective, making increased hemoglobin and hydrogen ion concentrations in the blood is called the Bohr effect.
concentration an even more important compensatory mechanism. The oxyhemoglobin curve is also shifted by changes in body tem-
(Hemoglobin structure and function are described in Chapter 19.) perature and increased or decreased levels of 2,3-diphosphoglycerate
Oxyhemoglobin association and dissociation. When hemoglobin (2,3-DPG), a substance normally present in erythrocytes. Hyperther-
molecules bind with oxygen, oxyhemoglobin (HbO2) forms. Binding mia and increased 2,3-DPG levels shift the curve to the right. Hypo-
occurs in the lungs and is called oxyhemoglobin association or hemoglo- thermia and decreased 2,3-DPG levels shift the curve to the left.
bin saturation with oxygen (Sao2). The reverse process, where oxygen
is released from hemoglobin, occurs in the body tissues at the cellular Carbon Dioxide Transport
level and is called hemoglobin desaturation. When hemoglobin satura- Carbon dioxide is carried in the blood in three ways: (1) dissolved in
tion and desaturation are plotted on a graph, the result is a distinc- plasma (Pco2), (2) as bicarbonate, and (3) as carbamino compounds
tive S-shaped curve known as the oxyhemoglobin dissociation curve (including binding to hemoglobin). As CO2 diffuses out of the cells
(Figure 25-17). into the blood, it dissolves in the plasma. Approximately 10% of the
Several factors can change the relationship between Pao2 and Sao2, total CO2 in venous blood and 5% of the CO2 in arterial blood are
causing the oxyhemoglobin dissociation curve to shift to the right transported dissolved in the plasma (Pvco2 and Paco2, respectively).
or left (see Figure 25-17). A shift to the right depicts hemoglobin’s As CO2 moves into the blood, it diffuses into the red blood cells. Within
decreased affinity for oxygen or an increase in the ease with which the red blood cells, CO2, with the help of the enzyme carbonic anhy-
oxyhemoglobin dissociates and oxygen moves into the cells. A shift to drase, combines with water to form carbonic acid and then quickly
the left depicts hemoglobin’s increased affinity for oxygen, which pro- dissociates into H+ and HCO− 3 . As carbonic acid dissociates, the H
+

motes association in the lungs and inhibits dissociation in the tissues. −

binds to hemoglobin, where it is buffered, and the HCO3 moves out
The oxyhemoglobin dissociation curve is shifted to the right by of the red blood cell into the plasma. Approximately 60% of the CO2
acidosis (low pH) and hypercapnia (increased Paco2). In the tissues, in venous blood and 90% of the CO2 in arterial blood are carried in
the increased levels of carbon dioxide and hydrogen ions produced the form of bicarbonate. The remainder combines with blood proteins,
by metabolic activity decrease the affinity of hemoglobin for oxygen. hemoglobin in particular, to form carbamino compounds. Approxi-
The curve is shifted to the left by alkalosis (high pH) and hypocapnia mately 30% of the CO2 in venous blood and 5% of the CO2 in arterial
(decreased Paco2). In the lungs, as carbon dioxide diffuses from the blood are carried as carbamino compounds.
674 CHAPTER 25  Structure and Function of the Pulmonary System

Percent
saturation
hemoglobin(SaO2)
INCREASED AFFINITY
Acute alkalosis (↑ pH)
Decreased PCO2
100 Decreased temperature
Low levels of 2,3-DPG
90 Carboxyhemoglobin
Methemoglobin
80 Abnormal hemoglobin
(left shift) Normal
70
DECREASED AFFINITY
60 Acute acidosis (↓ pH)
High PCO2
50 Increased temperature
High levels of 2,3-DPG
40 Abnormal hemoglobin
(right shift)
30

20

10

0
0 10 20 30 40 50 60 70 80 90 100
PaO2 (mmHg)

FIGURE 25-17  Oxyhemoglobin Dissociation Curve. The horizontal or flat segment of the curve at
the top of the graph is the arterial or association portion, or that part of the curve where oxygen is
bound to hemoglobin and occurs in the lungs. This portion of the curve is flat because partial pressure
changes of oxygen between 60 and 100 mm Hg do not significantly alter the percentage saturation of
hemoglobin with oxygen and allow adequate hemoglobin saturation at a variety of altitudes. If the rela-
tionship between Sao2 and Pao2 was linear (in a downward sloping straight line) instead of flat between
60 and 100 mm Hg, there would be inadequate saturation of hemoglobin with oxygen. The steep part
of the oxyhemoglobin dissociation curve represents the rapid dissociation of oxygen from hemoglobin
that occurs in the tissues. During this phase there is rapid diffusion of oxygen from the blood into tissue
cells. The P50 is the Pao2 at which hemoglobin is 50% saturated, normally 26.6 mm Hg. A lower than
normal P50 represents increased affinity of hemoglobin for O2; a high P50 is seen with decreased affin-
ity. Note that variation from the normal is associated with decreased (low P50) or increased (high P50)
availability of O2 to tissues (dashed lines). The shaded area shows the entire oxyhemoglobin dissocia-
tion curve under the same circumstances. 2,3-DPG, 2,3-Diphosphoglycerate. (From Lane EE, Walker
JF: Clinical arterial blood gas analysis, St Louis, 1987, Mosby.)

CO2 is 20 times more soluble than O2 and diffuses quickly from the the amount of CO2 carried by the blood decreases. Thus, in the tissue
tissue cells into the blood. The amount of CO2 able to enter the blood capillaries, O2 dissociation from hemoglobin facilitates the pickup of
is enhanced by diffusion of oxygen out of the blood and into the cells. CO2, and the binding of O2 to hemoglobin in the lungs facilitates the
Reduced hemoglobin (hemoglobin that is dissociated from oxygen) release of CO2 from the blood. This effect of oxygen on CO2 transport
can carry more CO2 than can hemoglobin saturated with O2. Therefore is called the Haldane effect.
the drop in So2 at the tissue level increases the ability of hemoglobin to
carry CO2 back to the lung.
The diffusion gradient for CO2 in the lung is only approximately
6 mm Hg (venous Pco2 = 46 mm Hg; alveolar Pco2 = 40 mm Hg)
(see Figure 25-16). Yet CO2 is so soluble in the alveolocapillary mem-
4 QUICK CHECK 25-5
1. What are the eight steps of gas transport?
brane that the CO2 in the blood quickly diffuses into the alveoli, where 2. Describe the relationship between ventilation and pulmonary blood flow.
it is removed from the lung with each expiration. Diffusion of CO2 3. What is the alveolocapillary membrane? How does it function in ventila-
in the lung is so efficient that diffusion defects that cause hypoxemia tion and perfusion?
(low oxygen content of the blood) do not as readily cause hypercapnia 4. Describe the process of oxyhemoglobin association and dissociation.
(excessive carbon dioxide in the blood). 5. What is barometric pressure? How is it related to physiologic pressure
The diffusion of CO2 out of the blood is also enhanced by oxygen measurements?
binding with hemoglobin in the lung. As hemoglobin binds with O2,
 CHAPTER 25  Structure and Function of the Pulmonary System 675

Control of the Pulmonary Circulation pulmonary hypertension (elevated pulmonary artery pressure) can
The caliber of pulmonary artery lumina decreases as smooth muscle result. The pulmonary vasoconstriction caused by low alveolar Po2 is
in the arterial walls contracts. Contraction increases pulmonary artery reversible if the alveolar Po2 is corrected. Chronic alveolar hypoxia can
pressure. Caliber increases as these muscles relax, decreasing blood result in permanent pulmonary artery hypertension, which eventually
pressure. Contraction (vasoconstriction) and relaxation (vasodilation) leads to right heart failure (cor pulmonale).
primarily occur in response to local humoral conditions, even though Acidemia also causes pulmonary artery constriction. If the acide-
the pulmonary circulation is innervated by the ANS as is the systemic mia is corrected, the vasoconstriction is reversed. (Respiratory aci-
circulation. dosis and metabolic acidosis are described in Chapter 4.) An elevated
The most important cause of pulmonary artery constriction is Paco2 value without a drop in pH does not cause pulmonary artery
a low alveolar Po2 (PAo2). Vasoconstriction caused by alveolar and constriction. Other biochemical factors that affect the caliber of ves-
pulmonary venous hypoxia, often termed hypoxic pulmonary vaso- sels in pulmonary circulation are histamine, prostaglandins, serotonin,
constriction, can affect only one portion of the lung (i.e., one lobe nitric oxide, and bradykinin (see Geriatric Considerations: Aging & the
that is obstructed, decreasing its PAo2) or the entire lung.10 If only one Pulmonary System).
segment of the lung is involved, the arterioles to that segment con-
strict, shunting blood to other, well-ventilated portions of the lung.
This reflex improves the lung’s efficiency by better matching ventila-
4 QUICK CHECK 25-6
1. What is the most important factor causing pulmonary artery constriction?
tion and perfusion. If all segments of the lung are affected, however, What other factors are involved?
vasoconstriction occurs throughout the pulmonary vasculature and

GERIATRIC CONSIDERATIONS
Aging & the Pulmonary System
Elasticity/Chest Wall
Chest wall compliance decreases because ribs become ossified and joints are
stiffer, which results in increased work of breathing.
Kyphoscoliosis may curve the vertebral column, decreasing lung volumes.
Respiratory muscle strength decreases.
Elastic recoil diminishes, possibly the result of loss of elastic fibers. NORMAL AGING
Result: Lung compliance increases and ventilatory capacity (VC) declines, resid- LUNG LUNG
ual volume (RV) increases, total lung capacity (TLC) is unchanged, ventilatory
reserves decline, ventilation-perfusion ratios fall.

Gas Exchange
Pulmonary capillary network decreases.
Alveoli dilate, and peripheral airways lose supporting tissues.
Surface area for gas exchange decreases.
pH and Pco2 do not change much, but Po2 declines.
Sensitivity of respiratory centers to hypoxia or hypercapnia decreases.
Ability to initiate an immune response against infection decreases.
Note: Maximum Pao2 at sea level can be estimated by multiplying person’s age
by 0.3 and subtracting the product from 100. Inspiratory
reserve volume Total lung
Exercise Tidal volume capacity
Decreased Pao2 and diminished ventilatory reserve lead to decreased exercise Expiratory
tolerance. reserve volume
Vital capacity
Early airway closure inhibits expiratory flow. Residual volume
Changes depend on activity and fitness levels earlier in life. Changes in Lung Volumes With Aging. With aging, note particularly the dense
An active, physically fit individual has fewer changes in function at any age than vital capacity and the increase in residual volume. (See also Lee J, Sandford A,
does a sedentary individual. Man P, Sin DD: Is the aging process accelerated in chronic obstructive pulmo-
Respiratory muscle strength and endurance decrease but can be enhanced by nary disease? Curr Opin Pulm Med 17(2):90–97, 2011; Preston ME et al: Effect
exercise. of menopause on the chemical control of breathing and its relationship with
acid-base status, Am J Physiol Regul Integr Comp Physiol 296(3):R722–R727,
2009; Sharma G, Goodwin J: Effect of aging on respiratory system physiology
and immunology, Clin Interven Aging 1(3):253–260, 2006; Smolej Narancic N
et al: New reference equations for forced spirometry in elderly persons, Respir
Med 103(4):621–628, 2009; Weiss CO et  al: Relationships of cardiac, pulmo-
nary, and muscle reserves and frailty to exercise capacity in older women,
J Gerontol A Biol Sci Med Sci 65(3):287–294, 2010; Miller MR: Structural and
physiological age-associated changes in aging lungs, Semin Respir Crit Care
Med 31(5):521–527, 2010.)
676 CHAPTER 25  Structure and Function of the Pulmonary System

DID YOU UNDERSTAND?

Structures of the Pulmonary System 7. The major muscle of inspiration is the diaphragm. When the diaphragm
1. The pulmonary system consists of the lungs, airways, chest wall, and pul- contracts, it moves downward in the thoracic cavity, creating a vacuum
monary and bronchial circulation. that causes air to flow into the lungs.
2. Air is inspired and expired through the conducting airways, which include 8. The alveoli produce surfactant, a lipoprotein that lines the alveoli. Surfac-
the nasopharynx, oropharynx, trachea, bronchi, and bronchioles to the six- tant reduces alveolar surface tension and permits the alveoli to expand as
teenth division. air enters.
3. Gas exchange occurs in structures beyond the sixteenth division: the 9. Compliance is the ease with which the lungs and chest wall expand dur-
respiratory bronchioles, the alveolar ducts, and the alveoli. Together these ing inspiration. Lung compliance is ensured by an adequate production of
structures compose the acinus. surfactant, whereas chest wall expansion depends on elasticity.
4. The chief gas-exchange units of the lungs are the alveoli. The membrane 10. Elastic recoil is the tendency of the lungs and chest wall to return to their
that surrounds each alveolus and contains the pulmonary capillaries is resting state after inspiration. The elastic recoil forces of the lungs and
called the alveolocapillary membrane. chest wall are in opposition and pull on each other, creating the normally
5. The gas-exchange airways are served by the pulmonary circulation, a sepa- negative pressure of the pleural space.
rate division of the circulatory system. The bronchi and other lung struc- 11. Gas transport depends on ventilation of the alveoli, diffusion across the
tures are served by a branch of the systemic circulation called the bronchial alveolocapillary membrane, perfusion of the pulmonary and systemic capil-
circulation. laries, and diffusion between systemic capillaries and tissue cells.
6. The chest wall, which contains and protects the contents of the thoracic 12. Efficient gas exchange depends on an even distribution of ventilation and
cavity, consists of the skin, ribs, and intercostal muscles, which lie between perfusion within the lungs. Both ventilation and perfusion are greatest in
the ribs. the bases of the lungs because the alveoli in the bases are more compli-
7. The chest wall is lined by a serous membrane called the parietal pleura; the ant (their resting volume is low) and perfusion is greater in the bases as a
lungs are encased in a separate membrane called the visceral pleura. The result of gravity.
area where these two pleurae contact and slide over one another is called 13. Almost all the oxygen that diffuses into pulmonary capillary blood is trans-
the pleural space. ported by hemoglobin, a protein contained within red blood cells. The
remainder of the oxygen is transported dissolved in plasma.
Function of the Pulmonary System 14. Oxygen enters the body by diffusing down the concentration gradient, from
1. The pulmonary system enables oxygen to diffuse into the blood and carbon high concentrations in the alveoli to lower concentrations in the capillaries.
dioxide to diffuse out of the blood. Diffusion ceases when alveolar and capillary oxygen pressures equilibrate.
2. Ventilation is the process by which air flows into and out of the gas- 15. Oxygen is loaded onto hemoglobin by the driving pressure exerted by Pao2
exchange airways. in the plasma. As pressure decreases at the tissue level, oxygen dissoci-
3. Most of the time, ventilation is involuntary. It is controlled by the sym- ates from hemoglobin and enters tissue cells by diffusion, again down the
pathetic and parasympathetic divisions of the autonomic nervous system, concentration gradient.
which adjust airway caliber (by causing bronchial smooth muscle to con- 16. Compared to oxygen, carbon dioxide is more soluble in plasma. Therefore
tract or relax) and control the rate and depth of ventilation. carbon dioxide diffuses readily from tissue cells into plasma. Carbon diox-
4. Neuroreceptors in the lungs (lung receptors) monitor the mechanical ide returns to the lungs dissolved in plasma, as bicarbonate, or in carb-
aspects of ventilation. Irritant receptors sense the need to expel unwanted amino compounds (e.g., bound to hemoglobin).
substances, stretch receptors sense lung volume (lung expansion), and 17. The pulmonary circulation is innervated by the autonomic nervous system
J-receptors sense pulmonary capillary pressure. (ANS), but vasodilation and vasoconstriction are controlled mainly by local
5. Chemoreceptors in the circulatory system and brain stem sense the effec- and humoral factors, particularly arterial oxygenation and acid-base status.
tiveness of ventilation by monitoring the pH status of cerebrospinal fluid
and the oxygen content (Po2) of arterial blood. GERIATRIC CONSIDERATIONS: Aging & the Pulmonary
6. Successful ventilation involves the mechanics of breathing: the interaction System
of forces and counterforces involving the muscles of inspiration and expi- 1. Aging affects the mechanical aspects of ventilation by decreasing chest
ration, alveolar surface tension, elastic properties of the lungs and chest wall compliance and elastic recoil of the lungs. Changes in these elastic
wall, and resistance to airflow. properties reduce ventilatory reserve.
2. Aging causes the Pao2 to decrease.
 CHAPTER 25  Structure and Function of the Pulmonary System 677

 KEY TERMS
•  cinus  663
A • H aldane effect  674 •  artial pressure (of a gas)  670
P
• Alveolar duct  663 • Hilum (pl. hila)  660 • Peripheral chemoreceptor  665
• Alveolar ventilation  665 • Hypoxic pulmonary • Pleura (pl. pleurae)  663
• Alveolocapillary membrane  663 vasoconstriction  675 • Pleural space (pleural cavity)  663
• Alveolus (pl. alveoli)  663 • Irritant receptor  666 • Respiratory bronchiole  663
• Bohr effect  673 • J-receptor  666 • Respiratory center  665
• Bronchus (pl. bronchi)  660 • Larynx  659 • Stretch receptor  666
• Carina  660 • Minute volume (minute ventilation)  664 • Surface tension  667
• Central chemoreceptor  666 • Nasopharynx  659 • Surfactant  663
• Collectin  667 • Oropharynx  659 • Thoracic cavity  663
• Compliance  668 • Oxygen saturation (Sao2)  672 • Trachea  660
• Elastic recoil  667 • Oxyhemoglobin (HbO2)  673 • Ventilation  664
• Goblet cell  660 • Oxyhemoglobin dissociation curve  673 • Ventilation-perfusion ratio ( V̇ / Q̇)  672

REFERENCES 6. Nattie E, Julius H, Comroe Jr: Distinguished lecture: central chemorecep-

tion: then…and now, J Appl Physiol 110(1):1–8, 2011.
1. Levitsky MG: Nunn’s applied respiratory physiology, ed 6, St Louis, 2007, 7. Blain GM, et al: Peripheral chemoreceptors determine the respiratory
Mosby. sensitivity of central chemoreceptors to CO(2), J Physiol 588(Pt 13):2455–
2. Barrett KE, et al: Gannong’s review of medical physiology, ed 23, New York, 2471, 2010.
2010, McGraw-Hill. 8. Brown LK: Hypoventilation syndromes, Clin Chest Med 31(2):249–270,
3. Clouter M, Thrall R: The respiratory system. In Koeppen BM, Stanton BA, 2010.
editors: Berne and Levy physiology, ed 6, St Louis, 2010, Mosby, (updated 9. Orgeig S, et al: Recent advances in alveolar biology: evolution and func-
addition). tion of alveolar proteins, Respir Physiol Neurobiol 173(suppl):S43–S54, 2010.
4. West JB: Respiratory physiology: the essentials, ed 8, Philadelphia, 2008, 10. Ward JP, McMurtry IF: Mechanisms of hypoxic pulmonary vasoconstric-
Lippincott Williams & Wilkins. tion and their roles in pulmonary hypertension: new findings for an old
5. Woodcock A, Young EC, Smith JA: New insights in cough, Br Med Bull problem, Curr Opin Pharmacol 9(3):287–296, 2009.
96:61–73, 2010.
CHAPTER

26
Alterations of Pulmonary Function
Valentina L. Brashers

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Clinical Manifestations of Pulmonary Alterations, 678 Pulmonary Disorders, 684
Signs and Symptoms of Pulmonary Disease, 678 Restrictive Lung Diseases, 684
Conditions Caused by Pulmonary Disease or Injury, 680 Obstructive Lung Diseases, 689
Disorders of the Chest Wall and Pleura, 682 Respiratory Tract Infections, 694
Chest Wall Restriction, 682 Pulmonary Vascular Disease, 698
Pleural Abnormalities, 682 Malignancies of the Respiratory Tract, 700

The lungs, with their large surface area, are constantly exposed to the physiological, psychological, social, and environmental factors, and
external environment. Therefore lung disease is greatly influenced by it may induce secondary physiological and behavioral responses.”1 It
conditions of the environment, occupation, and personal and social is often described as breathlessness, air hunger, shortness of breath,
habits. Pulmonary disease is often classified as acute or chronic, labored breathing, and preoccupation with breathing. Dyspnea may
obstructive or restrictive, or infectious or noninfectious and is caused be the result of pulmonary disease, or many other conditions such as
by alterations in the lung or heart. Symptoms of lung disease are com- pain, heart disease, trauma, and anxiety.2
mon and associated not only with primary lung disorders but also with In pulmonary conditions, the severity of the experience of dys-
diseases of other organ systems. pnea may not directly correlate with the severity of underlying disease.
Either diffuse or focal disturbances of ventilation, gas exchange, or
CLINICAL MANIFESTATIONS OF PULMONARY ventilation-perfusion relationships can cause dyspnea, as can increased
ALTERATIONS work of breathing or any disease that damages lung tissue (lung paren-
chyma). One proposed mechanism for dyspnea involves an impaired
Signs and Symptoms of Pulmonary Disease sense of effort where the perceived work of breathing is greater than the
Pulmonary disease is associated with many signs and symptoms, the actual motor response that is generated. Stimulation of many receptors
most common of which are dyspnea and cough. Others include abnor- can contribute to the sensation of dyspnea, including mechanorecep-
mal sputum, hemoptysis, altered breathing patterns, hypoventilation tors in the chest wall, upper airway receptors, and central and periph-
and hyperventilation, cyanosis, clubbing, and chest pain. eral chemoreceptors.3
The signs of dyspnea include flaring of the nostrils, use of accessory
Dyspnea muscles of respiration, and retraction (pulling back) of the intercostal
Dyspnea is defined as “a subjective experience of breathing discom- spaces. In dyspnea caused by parenchymal disease (e.g., pneumonia),
fort that is comprised of qualitatively distinct sensations that vary in retractions of tissue between the ribs (subcostal and intercostal retrac-
intensity. The experience derives from interactions among multiple tions) may be observed, more commonly in children. In upper airway

678
 CHAPTER 26  Alterations of Pulmonary Function 679

obstruction, supercostal retractions (retractions of tissues above the Hemoptysis usually indicates infection or inflammation that dam-
ribs) predominate. Dyspnea can be quantified by the use of both ordi- ages the bronchi (bronchitis, bronchiectasis) or the lung parenchyma
nal rating scales and visual analog scales and is frequently associated (pneumonia, tuberculosis, lung abscess). Other causes include can-
with significant anxiety. cer and pulmonary infarction. The amount and duration of bleeding
Dyspnea may occur transiently or can become chronic. Often the provide important clues about its source. Bronchoscopy, combined
first episode occurs with exercise and is called dyspnea on exertion. This with chest computed tomography (CT), is used to confirm the site of
type of dyspnea is common to many pulmonary disorders. Orthopnea bleeding.
is dyspnea that occurs when an individual lies flat and is common in
individuals with heart failure. The recumbent position redistributes Abnormal Breathing Patterns
body water, causes the abdominal contents to exert pressure on the Normal breathing (eupnea) is rhythmic and effortless. The resting ven-
diaphragm, and decreases the efficiency of the respiratory muscles. Sit- tilatory rate is 8 to 16 breaths per minute, and tidal volume ranges
ting in a forward-leaning posture or supporting the upper body on from 400 to 800 ml. A short expiratory pause occurs with each breath,
several pillows generally relieves orthopnea. Some individuals with and the individual takes an occasional deeper breath, or sighs. Sigh
pulmonary or cardiac disease awake at night gasping for air and have breaths, which help to maintain normal lung function, are usually 1.5
to sit or stand to relieve the dyspnea (paroxysmal nocturnal dyspnea to 2 times the normal tidal volume and occur approximately 10 to 12
[PND]). times per hour.
The rate, depth, regularity, and effort of breathing undergo char-
Cough acteristic alterations in response to physiologic and pathophysiologic
Cough is a protective reflex that helps clear the airways by an explosive conditions. Patterns of breathing automatically adjust to minimize the
expiration. Inhaled particles, accumulated mucus, inflammation, or work of respiratory muscles. Strenuous exercise or metabolic acidosis
the presence of a foreign body initiates the cough reflex by stimulating induces Kussmaul respiration (hyperpnea), which is characterized by
the irritant receptors in the airway. There are few such receptors in a slightly increased ventilatory rate, very large tidal volumes, and no
the most distal bronchi and the alveoli; thus it is possible for signifi- expiratory pause.
cant amounts of secretions to accumulate in the distal respiratory tree Labored breathing occurs whenever there is an increased work
without cough being initiated. The cough reflex consists of inspira- of breathing, especially if the airways are obstructed. In large airway
tion, closure of the glottis and vocal cords, contraction of the expira- obstruction, a slow ventilatory rate, large tidal volume, increased
tory muscles, and reopening of the glottis, causing a sudden, forceful effort, prolonged inspiration and expiration, and stridor or audible
expiration that removes the offending matter. The effectiveness of the wheezing (depending on the site of obstruction) are typical. In small
cough depends on the depth of the inspiration and the degree to which airway obstruction such as that seen in asthma and chronic obstruc-
the airways narrow, increasing the velocity of expiratory gas flow. tive pulmonary disease, a rapid ventilatory rate, small tidal volume,
Cough occurs frequently in healthy individuals; however, those with increased effort, prolonged expiration, and wheezing are often present.
an inability to cough effectively are at greater risk for pneumonia. Restricted breathing is commonly caused by disorders such as pul-
Acute cough is cough that resolves within 2 to 3 weeks of the onset monary fibrosis that stiffen the lungs or chest wall and decrease com-
of illness or resolves with treatment of the underlying condition. It is pliance. Small tidal volumes, rapid ventilatory rate (tachypnea), and
most commonly the result of upper respiratory tract infections, allergic rapid expiration are characteristic.
rhinitis, acute bronchitis, pneumonia, congestive heart failure, pulmo- Shock and severe cerebral hypoxia (insufficient oxygen in the brain)
nary embolus, or aspiration. Chronic cough is defined as cough that has contribute to gasping respirations that consist of irregular, quick inspi-
persisted for more than 3 weeks, although 7 or 8 weeks may be a more rations with an expiratory pause. Anxiety can cause sighing respira-
appropriate timeframe because acute cough and bronchial hyperreac- tions, which consist of irregular breathing characterized by frequent,
tivity can be prolonged in some cases of viral infection. In individuals deep sighing inspirations.
who do not smoke, chronic cough is commonly caused by postnasal Cheyne-Stokes respirations are characterized by alternating peri-
drainage syndrome, nonasthmatic eosinophilic bronchitis, asthma, ods of deep and shallow breathing. Apnea lasting from 15 to 60 sec-
or gastroesophageal reflux disease. In persons who smoke, chronic onds is followed by ventilations that increase in volume until a peak
bronchitis is the most common cause of chronic cough, although lung is reached; then ventilation (tidal volume) decreases again to apnea.
cancer must always be considered. Up to 33% of individuals taking Cheyne-Stokes respirations result from any condition that reduces
angiotensin-converting enzyme inhibitors for cardiovascular disease blood flow to the brain stem, which in turn slows impulses sending
develop chronic cough that resolves with discontinuation of the drug. information to the respiratory centers of the brain stem. Neurologic
impairment above the brain stem is also a contributing factor (see Fig-
Abnormal Sputum ure 14-1).
Changes in the amount, color, and consistency of sputum provide
information about progression of disease and effectiveness of therapy. Hypoventilation/Hyperventilation
The gross and microscopic appearances of sputum enable the clinician Hypoventilation is inadequate alveolar ventilation in relation to met-
to identify cellular debris or microorganisms, which aids in diagnosis abolic demands. Hypoventilation occurs when minute volume (tidal
and choice of therapy. volume times respiratory rate) is reduced. It is caused by alterations
in pulmonary mechanics or in the neurologic control of breathing.4
Hemoptysis When alveolar ventilation is normal, carbon dioxide (CO2) is removed
Hemoptysis is the expectoration of blood or bloody secretions. This from the lungs at the same rate as it is produced by cellular metabo-
is sometimes confused with hematemesis, which is the vomiting of lism; therefore arterial and alveolar Pco2 values remain at normal lev-
blood. Blood produced with coughing is usually bright red, has an els (40 mm Hg). With hypoventilation, CO2 removal is slower than
alkaline pH, and is mixed with frothy sputum. Blood that is vomited is CO2 production and the level of CO2 in the arterial blood (Paco2)
dark, has an acidic pH, and is mixed with food particles. increases, causing hypercapnia (Paco2 greater than 44 mm Hg) (see
680 CHAPTER 26  Alterations of Pulmonary Function

Table 25-2 for a definition of gas partial pressures and other pulmo- Clubbing — early
nary abbreviations). This results in respiratory acidosis that can affect
the function of many tissues throughout the body. Hypoventilation is
often overlooked until it is severe because breathing pattern and ven-
tilatory rate may appear to be normal and changes in tidal volume can
be difficult to detect clinically. Blood gas analysis (i.e., measurement of
the Paco2 of arterial blood) reveals the hypoventilation.3 Pronounced
hypoventilation can cause somnolence or disorientation.
Hyperventilation is alveolar ventilation exceeding metabolic Clubbing — moderate
demands. The lungs remove CO2 faster than it is produced by cellular
metabolism, resulting in decreased Paco2, or hypocapnia (Paco2 less
than 36 mm Hg). Hypocapnia results in a respiratory alkalosis that
also can interfere with tissue function. Like hypoventilation, hyper-
ventilation can be determined by arterial blood gas analysis. Increased
respiratory rate or tidal volume can occur with severe anxiety, acute
head injury, pain, and in response to conditions that cause insufficient
oxygenation of the blood. Clubbing — severe

Cyanosis
Cyanosis is a bluish discoloration of the skin and mucous membranes
caused by increasing amounts of desaturated or reduced hemoglobin
(which is bluish) in the blood. It generally develops when 5 g of hemo-
globin is desaturated, regardless of hemoglobin concentration. FIGURE 26-1  Clubbing of Fingers Caused by Chronic Hypox-
Peripheral cyanosis (slow blood circulation in fingers and toes) is emia. (Modified from Seidel HM et al: Mosby’s guide to physical
most often caused by poor circulation resulting from intense periph- examination, ed 7, St Louis, 2011, Mosby.)
eral vasoconstriction, such as that observed in persons who have
Raynaud disease, are in cold environments, or are severely stressed. over the painful area. Laughing or coughing makes pleural pain worse.
Peripheral cyanosis is best observed in the nail beds. Central cyanosis is Pleural pain is common with pulmonary infarction (tissue death)
caused by decreased arterial oxygenation (low Pao2) from pulmonary caused by pulmonary embolism and emanates from the area around
diseases or pulmonary or cardiac right-to-left shunts. Central cyanosis the infarction.
is best detected in buccal mucous membranes and lips. Pulmonary pain can be central chest pain that is pronounced after
Lack of cyanosis does not necessarily indicate that oxygenation coughing and occurs in individuals with infection and inflammation of
is normal. In adults, cyanosis is not evident until severe hypoxemia the trachea or bronchi (tracheitis or tracheobronchitis, respectively). It
is present and, therefore, is an insensitive indication of respiratory can be difficult to differentiate from cardiac pain. High blood pressure
failure. Severe anemia (inadequate hemoglobin concentration) and in the pulmonary circulation (pulmonary hypertension) can cause
carbon monoxide poisoning (in which hemoglobin binds to carbon pain during exercise that is often mistaken for cardiac pain (angina
monoxide instead of to oxygen) can cause inadequate oxygenation of pectoris).
tissues without causing cyanosis. Individuals with polycythemia (an Pain in the chest wall is muscle pain or rib pain. Excessive coughing
abnormal increase in numbers of red blood cells), however, may have (which makes the muscles sore) and rib fractures produce such pain.
cyanosis when oxygenation is adequate. Therefore, cyanosis must be Inflammation of the costochondral junction (costochondritis) also
interpreted in relation to the underlying pathophysiologic condition. can cause chest wall pain. Chest wall pain can often be reproduced by
If cyanosis is suggested, the Pao2 should be measured. pressing on the sternum or ribs.

Clubbing Conditions Caused by Pulmonary Disease or Injury

Clubbing is the selective bulbous enlargement of the end (distal Hypercapnia
segment) of a digit (finger or toe) (Figure 26-1); its severity can be Hypercapnia, or increased carbon dioxide concentration in the arte-
graded from 1 to 5 based on the extent of nail bed hypertrophy and rial blood (increased Paco2), is caused by hypoventilation of the alve-
the amount of changes in the nails themselves or as early, moderate oli. As discussed in Chapter 25, carbon dioxide is easily diffused from
or severe. It is usually painless. Clubbing is commonly associated with the blood into the alveolar space; thus, minute volume (respiratory
diseases that cause chronic hypoxemia, such as bronchiectasis, cystic rate times tidal volume) determines not only alveolar ventilation but
fibrosis, pulmonary fibrosis, lung abscess, and congenital heart disease. also Paco2. Hypoventilation is often overlooked because the breath-
It can sometimes be seen in individuals with lung cancer even with- ing pattern and ventilatory rate may appear to be normal; therefore
out hypoxemia because of the effects of inflammatory cytokines and it is important to obtain blood gas analysis to determine the severity
growth factors (hypertrophic osteoarthropathy).5 of hypercapnia and resultant respiratory acidosis (acid-base balance is
described in Chapter 4).
Pain There are many causes of hypercapnia. Most are a result of
Pain caused by pulmonary disorders originates in the pleurae, airways, decreased drive to breathe or an inadequate ability to respond to ven-
or chest wall.6 Infection and inflammation of the parietal pleura cause tilatory stimulation. Some of these causes include (1) depression of
sharp or stabbing pain (pleurodynia) when the pleura stretches during the ­respiratory center by drugs; (2) diseases of the medulla, includ-
inspiration. The pain is usually localized to a portion of the chest wall, ing infections of the central nervous system or trauma; (3) abnormali-
where a unique breath sound called a pleural friction rub may be heard ties of the spinal conducting pathways, as in spinal cord disruption
 CHAPTER 26  Alterations of Pulmonary Function 681

or poliomyelitis; (4) diseases of the neuromuscular junction or of the From

respiratory muscles themselves, as in myasthenia gravis or muscular pulmonary Airway
dystrophy; (5) thoracic cage abnormalities, as in chest injury or con- artery Impaired
ventilation
genital deformity; (6) large airway obstruction, as in tumors or sleep Alveolus
apnea; and (7) increased work of breathing or physiologic dead space,
as in emphysema.
Hypercapnia and the associated respiratory acidosis result in elec-
trolyte abnormalities that may cause dysrhythmias. Individuals also Alveolocapillary
may present with somnolence and even coma because of changes in membrane To Hypoxemia
intracranial pressure associated with high levels of arterial carbon Normal V/Q pulmonary vein Low V/Q
dioxide, which causes cerebral vasodilation. Alveolar hypoventilation
with increased alveolar CO2 concentration limits the amount of oxy-
gen available for diffusion into the blood, thereby leading to secondary Blocked Impaired
ventilation perfusion
hypoxemia.
Alveolar
Collapsed
dead space
Hypoxemia alveolus
Hypoxemia, or reduced oxygenation of arterial blood (reduced Pao2),
is caused by respiratory alterations, whereas hypoxia, or reduced oxy-
genation of cells in tissues, may be caused by alterations of other sys-
tems as well. Although hypoxemia can lead to tissue hypoxia, tissue Hypoxemia
Hypoxemia
hypoxia can result from other abnormalities unrelated to alterations of
pulmonary function, such as low cardiac output or cyanide poisoning. Shunt (very low) V/Q High V/Q
Hypoxemia results from problems with one or more of the major FIGURE 26-2  Ventilation-Perfusion ( V̇Q̇ ) Abnormalities.
mechanisms of oxygenation:
1. Oxygen delivery to the alveoli
a. Oxygen content of the inspired air (Fio2) no ventilation, the pulmonary capillaries in that area constrict and a
b. Ventilation of the alveoli right-to-left shunt occurs, resulting in decreased systemic Pao2 and
2. Diffusion of oxygen from the alveoli into the blood hypoxemia. Hypoxemia also can be caused by poor perfusion of well-
a. Balance between alveolar ventilation and perfusion ( V̇ / Q̇ ventilated portions of the lung (high V̇ / Q̇), resulting in wasted venti-
match) lation. The most common cause of high V̇ / Q̇ is a pulmonary embolus
b. Diffusion of oxygen across the alveolar capillary barrier that impairs blood flow to a segment of the lung. An area where alveoli
3. Perfusion of pulmonary capillaries are ventilated but not perfused is termed alveolar dead space.
The amount of oxygen in the alveoli is called the PAo2 and is depen- The second factor affecting diffusion of oxygen from the alveoli
dent on two factors. The first factor is the presence of adequate oxygen into the blood is the alveolocapillary membrane. Diffusion of oxygen
content of the inspired air. The amount of oxygen in inspired air is through the alveolocapillary membrane is impaired if the membrane
expressed as the percentage or fraction of air that is composed of oxy- is thickened or the surface area available for diffusion is decreased.
gen, called the Fio2. The Fio2 of air at sea level is approximately 21% or Thickened alveolocapillary membranes, as occur with edema (tissue
0.21. Anything that decreases the Fio2 (such as high altitude) decreases swelling) and fibrosis (formation of fibrous lesions), increase the time
the PAo2. The second factor is the amount of alveolar minute volume required for oxygen to diffuse from the alveoli into the capillaries. If
(tidal volume times respiratory rate). Hypoventilation results in an diffusion is slowed enough, the Po2 levels of alveolar gas and capil-
increase in PAco2 and a decrease in PAo2 such that there is less oxygen lary blood do not have time to equilibrate during the fraction of a sec-
available in the alveoli for diffusion into the blood. This type of hypox- ond that blood remains in the capillary. Destruction of alveoli, as in
emia can be completely corrected if alveolar ventilation is improved by emphysema, decreases the surface area available for diffusion. Hyper-
increases in the rate and depth of breathing. Hypoventilation causes capnia is seldom produced by impaired diffusion because carbon diox-
hypoxemia in unconscious persons; in persons with neurologic, mus- ide diffuses so easily from capillary to alveolus that the individual with
cular, or bone diseases that restrict chest expansion; and in individuals impaired diffusion would die from hypoxemia before hypercapnia
who have chronic obstructive pulmonary disease. could occur.
Diffusion of oxygen from the alveoli into the blood is also depen- Finally, hypoxemia can result from blood flow bypassing the lungs.
dent on two factors. The first is the balance between the amount of air This can occur because of intracardiac defects that cause right-to-left
that enters alveoli ( V̇ ) and the amount of blood perfusing the capillar- shunting or because of intrapulmonary arteriovenous malformations.
ies around the alveoli (Q̇). An abnormal ventilation-perfusion ratio Hypoxemia is often associated with a compensatory hyperventila-
( V̇ / Q̇) is the most common cause of hypoxemia (Figure 26-2). The tion and the resultant respiratory alkalosis (i.e., decreased Paco2 and
normal V̇ / Q̇ is 0.8 because perfusion is somewhat greater than venti- increased pH). However, in individuals with associated ventilatory
lation in the lung bases and because some blood is normally shunted difficulties, hypoxemia may be complicated by hypercapnia and respi-
to the bronchial circulation. V̇ / Q̇ mismatch refers to an abnormal ratory acidosis. Hypoxemia results in widespread tissue dysfunction
distribution of ventilation and perfusion. Hypoxemia can be caused and, when severe, can lead to organ infarction. In addition, hypoxic
by inadequate ventilation of well-perfused areas of the lung (low pulmonary vasoconstriction can contribute to increased pressures in
V̇ / Q̇). Mismatching of this type, called shunting, occurs in atelecta- the pulmonary artery (pulmonary artery hypertension) and lead to
sis, in asthma as a result of bronchoconstriction, and in pulmonary right heart failure or cor pulmonale. Clinical manifestations of acute
edema and pneumonia when alveoli are filled with fluid. When blood hypoxemia may include cyanosis, confusion, tachycardia, edema, and
passes through portions of the pulmonary capillary bed that receive decreased renal output.
682 CHAPTER 26  Alterations of Pulmonary Function

4 QUICK CHECK 26-1

1. List the primary signs and symptoms of pulmonary disease.
2. What abnormal breathing patterns are seen with pulmonary disease?
3. What mechanisms produce hypercapnia?
4. What mechanisms produce hypoxemia?

Acute Respiratory Failure

Respiratory failure is defined as inadequate gas exchange such that
Pao2 ≤50 mm Hg or Paco2 ≥50 mm Hg with pH ≤7.25. Respiratory
A B
failure can result from direct injury to the lungs, airways, or chest wall
or indirectly because of injury to another body system, such as the
brain or spinal cord. It can occur in individuals who have an otherwise
normal respiratory system or in those with underlying chronic pul-
monary disease. Most pulmonary diseases can cause episodes of acute
respiratory failure. If the respiratory failure is primarily hypercapnic, it
is the result of inadequate alveolar ventilation and the individual must
receive ventilatory support, such as with a bag-valve mask or mechani-
cal ventilator. If the respiratory failure is primarily hypoxemic, it is
the result of inadequate exchange of oxygen between the alveoli and C D
the capillaries and the individual must receive supplemental oxygen FIGURE 26-3  Flail Chest. Normal respiration: A, inspiration;
therapy. Many people will have combined hypercapnic and hypoxemic B, expiration. Paradoxical motion: C, inspiration, area of lung under-
respiratory failure and will require both kinds of support. lying unstable chest wall flattens on inspiration; D, expiration,
Respiratory failure is an important potential complication of unstable area inflates. Note movement of mediastinum toward
any major surgical procedure, especially those that involve the cen- opposite lung during inspiration.
tral nervous system, thorax, or upper abdomen. The most common
postoperative pulmonary problems are atelectasis, pneumonia, pul- musculoskeletal abnormalities that can impair ventilation are ankylos-
monary edema, and pulmonary emboli. People who smoke are at ing spondylitis (see Chapter 37) and pectus excavatum (a deformity
risk, particularly if they have preexisting lung disease. Limited cardiac characterized by depression of the sternum).
reserve, chronic renal failure, chronic hepatic disease, and infection Impairment of respiratory muscle function caused by neuromus-
also increase the tendency to develop postoperative respiratory failure. cular disease also can restrict the chest wall and impair pulmonary
Prevention of postoperative respiratory failure includes frequent posi- function. Muscle weakness can result in hypoventilation, inability to
tion changes, deep-breathing exercises, and early ambulation to prevent remove secretions, and hypoxemia. Respiratory difficulty is the most
atelectasis and accumulation of secretions. Humidification of inspired air common cause of hospital admission for individuals with neuromus-
can help loosen secretions. Incentive spirometry gives individuals imme- cular diseases such as poliomyelitis, muscular dystrophy, myasthenia
diate feedback about tidal volumes, which encourages them to breathe gravis, and Guillain-Barré syndrome (see Chapter 15).
deeply. Supplemental oxygen is given for hypoxemia, and antibiotics are Trauma to the thorax or upper abdomen can restrict chest expan-
given as appropriate to treat infection. If respiratory failure develops, the sion because of pain. Trauma to the chest also can cause structural and
individual may require mechanical ventilation for a time. mechanical changes that impair the ability of the chest to expand nor-
mally. Flail chest results from the fracture of several consecutive ribs in
more than one place or fracture of the sternum and several consecutive
DISORDERS OF THE CHEST WALL AND PLEURA ribs. These multiple fractures result in instability of a portion of the
There are many conditions that can affect the chest wall and/or pleura chest wall, causing paradoxic movement of the chest with breathing.
that impact the function of the respiratory system. Chest wall disor- During inspiration the unstable portion of the chest wall moves inward
ders primarily affect tidal volume and, therefore, result in hypercapnia. and during expiration it moves outward, impairing movement of gas
Pleural diseases impact both ventilation and oxygenation. in and out of the lungs (Figure 26-3).
Chest wall restriction results in a decrease in tidal volume. An
Chest Wall Restriction increase in respiratory rate can compensate for small decreases in tidal
If the chest wall is deformed, traumatized, immobilized, or heavy from volume, but many individuals will progress to hypercapnic respiratory
the accumulation of fat, the work of breathing increases and ventila- failure. Diagnosis of chest restriction is made by pulmonary function
tion may be compromised because of a decrease in tidal volume. The testing (reduction in forced vital capacity [FVC]), arterial blood gas
degree of ventilatory impairment depends on the severity of the chest measurement (hypercapnia), and radiographs. Treatment is aimed at
wall abnormality. Grossly obese individuals are often dyspneic on any reversible underlying cause but is otherwise supportive. In severe
exertion or when recumbent. Individuals with severe kyphoscoliosis cases, mechanical ventilation may be indicated.
(lateral bending and rotation of the spinal column, with distortion
of the thoracic cage) often present with dyspnea on exertion that can Pleural Abnormalities
progress to respiratory failure. Such individuals also are susceptible to Pneumothorax. Pneumothorax is the presence of air or gas in the
lower respiratory tract infections. Both obesity and kyphoscoliosis are pleural space caused by a rupture in the visceral pleura (which sur-
risk factors for respiratory disease in individuals admitted to the hos- rounds the lungs) or the parietal pleura and chest wall. As air separates
pital for other problems, particularly those who require surgery. Other the visceral and parietal pleurae, it destroys the negative pressure of the
 CHAPTER 26  Alterations of Pulmonary Function 683

Outside air enters

because of disruption
of chest wall and
parietal pleura
Normal
lung

Chest Lung air enters

wall Mediastinum because of disruption of
visceral pleura

Pleural
space

Diaphragm

FIGURE 26-4  Pneumothorax. Air in the pleural space causes the lung to collapse around the hilus and
may push mediastinal contents (heart and great vessels) toward the other lung.

TABLE 26-1 MECHANISM OF PLEURAL EFFUSION*

TYPE OF FLUID/EFFUSION SOURCE OF ACCUMULATION PRIMARY OR ASSOCIATED DISORDER
Transudate (hydrothorax) Watery fluid that diffuses out of capillaries beneath Cardiovascular disease that causes high pulmonary capillary
pleura (i.e., capillaries in lung or chest wall) pressures; liver or kidney disease that disrupts plasma protein
production, causing hypoproteinemia (decreased oncotic pres-
sure in blood vessels)
Exudate Fluid rich in cells and proteins (leukocytes, plasma Infection, inflammation, or malignancy of pleura that stimulates
proteins of all kinds; see Chapter 5) that migrates mast cells to release biochemical mediators that increase
out of capillaries capillary permeability
Pus (empyema) Microorganisms and debris of infection (leukocytes, Pulmonary infections, such as pneumonia; lung abscesses;
cellular debris) accumulate in pleural space infected wounds
Blood (hemothorax) Hemorrhage into pleural space Traumatic injury, surgery, rupture, or malignancy that damages
blood vessels
Chyle (chylothorax) Chyle (milky fluid containing lymph and fat droplets) Traumatic injury, infection, or disorder that disrupts lymphatic
that moves from lymphatic vessels into pleural transport
space instead of passing from gastrointestinal tract
to thoracic duct

*The principles of diffusion are described in Chapter 1; mechanisms that increase capillary permeability and cause exudation of cells and proteins
are discussed in Chapter 5.

pleural space and disrupts the equilibrium between elastic recoil forces have a significant family history of primary pneumothorax that has
of the lung and chest wall. The lung then tends to recoil by collapsing been linked to mutations in the folliculin gene.7
toward the hilum (Figure 26-4). A secondary pneumothorax can be caused by chest trauma (such as
Primary (spontaneous) pneumothorax, which occurs unexpectedly a rib fracture or stab and bullet wounds that tear the pleura; rupture of
in healthy individuals (usually men) between 20 and 40 years of age, a bleb or bulla [larger vesicle], as occurs in emphysema; or mechanical
is caused by the spontaneous rupture of blebs (blister-like formations) ventilation, particularly if it includes positive end-expiratory pressure
on the visceral pleura. Bleb rupture can occur during sleep, rest, or [PEEP]).
exercise. The ruptured blebs are usually located in the apices of the Both primary pneumothorax and secondary pneumothorax can
lungs. The cause of bleb formation is not known, although more than present as either open or tension. In open (communicating) pneu-
80% of these individuals have been found to have emphysema-like mothorax, air pressure in the pleural space equals barometric pres-
changes in their lungs even if they have no history of smoking or no sure because air that is drawn into the pleural space during inspiration
known genetic disorder. Approximately 10% of affected individuals (through the damaged chest wall and parietal pleura or through the
684 CHAPTER 26  Alterations of Pulmonary Function

lungs and damaged visceral pleura) is forced back out during expira-
tion. In tension pneumothorax, however, the site of pleural rupture
4 QUICK CHECK 26-2
1. How does chest wall restriction affect ventilation?
acts as a one-way valve, permitting air to enter on inspiration but pre-
2. How does pneumothorax differ from pleural effusion?
venting its escape by closing during expiration. As more and more air
3. What causes empyema?
enters the pleural space, air pressure in the pneumothorax begins to
exceed barometric pressure. Air pressure in the pleural space pushes
against the already recoiled lung, causing compression atelectasis, and ultrasound-guided pleural drainage, instillation of fibrinolytic agents,
against the mediastinum, compressing and displacing the heart and or introduction of deoxyribonuclease (DNase) into the pleural space is
great vessels. The pathophysiologic effects of tension pneumothorax are needed for adequate drainage.11
life-threatening.
Clinical manifestations of spontaneous or secondary pneumotho- PULMONARY DISORDERS
rax begin with sudden pleural pain, tachypnea, and dyspnea. Manifes-
tations depend on the size of the pneumothorax. Physical examination Restrictive Lung Diseases
may reveal absent or decreased breath sounds and hyperresonance Restrictive lung diseases are characterized by decreased compliance of
to percussion on the affected side. Tension pneumothorax may be the lung tissue. This means that it takes more effort to expand the lungs
complicated by severe hypoxemia, tracheal deviation away from the during inspiration, which increases the work of breathing. Individuals
affected lung, and hypotension (low blood pressure). Deterioration with lung restriction complain of dyspnea and have an increased respi-
occurs rapidly and immediate treatment is required. Diagnosis of ratory rate and decreased tidal volume. Pulmonary function testing
pneumothorax is made with chest radiographs and computed tomog- discloses a decrease in forced vital capacity (FVC). Restrictive lung dis-
raphy (CT). Pneumothorax is treated with insertion of a chest tube eases commonly cause V̇ / Q̇ mismatch and affect the alveolocapillary
that is attached to a water-seal drainage system with suction. After the membrane, which reduces the diffusion of oxygen from the alveoli into
pneumothorax is evacuated and the pleural rupture is healed, the chest the blood and leads to hypoxemia. Some of the most common restric-
tube is removed. For individuals with persistent air leaks, other inter- tive lung diseases in adults are aspiration, atelectasis, bronchiectasis,
ventions may be needed including surgery, pleurodesis, endobronchial bronchiolitis, pulmonary fibrosis, inhalational disorders, pneumoco-
embolization, or thoracoscopic gluing techniques.8,9 niosis, allergic alveolitis, pulmonary edema, and acute respiratory dis-
Pleural effusion. Pleural effusion is the presence of fluid in the tress syndrome.
pleural space. The most common mechanism of pleural effusion is
migration of fluids and other blood components through the walls of Aspiration
intact capillaries bordering the pleura. Pleural effusions that enter the Aspiration is the passage of fluid and solid particles into the lung. It
pleural space from intact blood vessels can be transudative (watery) or tends to occur in individuals whose normal swallowing mechanism
exudative (high concentrations of white blood cells and plasma pro- and cough reflex are impaired by central or peripheral nervous system
teins). Other types of pleural effusion are characterized by the pres- abnormalities. Predisposing factors include an altered level of con-
ence of microorganisms (empyema), blood (hemothorax), or chyle sciousness caused by substance abuse, sedation, or anesthesia; seizure
(chylothorax). Mechanisms of pleural effusion are summarized in disorders; cerebrovascular accident; and neuromuscular disorders that
Table 26-1. cause dysphagia. Elderly individuals also are at increased risk for aspi-
Small collections of fluid may not affect lung function and may ration.12 The right lung, particularly the right lower lobe, is more sus-
remain undetected. Most will be removed by the lymphatic system ceptible to aspiration than the left lung because the branching angle of
once the underlying condition is resolved. Dyspnea, compression atel- the right main stem bronchus is straighter than the branching angle of
ectasis with impaired ventilation, and pleural pain are common. Medi- the left main stem bronchus.
astinal shift and cardiovascular manifestations occur in a large, rapidly The aspiration of large food particles or foreign bodies can obstruct
developing effusion. Physical examination shows decreased breath a bronchus, resulting in bronchial inflammation and collapse of air-
sounds and dullness to percussion on the affected side. A pleural fric- ways distal to the obstruction. Clinical manifestations include the sud-
tion rub can be heard over areas of inflamed pleura. den onset of choking, coughing, vomiting, dyspnea, and wheezing. If
Diagnosis is confirmed by chest x-ray and thoracentesis (needle the aspirated solid is not identified and removed by bronchoscopy, a
aspiration), which can determine the type of effusion and provide chronic, local inflammation develops that may lead to recurrent infec-
symptomatic relief. If the effusion is large, drainage usually requires tion and bronchiectasis (permanent dilation of the bronchus). Once
the placement of a chest tube and surgical interventions may be needed the pathologic process has progressed to bronchiectasis, surgical resec-
to prevent recurrence of the effusion.10 tion of the affected area is usually required.
Empyema. Empyema (infected pleural effusion) is the presence of Aspiration of acidic gastric fluid (pH <2.5) may cause severe pneu-
microorganisms and cellular debris (pus) in the pleural space. Empy- monitis (lung inflammation). Bronchial damage includes inflam-
ema occurs most commonly in older adults and children and usually mation, loss of ciliary function, and bronchospasm. In the alveoli,
develops as a complication of pneumonia, surgery, trauma, or bron- acidic fluid damages the alveolocapillary membrane, allowing plasma
chial obstruction from a tumor. Commonly documented infectious and blood cells to move from capillaries into the alveoli, resulting in
organisms include Staphylococcus aureus, Escherichia coli, anaerobic hemorrhagic pneumonitis. The lung becomes stiff and noncompliant
bacteria, and Klebsiella pneumoniae. as surfactant production is disrupted, leading to further edema and
Individuals with empyema present clinically with cyanosis, fever, collapse.
tachycardia (rapid heart rate), cough, and pleural pain. Breath sounds Preventive measures for individuals at risk are more effective than
are decreased directly over the empyema. Diagnosis is made by chest treatment of known aspiration. The most important preventive mea-
radiographs, thoracentesis, and sputum culture. The treatment for sures include employment of the semirecumbent position, surveillance
empyema includes the administration of appropriate antimicrobials of enteral feeding, use of promotility agents, and avoidance of excessive
and drainage of the pleural space with a chest tube. In severe cases, sedation. Nasogastric tubes, which are often used to remove stomach
 CHAPTER 26  Alterations of Pulmonary Function 685

Inspired air Inspired air

Mucous plug Mucous plug

Normal Closed pore Open pore
alveolus of Kohn of Kohn

Atelectatic
alveolus

Low inspiratory volume High inspiratory volume

(shallow breathing) (deep breathing)
A B
FIGURE 26-5  Pores of Kohn. A, Absorption atelectasis caused by lack of collateral ventilation through
pores of Kohn. B, Restoration of collateral ventilation during deep breathing.

contents, are used to prevent aspiration but also can cause aspiration if Bronchiectasis
fluid and particulate matter are regurgitated as the tube is being placed. Bronchiectasis is persistent abnormal dilation of the bronchi. Hos-
Treatment of aspiration includes use of supplemental oxygen and pitalizations for bronchiectasis have steadily increased in the United
mechanical ventilation with positive end-expiratory pressure (PEEP), States over the past two decades and most commonly occur in women
restriction of fluid intake, and administration of corticosteroids. Bac- older than 60 years.14 Cystic fibrosis is the most common cause of
terial pneumonia may develop as a complication of aspiration pneu- bronchiectasis in children. In adults it usually occurs in conjunction
monitis and must be treated with broad-spectrum antimicrobials. with other respiratory conditions that cause chronic inflammation
of the bronchial wall, such as obstruction of an airway with mucous
Atelectasis plugs, atelectasis, aspiration of a foreign body, infection, tuberculo-
Atelectasis is the collapse of lung tissue. There are three types of sis, congenital weakness of the bronchial wall, or impaired defense
atelectasis: mechanisms. Chronic inflammation of the bronchi leads to destruc-
1. Compression atelectasis is caused by external pressure exerted by tion of elastic and muscular components of their walls and permanent
tumor, fluid, or air in pleural space or by abdominal distention dilation. Bronchiectasis also is associated with a number of systemic
pressing on a portion of lung, causing alveoli to collapse. disorders, such as rheumatologic disease, inflammatory bowel disease,
2. Absorption atelectasis results from removal of air from obstructed and immunodeficiency syndromes (e.g., acquired immunodeficiency
or hypoventilated alveoli or from inhalation of concentrated oxy- syndrome [AIDS]).
gen or anesthetic agents. The primary symptom of bronchiectasis is a chronic productive
3. Surfactant impairment results from decreased production or inac- cough that may date back to a childhood illness or infection. The dis-
tivation of surfactant, which is necessary to reduce surface tension ease is commonly associated with recurrent lower respiratory tract
in the alveoli and thus prevent lung collapse during expiration. infections and expectoration of voluminous amounts of foul-smelling
Surfactant impairment can occur because of premature birth, acute purulent sputum (measured in cupfuls). Hemoptysis and clubbing of
respiratory distress syndrome, anesthesia induction, or mechanical the fingers (from chronic hypoxemia) are common. Pulmonary func-
ventilation. tion studies show decreased vital capacity (VC) and expiratory flow
Atelectasis tends to develop after surgery and is estimated to occur rates. Hypoxemia eventually leads to cor pulmonale (see p. 700). Diag-
in more than 90% of individuals administered a general anesthetic.13 nosis is usually confirmed by the use of high-resolution computed
Postoperative persons are often in pain, breathe shallowly, are reluc- tomography. Bronchiectasis is treated with antibiotics, bronchodila-
tant to change position, and produce viscous secretions that tend to tors, chest physiotherapy, and supplemental oxygen.
pool in dependent portions of the lung.
Clinical manifestations of atelectasis are similar to those of pul- Bronchiolitis
monary infection including dyspnea, cough, fever, and leukocytosis. Bronchiolitis is a diffuse, inflammatory obstruction of the small air-
Prevention and treatment of postoperative atelectasis usually include ways or bronchioles occurring most commonly in children. In adults
deep-breathing exercises, frequent position changes, and early ambu- it usually accompanies chronic bronchitis but can occur in otherwise
lation. Deep breathing and the use of an incentive spirometer help healthy individuals in association with an upper or lower respiratory
open connections between patent and collapsed alveoli, called pores tract viral infection or with inhalation of toxic gases. Bronchiolitis also
of Kohn (Figure 26-5). This allows air to flow into the collapsed alve- is a serious complication of stem cell and lung transplantation and can
oli (collateral ventilation) and aids in the expulsion of intrabronchial progress to bronchiolitis obliterans, a fibrotic process that occludes
obstructions. airways and causes permanent scarring of the lungs.15 Bronchiolitis
686 CHAPTER 26  Alterations of Pulmonary Function

obliterans organizing pneumonia (BOOP) is a complication of bron- mechanical ventilation with PEEP, and support of the cardiovascular
chiolitis obliterans in which the alveoli and bronchioles become filled system. Steroids are sometimes used, although their effectiveness has
with plugs of connective tissue. This complication of lung transplant not been well documented. Most individuals recover quickly. Some,
has a high morbidity. however, may improve initially and then deteriorate as a result of
Bronchiolitis frequently presents with a rapid ventilatory rate; bronchiectasis or bronchiolitis (inflammation of the bronchioles).
marked use of accessory muscles; low-grade fever; dry, nonproductive Prolonged exposure to high concentrations of supplemental oxy-
cough; and hyperinflated chest. A decrease in the ventilation-perfusion gen can result in a relatively rare condition known as oxygen toxicity.
ratio results in hypoxemia. Diagnosis is made by spirometry and bron- The basic underlying mechanism of injury is a severe inflammatory
choscopy with biopsy. Bronchiolitis is treated with appropriate antibi- response mediated by toxic oxygen radicals. Damage to alveolocapil-
otics, corticosteroids, immunosuppressive agents, and chest physical lary membranes results in disruption of surfactant production, inter-
therapy (humidified air, coughing and deep breathing, postural drain- stitial and alveolar edema, and a decrease in lung compliance. In infants
age) as indicated by the underlying cause. this can lead to a condition known as bronchopulmonary dysplasia in
which there is severe scarring of the lung.18 Treatment involves ventila-
Pulmonary Fibrosis tory support and a reduction of inspired oxygen concentration to less
Pulmonary fibrosis is an excessive amount of fibrous or connective than 60% as soon as the individual can tolerate this change. Surfactant
tissue in the lung. The most common form has no known cause and replacement and antioxidant therapies are being explored.19
therefore is called idiopathic pulmonary fibrosis. Pulmonary fibrosis Pneumoconiosis. Pneumoconiosis represents any change in the
also can be caused by formation of scar tissue after active pulmonary lung caused by inhalation of inorganic dust particles, usually in the
disease (e.g., acute respiratory distress syndrome, tuberculosis), in workplace. As in all cases of environmentally acquired lung disease,
association with a variety of autoimmune disorders (e.g., rheumatoid the individual’s history of exposure is important in determining the
arthritis, progressive systemic sclerosis, sarcoidosis), or by inhalation diagnosis. Pneumoconiosis often occurs after years of exposure to the
of harmful substances (e.g., coal dust, asbestos). offending dust, with progressive fibrosis of lung tissue.
Fibrosis causes a marked loss of lung compliance. The lung becomes The dusts of silica, asbestos, and coal are the most common causes
stiff and difficult to ventilate, and the diffusing capacity of the alveolo- of pneumoconiosis. Others include talc, fiberglass, clays, mica, slate,
capillary membrane may decrease, causing hypoxemia. Diffuse pulmo- cement, cadmium, beryllium, tungsten, cobalt, aluminum, and iron.
nary fibrosis has a poor prognosis. Deposition of these materials in the lungs cause the release of proin-
Idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis flammatory cytokines, such as interleukin-1 beta (IL-1β).20 This leads to
(IPF) is the most common idiopathic interstitial lung disorder. It is chronic inflammation with scarring of the alveolar capillary membrane
more common in men than in women and most cases occur after age resulting in pulmonary fibrosis and progressive pulmonary deteriora-
60. Although IPF is characterized by chronic inflammation, recent tion. Clinical manifestations with advancement of disease include cough,
studies suggest that it results from aberrant healing responses to epi- chronic sputum production, dyspnea, decreased lung volumes, and
thelial cell injury, which probably occurs in response to a combination hypoxemia. Diagnosis is confirmed by chest x-ray and computed tomog-
of environmental insults and genetic predispositions.16,17 Fibro­ raphy (CT). Treatment is usually palliative and focuses on preventing
proliferation of the interstitial lung tissue around the alveoli causes further exposure, particularly in the workplace. New therapies being
decreased oxygen diffusion across the alveolocapillary membrane and investigated include blockers of inflammatory cytokines, such as IL-1β.20
hypoxemia. As the disease progresses, decreased lung compliance leads Allergic alveolitis. Inhalation of organic dusts can result in an
to increased work of breathing, decreased tidal volume, and resultant allergic inflammatory response called extrinsic allergic alveolitis,
hypoventilation with hypercapnia. or hypersensitivity pneumonitis.21 Many allergens can cause this
The primary symptom of IPF is increasing dyspnea on exertion. disorder, including grains, silage, bird droppings or feathers, wood
Physical examination reveals diffuse inspiratory crackles. The diagnosis dust (particularly redwood and maple), cork dust, animal pelts, cof-
is confirmed by pulmonary function testing (decreased FVC), high-res- fee beans, fish meal, mushroom compost, and molds that grow on
olution computed tomography, and lung biopsy. Treatment includes sugarcane, barley, and straw. The lung inflammation, or pneumoni-
corticosteroids and cytotoxic drugs, although success rates are low and tis, occurs after repeated, prolonged exposure to the allergen. Lym-
toxicities are high. Newer therapies include antifibrotic drugs (such phocytes and inflammatory cells infiltrate the interstitial lung tissue,
as N-acetylcysteine and pirfenidone), interferon, and anticoagulation releasing a variety of autoimmune and inflammatory cytokines. Recent
therapy.16 Selected individuals may benefit from lung transplantation. studies suggest an important role for interleukin-17, which promotes
epithelial cell injury.21
Inhalation Disorders Allergic alveolitis can be acute, subacute, or chronic. The acute
Exposure to toxic gases. Inhalation of gaseous irritants can cause form causes fever, cough, and chills a few hours after exposure. In the
significant respiratory dysfunction. Commonly encountered toxic subacute form, coughing and dyspnea are common and sometimes
gases include smoke, ammonia, hydrogen chloride, sulfur dioxide, necessitate hospital care. Diagnosis is made by history of exposure,
chlorine, phosgene, and nitrogen dioxide. Inhalation injuries in burns chest x-ray, and serologic testing. Treatment consists of removal of
can include toxic gases from household or industrial combustants, the offending agent and administration of corticosteroids. Recovery is
heat, and smoke particles. Inhaled toxic particles cause damage to the complete if the offending agent can be avoided in the future. With con-
airway epithelium, mucus secretion, inflammation, mucosal edema, tinued exposure, the disease becomes chronic and pulmonary fibrosis
ciliary damage, pulmonary edema, and surfactant inactivation. The develops.
cellular effects of toxic gases are described in Chapter 2. Acute toxic
inhalation is frequently complicated by acute respiratory distress syn- Pulmonary Edema
drome (ARDS) and pneumonia. Initial symptoms include burning Pulmonary edema is excess water in the lung. The normal lung is
of the eyes, nose, and throat; coughing; chest tightness; and dyspnea. kept dry by lymphatic drainage and a balance among capillary hydro-
Hypoxemia is common. Treatment includes supplemental oxygen, static pressure, capillary oncotic pressure, and capillary permeability.
 CHAPTER 26  Alterations of Pulmonary Function 687

Valvular dysfunction Injury to capillary Blockage of

Coronary artery endothelium lymphatic vessels
disease
Left ventricular
dysfunction

Increased left Increased capillary Inability to remove

atrial pressure permeability and excess fluid from
disruption of surfactant interstitial space
production by alveoli

Increased pulmonary Movement of fluid and plasma Accumulation of fluid

capillary hydrostatic proteins from capillary to in interstitial space
pressure interstitial space (alveolar
septum) and alveoli

Pulmonary edema

FIGURE 26-6  Pathogenesis of Pulmonary Edema.

In addition, surfactant lining the alveoli repels water, keeping fluid heart failure, therapy is geared toward improving cardiac output with
from entering the alveoli. Predisposing factors for pulmonary edema diuretics, vasodilators, and drugs that improve the contraction of the
include heart disease, acute respiratory distress syndrome, and inhala- heart muscle. If edema is the result of increased capillary permeabil-
tion of toxic gases. The pathogenesis of pulmonary edema is shown in ity resulting from injury, the treatment is focused on removing the
Figure 26-6. offending agent and implementing supportive therapy to maintain
The most common cause of pulmonary edema is left-sided heart adequate ventilation and circulation. Individuals with either type of
disease. When the left ventricle fails, filling pressures on the left side of pulmonary edema require supplemental oxygen. Positive-pressure
the heart increase. Vascular volume redistributes into the lungs, caus- mechanical ventilation may be needed if edema significantly impairs
ing an increase in pulmonary capillary hydrostatic pressure. When the ventilation and oxygenation.
hydrostatic pressure exceeds oncotic pressure (which holds fluid in the
capillary), fluid moves out into the interstitial space (the space within Acute Respiratory Distress Syndrome
the alveolar septum between alveolus and capillary). When the flow Acute respiratory distress syndrome (ARDS) is characterized by
of fluid out of the capillaries exceeds the lymphatic system’s ability to acute lung inflammation and diffuse alveolocapillary injury. Acute
remove it, pulmonary edema develops. lung injury (ALI) is a less severe form of lung inflammation. Both
Another cause of pulmonary edema is capillary injury that ARDS and ALI are defined as (1) the acute onset of bilateral infil-
increases capillary permeability, as in cases of acute respiratory dis- trates on chest radiograph, (2) a low ratio of partial pressure of arte-
tress syndrome or inhalation of toxic gases, such as ammonia. Capil- rial oxygen to the fraction of inhaled oxygen, and (3) the absence of
lary injury and inflammation causes water and plasma proteins to clinical evidence of left atrial hypertension.22 In the United States
leak out of the capillary and move into the interstitial space, increas- more than 30% of intensive care unit (ICU) admissions are com-
ing the interstitial oncotic pressure (which is usually very low). As plicated by ARDS. Advances in therapy have decreased overall
the interstitial oncotic pressure begins to exceed capillary oncotic mortality in people younger than 60 years to approximately 40%,
pressure, water moves out of the capillary and into the lung. (This although mortality in older adults and those with severe infections
phenomenon is discussed in Chapter 4, Figures 4-1 and 4-2.) Pul- remains much higher. The most common predisposing factors are
monary edema also can result from obstruction of the lymphatic sys- sepsis and multiple trauma; however, there are many other causes,
tem. Drainage can be blocked by compression of lymphatic vessels by including pneumonia, burns, aspiration, cardiopulmonary bypass
edema, tumors, and fibrotic tissue and by increased systemic venous surgery, pancreatitis, blood transfusions, drug overdose, inhalation
pressure. of smoke or noxious gases, fat emboli, high concentrations of sup-
Clinical manifestations of pulmonary edema include dyspnea and plemental oxygen, radiation therapy, and disseminated intravascular
increased work of breathing. Physical examination may disclose inspi- coagulation.
ratory crackles (rales) and dullness to percussion over the lung bases.
V̇ / Q̇ mismatch leads to hypoxemia. In severe edema, pink frothy PATHOPHYSIOLOGY  All disorders causing ARDS cause massive
sputum is expectorated and lung compliance decreases, leading to pulmonary inflammation that injures the alveolocapillary membrane
decreased tidal volume and hypercapnia. and produces severe pulmonary edema, V̇ / Q̇ mismatch (shunting),
The treatment of pulmonary edema depends on its cause. If the and hypoxemia (Figure 26-7). Most commonly, this occurs indirectly
edema is caused by increased hydrostatic pressure that results from because of the effects of inflammatory mediators released in response
688 CHAPTER 26  Alterations of Pulmonary Function

Indirect or direct lung injury

Alveolar Capillary Activation of

epithelial injury endothelial injury complement

Type II pneumocyte Activation of

damage platelets, neutrophils Release of
and macrophages growth factors
(e.g., TGF-)
Decreased
surfactant Release of
inflammatory cytokines Fibrosing
(e.g., TNF, IL-1, ROS) alveolitis
Atelectasis and decreased
lung compliance
Increased Chronic
alveolocapillary pulmonary
permeability and insufficiency
Decreased tidal Vasoconstriction
volume (hypercapnia) alveolar flooding
(edema)

Acute respiratory V/Q mismatch

failure (hypoxemia)

FIGURE 26-7  Pathogenesis of Acute Respiratory Distress Syndrome (ARDS). IL-1, Interleukin-1;
ROS, reactive oxygen species; TGF-β, transforming growth factor-beta; TNF, tumor necrosis factor.

to systemic disorders, such as sepsis and trauma. The damage also can increases susceptibility to bacterial infection and pneumonia, and
occur directly, because of the aspiration of highly acidic gastric con- decreases surfactant production.24 Alveoli and respiratory bronchioles
tents or the inhalation of toxic gases. Injury to the pulmonary capillary fill with fluid or collapse. The lungs become less compliant, the work of
endothelium stimulates platelet aggregation and intravascular micro- breathing increases, ventilation of alveoli decreases, and hypercapnia
thrombus formation. Endothelial damage also initiates the comple- develops. The end result is acute respiratory failure.
ment cascade, stimulating neutrophil and macrophage activity and the Approximately 24 to 48 hours after the acute phase of ARDS,
inflammatory response.23 hyaline membranes form. Inflammatory cells release growth factors
Once activated, macrophages produce toxic mediators such as and, after approximately 7 days, fibrosis progressively obliterates the
tumor necrosis factor (TNF) and interleukin 1 (IL-1). The role of alveoli, respiratory bronchioles, and interstitium (fibrosing alveolitis),
neutrophils is central to the development of ARDS. Activated neu- which can result in chronic pulmonary insufficiency.25 Functional
trophils release a battery of inflammatory mediators, including pro- residual capacity declines, and more severe right-to-left shunting is
teolytic enzymes, toxic oxygen products, arachidonic acid metabolites evident.
(prostaglandins, thromboxanes, leukotrienes), and platelet-activating The chemical mediators responsible for the alveolocapillary dam-
factor.23,24 These mediators extensively damage the alveolocapillary age of ARDS often cause widespread inflammation, endothelial dam-
membrane and greatly increase capillary membrane permeability. This age, and capillary permeability throughout the body resulting in the
allows fluids, proteins, and blood cells to leak from the capillary bed systemic inflammatory response syndrome (SIRS), which then leads to
into the pulmonary interstitium and alveoli. The resulting pulmonary multiple organ dysfunction syndrome (MODS). In fact, death may not
edema severely reduces lung compliance and impairs alveolar ventila- be caused by respiratory failure alone but by MODS associated with
tion. Because this form of pulmonary edema is not secondary to heart ARDS. (MODS is discussed in Chapter 23.)
failure, ARDS is often referred to as noncardiogenic pulmonary edema.
Mediators released by neutrophils and macrophages also cause pul- CLINICAL MANIFESTATIONS  The classic signs and symptoms
monary vasoconstriction, which leads to worsening V̇ / Q̇ mismatch of ARDS are marked dyspnea; rapid, shallow breathing; inspiratory
and hypoxemia. crackles; respiratory alkalosis; decreased lung compliance; hypox-
The initial lung injury also damages the alveolar epithelium. This emia unresponsive to oxygen therapy (refractory hypoxemia);
type II alveolar cell injury increases alveolocapillary permeability, and diffuse alveolar infiltrates seen on chest radiographs, without
 CHAPTER 26  Alterations of Pulmonary Function 689

evidence of cardiac disease. Symptoms develop progressively, as States but the incidence of asthma has increased, especially in urban
follows: areas.
Dyspnea and hypoxemia Asthma is a familial disorder, and more than 100 genes have been
↓
identified that may play a role in the susceptibility and pathogenesis of
Hyperventilation and respiratory alkalosis
asthma, including those that influence the production of interleukin-4
↓
(IL-4) and interleukin-5 (IL-5), immunoglobulin E (IgE), eosinophils,
Decreased tissue perfusion, organ dysfunction, and metabolic acidosis
mast cells, and β-adrenergic receptors as well as those that increase
↓
bronchial hyperresponsiveness.30 The expression of these genetic fac-
Increased work of breathing, decreased tidal volume, and hypoventilation
tors is influenced by other risk factors including age at onset of disease;
↓
levels of allergen exposure; urban residence; exposure to air pollution,
Respiratory acidosis and worsening hypoxemia
tobacco smoke, and environmental tobacco smoke; recurrent respira-
↓
tory tract viral infections; gastroesophageal reflux disease; and obe-
Hypotension, decreased cardiac output, death
sity.28,31,32 There is considerable evidence that exposure to high levels
of certain allergens during childhood increases the risk for asthma.
EVALUATION AND TREATMENT  Diagnosis is based on physical Furthermore, decreased exposure to certain infectious organisms
examination, analysis of blood gases, and radiologic examination. appears to create an immunologic imbalance that favors the develop-
Measurement of serum biomarkers, such as TNF, brain natriuretic ment of allergy and asthma. This complex relationship has been called
peptide (BNP), and IL-8, may aid in the diagnosis of ARDS in cases the hygiene hypothesis.33 Urban exposure to pollution and cockroaches,
of trauma.26 Treatment is based on early detection, supportive ther- decreased exercise, and increased obesity play a role in the increasing
apy, and prevention of complications. Supportive therapy is focused prevalence of asthma, particularly in children.
on maintaining adequate oxygenation and ventilation while pre-
venting infection. This often requires alternative modes of mechani- PATHOPHYSIOLOGY  Many cells and cellular elements contribute
cal ventilation. Pharmacologic therapy continues to be explored.27 to the persistent inflammation of the bronchial mucosa and hyperre-
Low-dose corticosteroids may improve survival in selected indi- sponsiveness of the airways, including mast cells, eosinophils, baso-
viduals, and surfactant can be given to improve lung compliance. phils, macrophages (dendritic cells), neutrophils, and lymphocytes.
Anticoagulant therapy with recombinant human activated protein Inflammatory mediators released by these cells increase capillary
C improves outcomes in sepsis associated with ARDS and continues permeability and stimulate smooth muscle contraction and increased
to be evaluated. secretion of mucus. Airway epithelial exposure to antigen initiates both
an innate and an adaptive immune response (type I hypersensitivity)

4 QUICK CHECK 26-3

in sensitized individuals (see Chapter 7).34,35 There is both an immedi-
ate (acute asthmatic response) and a late (delayed) response.
1. Contrast aspiration and atelectasis. During the early asthmatic response antigen exposure to the bron-
2. What are some of the causes of pulmonary fibrosis? chial mucosa activates B cells (plasma cells) to produce antigen-specific
3. What symptoms are produced by inhalation of toxic gases? IgE. Cross-linking of IgE molecules with the antigen on the surface of
4. Describe pneumoconiosis, and give two examples. mast cells causes mast cell degranulation with the release of inflam-
5. Briefly describe the role of neutrophils in acute respiratory distress matory mediators including histamine, bradykinins, leukotrienes and
­syndrome (ARDS). prostaglandins, platelet activating factor, and interleukins (see Figures
5-8 and 7-9 for additional details).35 These mediators cause vasodi-
lation, increased capillary permeability, mucosal edema, bronchial
Obstructive Lung Diseases smooth muscle contraction (bronchospasm), and mucus secretion
Obstructive lung disease is characterized by airway obstruction that from mucosal goblet cells with narrowing of the airways and obstruc-
is worse with expiration. More force (i.e., use of accessory muscles of tion to airflow (see Figures 26-8 and 27-7, A).36 Other inflammatory
expiration) is required to expire a given volume of air and emptying cytokines, such as TNF and IL-1, have been found to alter muscarinic
of the lungs is slowed. In adults the major obstructive lung diseases receptor function and lead to increased levels of acetylcholine, which
are asthma, chronic bronchitis, and emphysema. Asthma is one of the cause bronchial smooth muscle contraction and mucus secretion. The
most common lung disorders in the United States. Because many indi- late asthmatic response begins 4 to 8 hours after the early response (see
viduals have both chronic bronchitis and emphysema, these diseases Figure 27-7, B). Chemotactic recruitment of neutrophils, eosinophils,
together are often called chronic obstructive pulmonary disease (COPD). and lymphocytes during the acute response causes a latent release of
Asthma is more acute and intermittent than COPD, even though it can inflammatory mediators, again inciting bronchospasm, edema, and
be chronic (Figure 26-8). The unifying symptom of obstructive lung mucus secretion with obstruction to airflow. Synthesis of leukotrienes
diseases is dyspnea, and the unifying sign is wheezing. Individuals have contributes to prolonged smooth muscle contraction. Eosinophils
an increased work of breathing, ventilation-perfusion mismatching, cause direct tissue injury with fibroblast proliferation and airway scar-
and a decreased forced expiratory volume in 1 second (FEV1). ring. Release of toxic neuropeptides contributes to increased bronchial
hyperresponsiveness. Damage to ciliated epithelial cells contributes to
Asthma impaired mucociliary function, with the accumulation of mucus and
Asthma is a chronic inflammatory disorder of the bronchial mucosa cellular debris forming plugs in the airways (see Figures 26-9 and 27-7
that causes hyperresponsiveness and constriction of the airways.28 for additional details).35,37 Untreated inflammation can lead to long-
Asthma occurs at all ages, with approximately half of all cases develop- term airway damage that is irreversible, known as airway remodeling
ing during childhood (see Chapter 27) and another third before age (subepithelial fibrosis, smooth muscle hypertrophy).38
40. In the United States asthma has been diagnosed in more than 34 Airway obstruction increases resistance to airflow and decreases
million persons.29 Death rates have declined since 1995 in the United flow rates, especially expiratory flow. Impaired expiration causes air
690 CHAPTER 26  Alterations of Pulmonary Function

Pulmonary artery
Cartilage Submucosal
gland
Mast cell Basement
Parasympathetic membrane
nerve
Smooth
muscle
Bronchioles

Epithelium
Respiratory Goblet cell
bronchioles Normal
Alveoli alveoli
A B

Enlarged
submucosal Degranulation
gland of mast cell
Mucus
accumulation Smooth muscle
constriction

Mucous
plug
Mucous
Inflammation plug
of epithelium
Mucous
Hyperinflation Hyperinflation accumulation
of alveoli of alveoli
C D
FIGURE 26-8  Airway Obstruction Caused by Emphysema, Chronic Bronchitis, and Asthma.
A, The normal lung. B, Emphysema: enlargement and destruction of alveolar walls with loss of elastic-
ity and trapping of air; (left) panlobular emphysema showing abnormal weakening and enlargement of
all air spaces distal to the terminal bronchioles (normal alveoli shown for comparison only); (right) cen-
trilobular emphysema showing abnormal weakening and enlargement of the respiratory bronchioles
in the proximal portion of the acinus. C, Chronic bronchitis: inflammation and thickening of mucous
membrane with accumulation of mucus and pus leading to obstruction; characterized by cough.  
D, Bronchial asthma: thick mucus, mucosal edema, and smooth muscle spasm causing obstruction of
small airways; breathing becomes labored, and expiration is difficult. (Modified from Des Jardins T, Bur-
ton GG: Clinical manifestations and assessment of respiratory disease, ed 5, St Louis, 2006, Mosby.)

trapping, hyperinflation distal to obstructions, and increased work of increasing CO2 retention and respiratory acidosis. Respiratory acido-
breathing. Changes in resistance to airflow are not uniform throughout sis signals respiratory failure, especially when left ventricular filling,
the lungs and the distribution of inspired air is uneven, with more air and thus cardiac output, becomes compromised because of severe
flowing to the less resistant portions. Continued air trapping increases hyperinflation.
intrapleural and alveolar gas pressures and causes decreased perfusion
of the alveoli. Increased alveolar gas pressure, decreased ventilation, CLINICAL MANIFESTATIONS  Between attacks, individuals are
and decreased perfusion lead to variable and uneven ventilation-per- asymptomatic and pulmonary function tests are normal. At the
fusion relationships within different lung segments. Hyperventilation beginning of an attack, the individual experiences chest constriction,
is triggered by lung receptors responding to increased lung volume expiratory wheezing, dyspnea, nonproductive coughing, prolonged
and obstruction. The result is early hypoxemia without CO2 reten- expiration, tachycardia, and tachypnea. Severe attacks involve the
tion. Hypoxemia further increases hyperventilation through stimula- accessory muscles of respiration and wheezing is heard during both
tion of the respiratory center, causing Paco2 to decrease and pH to inspiration and expiration. A pulsus paradoxus (decrease in systolic
increase (respiratory alkalosis). With progressive obstruction of expi- blood pressure during inspiration of more than 10 mm Hg) may be
ratory airflow, air trapping becomes more severe and the lungs and noted. Peak flow measurements should be obtained. Because the sever-
thorax become hyperexpanded, positioning the respiratory muscles at ity of blood gas alterations is difficult to evaluate by clinical signs alone,
a mechanical disadvantage. This leads to a fall in tidal volume with arterial blood gas tensions should be measured if oxygen saturation
 CHAPTER 26  Alterations of Pulmonary Function 691

Allergen or irritant exposure

Immune activation Mast cell degranulation

(IL-4, IgE production)

Vasoactive mediators Chemotactic mediators

Vasodilation Cellular infiltration

Increased capillary permeability (neutrophils, lymphocytes, eosinophils)

Bronchospasm Autonomic
Vascular congestion dysregulation
Mucous secretion
Impaired mucociliary function
Thickening of airway walls
Increased contractile response of Release of toxic
bronchial smooth muscle neuropeptides

Bronchial hyperresponsiveness Epithelial desquamation

Airway obstruction and fibrosis
FIGURE 26-9  Pathophysiology of Asthma. Allergen or irritant exposure results in a cascade
of ­inflammatory events leading to acute and chronic airway dysfunction (also see Figure 27-7).

falls below 90%. Usual findings are hypoxemia with an associated hospitalization is necessary. Antibiotics are not indicated for acute
respiratory alkalosis. In the late asthma response, symptoms can be asthma unless there is a documented bacterial infection.39
even more severe than the initial attack. Management of asthma begins with avoidance of allergens and irri-
If bronchospasm is not reversed by usual measures, the individual tants. Individuals with asthma tend to underestimate the severity of
is considered to have severe bronchospasm or status asthmaticus. If their asthma and extensive education is important, including use of
status asthmaticus continues, hypoxemia worsens, expiratory flows a peak flow meter and adherence to an action plan should symptoms
and volumes decrease further, and effective ventilation decreases. worsen. In the mildest form of asthma (intermittent), short-acting
Acidosis develops as Paco2 level begins to rise. Asthma becomes life- beta-agonist inhalers are prescribed. For all categories of persistent
threatening at this point if treatment does not reverse this process asthma, anti-inflammatory medications are essential and inhaled cor-
quickly. A silent chest (no audible air movement) and a Paco2 >70 ticosteroids are the mainstay of therapy. In individuals who are not
mm Hg are ominous signs of impending death. adequately controlled with inhaled corticosteroids, leukotriene antag-
onists can be considered. In more severe asthma, long-acting beta
EVALUATION AND TREATMENT  The diagnosis of asthma is sup- agonists can be used to control persistent bronchospasm; however,
ported by a history of allergies and recurrent episodes of wheezing, dys- these agonists can actually worsen asthma in some individuals with
pnea, and cough or exercise intolerance. Further evaluation includes certain genetic polymorphisms (see Health Alert: Pharmacogenetics
spirometry, which may document reversible decreases in FEV1 during and Beta Agonists in the Treatment of Asthma). Immunotherapy has
an induced attack. been shown to be an important tool in reducing asthma exacerbations
The evaluation of an acute asthma attack requires the rapid assess- and can now be given sublingually.40 Monoclonal antibodies to IgE
ment of arterial blood gases and expiratory flow rates (using a peak (omalizumab) have been found to be helpful in selected individuals.
flow meter) and a search for underlying triggers, such as infection. The National Asthma Education and Prevention Program offers step-
Hypoxemia and respiratory alkalosis are expected early in the course wise guidelines for the diagnosis and management of chronic asthma
of an acute attack. The development of hypercapnia with respiratory based on clinical severity and they may be reviewed at www.nhlbi.nih.
acidosis signals the need for mechanical ventilation. Management of gov/guidelines/asthma/asthgdln.htm.28
the acute asthma attack requires immediate administration of oxygen
and inhaled beta-agonist bronchodilators. In addition, oral corticoste- Chronic Obstructive Pulmonary Disease
roids should be administered early in the course of management. Care- Chronic obstructive pulmonary disease (COPD) is defined as a
ful monitoring of gas exchange and airway obstruction in response preventable and treatable disease with some significant extrapulmo-
to therapy provides information necessary to determine whether nary effects that may contribute to the severity in individual patients.
692 CHAPTER 26  Alterations of Pulmonary Function

HEALTH ALERT
Pharmacogenetics and Beta Agonists in the Treatment of Asthma
Long-acting beta agonists (LABAs) (salmeterol and formoterol) are recommended inflammation and airway damage. There also is some evidence to suggest that
by the National Asthma Education and Prevention Program (NAEPP) to be used persons who have a polymorphism of the beta-adrenergic receptor gene (ADRβ2)
in conjunction with inhaled corticosteroids as step 3 therapy for asthma. LABAs are at risk for complications if they use LABAs. This polymorphism is known as
have been found to improve symptoms in many individuals and exert both a the Arg16Arg genotype and is associated with an increased risk for worsening
bronchodilatory and an anti-inflammatory effect on the airways. However, the bronchospasm, increased hospitalizations, and increased mortality when using
safety of LABAs has been questioned because of increased mortality in some LABAs. This genotype occurs more frequently in blacks and may explain some
populations using these drugs. Recent evidence suggests that the reason for this of the differences in asthma mortality among these individuals. Studies continue
increased mortality is that those individuals who exhibited worsening symptoms to evaluate other genes and their relationship to medication response, a field of
while taking LABAs used these medications alone, instead of in conjunction study now known as pharmacogenetics.
with inhaled steroids as recommended. Thus they were simply masking ongoing

Data from Ducharme FM, Lasserson TJ, Cates CJ: Addition to inhaled corticosteroids of long-acting beta2-agonists versus anti-leukotrienes for
chronic asthma, Cochrane Database Syst Rev 5:CD003137, 2011; Schachter EN: New β2-adrenoceptor agonists for the treatment of chronic obstruc-
tive pulmonary disease, Drugs Today (Barc) 6(12):911–918, 2010; Sears MR: The addition of long-acting beta-agonists to inhaled corticosteriods in
asthma, Curr Opin Pulm Med 17(1):23–28, 2011; Hodgson D, Mortimer K, Harrison T: Budesonide/formoterol in the treatment of asthma, Expert Rev
Respir Med 4(5):557–566, 2010; Chung LP, Waterer G,Thompson PJ: Pharmacogenetics of β2 adrenergic receptor gene polymorphisms, long-acting
β-agonists and asthma,Clin Exp Allergy 41(3):312–326, 2011.

Tobacco smoke
Air pollution
Inherited
1-antitrypsin deficiency
Inflammation of the
airway epithelium

Infiltration of inflammatory
cells and release of cytokines
Systemic effects Inhibition of normal
(neutrophils, macrophages,
(muscle weakness, weight loss) endogenous antiproteases
lymphocytes, leukotrienes,
interleukins)

Continuous bronchial Increased protease activity

irritation and inflammation with breakdown of elastin
in connective tissue of lungs
(elastases, cathepsins, etc.)

Chronic bronchitis Emphysema

(bronchial edema, hypersecretion of (destruction of alveolar septa and
mucus, bacterial colonization of airways) loss of elastic recoil of bronchial walls)

Airway obstruction
Air trapping
Loss of surface area for gas exchange
Frequent exacerbations
(infections, bronchospasm)

Dyspnea
Cough
Hypoxemia
Hypercapnia
Cor pulmonale

FIGURE 26-10  Pathogenesis of Chronic Bronchitis and Emphysema (Chronic Obstructive Pulmo-
nary Disease [COPD]).
 CHAPTER 26  Alterations of Pulmonary Function 693

Air movement Air movement TABLE 26-2 CLINICAL MANIFESTATIONS

during INSPIRATION during EXPIRATION OF CHRONIC OBSTRUCTIVE
LUNG DISEASE
CLINICAL
Mucous
Bronchial MANIFESTATIONS BRONCHITIS EMPHYSEMA
plug
Muscle walls Productive cough Classic sign Late in course with infection
collapse
Dyspnea Late in course Common
Wheezing Intermittent Common
History of smoking Common Common
Barrel chest Occasionally Classic
Prolonged expiration Always present Always present
Cyanosis Common Uncommon
Chronic hypoventilation Common Late in course
Polycythemia Common Late in course
Cor pulmonale Common Late in course

The lung’s defense mechanisms are, therefore, compromised, increas-

ing susceptibility to pulmonary infection and injury. Frequent infec-
tious exacerbations are complicated by bronchospasm with dyspnea
Alveolar walls and productive cough.45 The pathogenesis of chronic bronchitis is
shown in Figure 26-10.
FIGURE 26-11  Mechanisms of Air Trapping in COPD. Mucous
plugs and narrowed airways cause air trapping and hyperinflation Initially this process affects only the larger bronchi, but eventually
of alveoli on expiration. During inspiration, the airways are pulled all airways are involved. The thick mucus and hypertrophied bronchial
open, allowing gas to flow past the obstruction. During expiration, smooth muscle constrict the airways and lead to obstruction, particu-
decreased elastic recoil of the bronchial walls results in collapse of larly during expiration when the airways are narrowed (Figure 26-11).
the airways and prevents normal expiratory airflow. Obstruction eventually leads to ventilation-perfusion mismatch with
hypoxemia. The airways collapse early in expiration, trapping gas in
Its pulmonary component is characterized by airflow limitation that the distal portions of the lung. Air trapping expands the thorax and
is not fully reversible. The airflow limitation is usually progressive and positions the respiratory muscles at a mechanical disadvantage. This
associated with an abnormal inflammatory response of the lung to leads to decreased tidal volume, hypoventilation, and hypercapnia.
noxious particles or gases.41 COPD is the fourth leading cause of death
in the United States and is the sixth leading cause of death worldwide. CLINICAL MANIFESTATIONS  Table 26-2 lists the common clinical
Overall mortality from COPD has increased in the United States over manifestations of chronic obstructive lung disease, chronic bronchitis,
the past 30 years; however, COPD mortality in women has increased and emphysema.
more than twice that amount.42 Risk factors for COPD include tobacco
smoke (cigarette, pipe, cigar, and environmental tobacco smoke), occu- EVALUATION AND TREATMENT  Diagnosis is based on physical
pational dusts and chemicals (vapors, irritants, and fumes), indoor air examination, chest radiograph, pulmonary function tests, and blood
pollution from biomass fuel used for cooking and heating (in poorly gas analyses; these tests reflect the progressive nature of the disease.
vented dwellings), outdoor air pollution, and any factor that affects Prevention of chronic bronchitis is essential because pathologic
lung growth during gestation and childhood (low birthweight, respi- changes are not reversible. By the time an individual seeks medical care
ratory tract infections).41 Genetic susceptibilities have been identified for symptoms, considerable airway damage is present. If the individual
including polymorphisms of genes that code for tumor necrosis factor, stops smoking, disease progression can be halted.
surfactant, proteases, and antiproteases.43 An inherited mutation in the Bronchodilators and expectorants are prescribed as needed to con-
α1-antitrypsin gene results in the development of COPD at an early age, trol cough and reduce dyspnea. Chest physical therapy may be help-
even in individuals who do not smoke. ful and includes deep breathing and postural drainage.41 During acute
exacerbations (infection and bronchospasm), individuals require
Chronic Bronchitis treatment with antibiotics and steroids and may need mechanical
COPD includes the pathologic lung changes consistent with emphy- ventilation.45 Chronic use of oral steroids may be needed late in the
sema or chronic bronchitis. Chronic bronchitis is defined as hyperse- course of the disease but should be considered a last resort. Individuals
cretion of mucus and chronic productive cough for at least 3 months with severe hypoxemia will require home oxygen therapy. Teaching
of the year (usually the winter months) for at least 2 consecutive years. includes nutritional counseling, respiratory hygiene, recognition of the
early signs of infection, and techniques that relieve dyspnea, such as
PATHOPHYSIOLOGY  Inspired irritants result in airway inflamma- pursed-lip breathing.
tion with infiltration of neutrophils, macrophages, and lymphocytes
into the bronchial wall. Continual bronchial inflammation causes Emphysema
bronchial edema and increases the size and number of mucous glands Emphysema is abnormal permanent enlargement of gas-exchange
and goblet cells in the airway epithelium. Thick, tenacious mucus is airways (acini) accompanied by destruction of alveolar walls without
produced and cannot be cleared because of impaired ciliary function.44 obvious fibrosis. Obstruction results from changes in lung tissues,
694 CHAPTER 26  Alterations of Pulmonary Function

CLINICAL MANIFESTATIONS  The clinical manifestations of

emphysema are listed in Table 26-2.

EVALUATION AND TREATMENT  Pulmonary function testing, chest

x-ray, high-resolution computed tomography (CT), and arterial blood
gas measurements are used to diagnose emphysema. Pulmonary func-
tion measurements, especially FEV1 values, also are helpful in deter-
mining the stage of disease, appropriate treatment, and prognosis.
Chronic management of emphysema begins with smoking cessation.
Pharmacologic management is based on clinical severity (mild, mod-
erate, severe, or very severe).41 Inhaled anticholinergic agents and beta
agonists should be prescribed.47 Inhaled corticosteroids are indicated
for severe COPD, although long-term therapy with oral steroids should
be avoided if possible. Pulmonary rehabilitation, improved nutrition,
and breathing techniques all can improve symptoms. Progressive pul-
FIGURE 26-12  Bullous Emphysema with Large Apical and Sub- monary dysfunction with hypoxemia and hypercapnia may require
pleural Bullae (see arrows). (From Kumar V et al, editors: Robbins long-term oxygen therapy and ventilation if indicated.41 A class of
basic pathology, ed 8, Philadelphia, 2007, Saunders/Elsevier.) drugs called phosphodiesterase E4 (PDE4) inhibitors are proving to be
effective in selected individuals with severe COPD.48 Selected individu-
rather than mucus production and inflammation as in chronic bron- als with severe emphysema can benefit from lung reduction surgery or
chitis. The major mechanism of airflow limitation is loss of elastic lung transplantation.
recoil (see Figure 26-11).
Primary emphysema, which accounts for 1% to 3% of all cases
of emphysema, is commonly linked to an inherited deficiency of the
enzyme α1-antitrypsin, which is a major component of α1-globulin, a
4 QUICK CHECK 26-4
1. What mechanisms cause airway obstruction in asthma?
plasma protein. Normally α1-antitrypsin inhibits the action of many 2. How does emphysema affect oxygenation and ventilation?
proteolytic enzymes; therefore α1-antitrypsin deficiency (an autoso- 3. Define chronic bronchitis.
mal recessive trait) produces an increased likelihood of developing
emphysema because proteolysis in lung tissues is not inhibited. α1-
Antitrypsin deficiency is suggested in individuals who develop emphy-
sema before 40 years of age and in individuals who do not smoke but Respiratory Tract Infections
still develop the disease. The major cause of secondary emphysema is Respiratory tract infections are the most common cause of short-term
the inhalation of cigarette smoke, although air pollution, occupational disability in the United States. Most of these infections—the common
exposures, and childhood respiratory tract infections are known to be cold, pharyngitis (sore throat), and laryngitis—involve only the upper
contributing factors. airways. Although the lungs have direct contact with the atmosphere,
they usually remain sterile. Infections of the lower respiratory tract
PATHOPHYSIOLOGY  Emphysema begins with destruction of alveo- occur most often in individuals whose normal defense mechanisms are
lar septa, which eliminates portions of the pulmonary capillary bed impaired.
and increases the volume of air in the acinus. It is postulated that
inhaled oxidants in tobacco smoke and air pollution inhibit the activ- Pneumonia
ity of endogenous antiproteases and stimulate inflammation with Pneumonia is infection of the lower respiratory tract caused by
increased activity of the proteases (e.g., elastase). Thus the balance is bacteria, viruses, fungi, protozoa, or parasites. It is the sixth lead-
tipped toward alveolar destruction and loss of the normal elastic recoil ing cause of death in the United States. The incidence and mortality
of the bronchi (see Figure 26-10). Cellular apoptosis and early cellu- of pneumonia are highest in the elderly. Risk factors for pneumo-
lar senescence contribute to loss of alveolar cells and reduced surface nia include advanced age, compromised immunity, underlying lung
area for gas exchange.46 Alveolar destruction also produces large air disease, alcoholism, altered consciousness, impaired swallowing,
spaces within the lung parenchyma (bullae) and air spaces adjacent smoking, endotracheal intubation, malnutrition, immobilization,
to pleurae (blebs) (Figure 26-12). Bullae and blebs are not effective underlying cardiac or liver disease, and residence in a nursing home.
in gas exchange and result in significant ventilation-perfusion ( V̇ / Q̇) Individuals who live in poverty also are at significantly increased risk
mismatching and hypoxemia. Expiration becomes difficult because for pneumonia.49 The causative microorganism influences how the
loss of elastic recoil reduces the volume of air that can be expired pas- individual presents clinically, how the pneumonia should be treated,
sively and air is trapped in the lungs (see Figure 26-11). Air trapping and the prognosis. Community-acquired pneumonia (CAP) tends
causes hyperexpansion of the chest, placing the muscles of respiration to be caused by different microorganisms as compared with those
at a mechanical disadvantage. This results in increased workload of infections acquired in the hospital (nosocomial). In addition, the
breathing, so that late in the course of disease, many individuals will characteristics of the individual are important in determining which
develop hypoventilation and hypercapnia. Persistent inflammation etiologic microorganism is likely; for example, immunocompromised
in the airways can result in hyperreactivity of the bronchi with bron- individuals tend to be susceptible to opportunistic infections that are
choconstriction, which may be partially reversible with bronchodila- uncommon in normal adults. In general, nosocomial infections and
tors. Chronic inflammation also can have significant systemic effects those affecting immunocompromised individuals have a higher mor-
including weight loss, muscle weakness, and increased susceptibility to tality than CAPs. Some of the most common causal microorganisms
comorbidities, such as infection. are included in the list at the top of p. 695.
 CHAPTER 26  Alterations of Pulmonary Function 695

COMMUNITY- IMMUNO­ HEALTH ALERT

ACQUIRED NOSOCOMIAL COMPROMISED
Ventilator-Associated Pneumonia (VAP)
PNEUMONIA (CAP) PNEUMONIA INDIVIDUALS
Streptococcus Pseudomonas Pneumocystis jiroveci Ventilator-associated pneumonia (VAP) is a common complication of mechani-
­pneumoniae aeruginosa cal ventilation and is the most serious infection in the intensive care unit. Mor-
tality ranges from 15% to 70% depending on the underlying condition of the
Mycoplasma ­pneumoniae Staphylococcus Mycobacterium affected individual. Risk factors include age greater than 65 years, presence of
aureus ­tuberculosis comorbidities, length of intubation time, use of sedation, supine posture, poor
Haemophilus ­influenzae Klebsiella Atypical mycobacteria oral hygiene, and immunocompromised status. Common etiologic microorgan-
­pneumoniae isms include Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella
Oral anaerobic bacteria Escherichia coli Fungi species, Escherichia coli, Acinetobacter species, and Enterobacter species.
Multidrug-resistant strains are common. Bacterial colonization of the orophar-
Influenza virus Respiratory viruses ynx occurs soon after placement of the endotracheal (ET) tube with subsequent
Respiratory ­syncytial aspiration and pooling of bacteria near the ET tube cuff. Many bacteria are
virus capable of forming a protective coating, called a biofilm, on the surface of the
Staphylococcus aureus Protozoa ET tube that contributes to bacterial replication and makes microorganisms
Chlamydia ­pneumoniae Parasites less vulnerable to antibiotics. Injury to the tracheal mucosa and decreased
mucociliary clearance contribute to lower airway infection. Implementation
Moraxella catarrhalis of certain treatment protocols has shown improved outcomes regarding VAP
prevention and mortality reduction, especially the use of a “bundle” of tech-
niques including raising the head of the bed, improving oral hygiene, provid-
The most common community-acquired pneumonia is caused ing continuous suction of subglottic secretions by antimicrobial-impregnated
by Streptococcus pneumoniae (also known as pneumococcus), which ET tubes, instilling saline before suctioning and rapidly instituting antibiotic
results in hospitalization in more than half of affected individuals and therapy, using checklists, and encouraging effective team communication.
an overall hospital mortality of 10%.50 Mycoplasma pneumoniae is a
common cause of pneumonia in young people, especially those liv- Data from Blamoun J et al: Efficacy of an expanded ventilator bundle
ing in group housing such as dormitories and army barracks. Com- for the reduction of ventilator-associated pneumonia in the medical
munity-acquired methicillin-resistant Staphylococcus aureus (MRSA) intensive care unit, Am J Infect Control 37:172–175, 2009; Lipitz-
is becoming more common.51,52 Influenza and respiratory syncytial Snyderman A et al: Impact of a statewide intensive care unit qual-
virus are the most common causes of viral community-acquired pneu- ity improvement initiative on hospital mortality and length of stay:
monia in adults.53 Nosocomial pneumonia is a frequent complication retrospective comparative analysis, Br Med J 342:d219, 2011; Lorente
L, Blot S, Rello J: New issues and controversies in the prevention
in the intensive care unit, most often in persons placed on mechani-
of ventilator-associated pneumonia, Am J Respir Crit Care Med
cal ventilation (ventilator-associated pneumonia [VAP]) (see Health
182(7):870–876, 2010; Palmer LB: Ventilator-associated infection, Curr
Alert: Ventilator-Associated Pneumonia [VAP]). Pseudomonas aerugi- Opin Pulmon Med 15(3):230–235, 2009; Jones RN: Microbial etiolo-
nosa, other gram-negative microorganisms, and Staphylococcus aureus gies of hospital-acquired bacterial pneumonia and ventilator-associated
(including MRSA) are the most common etiologic agents in nosoco- bacterial pneumonia, Clin Infect Dis 51(suppl 1):S81–S87, 2010;
mial pneumonia. Immunocompromised individuals (e.g., those with Vincent JL et al: Diagnosis, management and prevention of ventilator-
human ­immunodeficiency virus [HIV] or those undergoing organ associated pneumonia: an update, Drugs 70(15):1927–1944, 2010.
transplantation) are especially susceptible to Pneumocystis jiroveci (for-
merly called P. carinii), mycobacterial infections, and fungal infections
of the respiratory tract. These infections can be difficult to treat and aureus). The most important guardian cell of the lower respiratory
have a high mortality. tract is the alveolar macrophage; it recognizes pathogens through its
pattern-recognition receptors (e.g., Toll-like receptors) and then acti-
PATHOPHYSIOLOGY  Aspiration of oropharyngeal secretions is the vates both innate and adaptive immune responses. Release of tumor
most common route of lower respiratory tract infection; thus, the necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) from mac-
nasopharynx and oropharynx constitute the first line of defense for rophages contributes to widespread inflammation in the lung and
most infectious agents. Another route of infection is through the inha- recruitment of neutrophils from the capillaries of the lungs into the
lation of microorganisms that have been released into the air when alveoli. Macrophages also present infectious antigens to the adaptive
an infected individual coughs, sneezes, or talks, or from aerosolized immune system, activating T cells and B cells with the induction of
water such as that from contaminated respiratory therapy equipment. both cellular and humoral immunity. The resulting inflammatory
This route of infection is most important in viral and mycobacterial mediators and immune complexes can damage bronchial mucous
pneumonias and in Legionella outbreaks. Pneumonia also can occur membranes and alveolocapillary membranes, causing the acini and
when bacteria are spread to the lung in the blood from bacteremia terminal bronchioles to fill with infectious debris and exudate. In
that can result from infection elsewhere in the body or from IV drug addition, some microorganisms release toxins from their cell walls that
abuse. can cause further lung damage and consolidation of lung tissue. The
In healthy individuals, pathogens that reach the lungs are expelled accumulation of exudate in the acinus leads to dyspnea and to V̇ / Q̇
or controlled by mechanisms of self-defense (see Chapters 5, 6, and 7). mismatching and hypoxemia.
If a microorganism evades the upper airway defense mechanisms, such Pneumococcal pneumonia. Pneumococci can infect the lungs
as the cough reflex and mucociliary clearance, the next line of defense through inhalation of aerosolized bacteria or more commonly by aspi-
is the airway epithelial cell. Airway epithelial cells can recognize some ration of colonized oropharyngeal secretions. These bacteria have sev-
pathogens directly (e.g., Pseudomonas aeruginosa and Staphylococcus eral virulence factors; most importantly, they have capsules that make
696 CHAPTER 26  Alterations of Pulmonary Function

Aspiration of Streptococcus pneumoniae

Adherence to
alveolar macrophages:
exposure of cell wall
components

Inflammatory response:
attraction of neutrophils;
release of inflammatory mediators;
accumulation of fibrinous exudate,
red blood cells, and bacteria

Gray hepatization and

Red hepatization Leukocyte infiltration deposition of fibrin on
and consolidation
(neutrophils and pleural surfaces;
of lung parenchyma
macrophages) phagocytosis in alveoli

Resolution of infection:
macrophages in alveoli ingest
and remove degenerated neutrophils,
fibrin, and bacteria
FIGURE 26-13  Pathophysiologic Course of Pneumococcal Pneumonia.

phagocytosis by alveolar macrophages more difficult and they have EVALUATION AND TREATMENT  Diagnosis is made on the basis of
the ability to release a variety of toxins, including pneumolysin, which physical examination, white blood cell count, chest x-ray, stains and
damages airway and alveolar cells.54 An intense inflammatory response cultures of respiratory tract secretions, and blood cultures. The white
is initiated with release of TNF-α and IL-1. Neutrophils and inflamma- blood cell count is usually elevated, although it may be low if the indi-
tory exudates cause alveolar edema, which leads to the other changes vidual is debilitated or immunocompromised. Serum biologic markers
shown in Figure 26-13. are increasingly being used to differentiate bacterial from other causes
Viral pneumonia. Viral pneumonia is usually mild and self- of pneumonia (see Health Alert: Serum Biomarkers for the Diagnosis
limiting but can set the stage for a secondary bacterial infection by of Pneumonia). Chest radiographs show infiltrates that may involve a
damaging ciliated epithelial cells, which normally prevent patho- single lobe of the lung or may be more diffuse. Once the diagnosis of
gens from reaching the lower airways. Influenza pneumonia can be pneumonia has been made, the pathogen is identified by means of spu-
severe, especially influenza A of the H1N1 type.55 Immunocompro- tum characteristics (Gram stain, color, odor) and cultures or, if sputum
mised individuals are at risk for very serious viral infections, such as is absent, blood cultures. Because many pathogens exist in the normal
pneumonia caused by cytomegalovirus. Viral pneumonia also can be oropharyngeal flora, the specimen may be contaminated with patho-
a complication of another viral illness, such as chickenpox or measles gens from oral secretions. If sputum studies fail to identify the pathogen,
(spread from the blood). Viruses destroy the ciliated epithelial cells the individual is immunocompromised, or the individual’s condition
and invade the goblet cells and bronchial mucous glands. Sloughing worsens, further diagnostic studies may include bronchoscopy or lung
of destroyed bronchial epithelium occurs throughout the respira- biopsy. Positive identification of viruses can be difficult. Blood cultures
tory tract, preventing mucociliary clearance. Bronchial walls become often help to identify the virus if systemic disease is present.
edematous and infiltrated with leukocytes. In severe cases, the alve- Prevention of pneumonia includes prevention of aspiration, respi-
oli are involved with decreased compliance and increased work of ratory isolation of immunocompromised individuals, and vaccina-
breathing. tion for appropriate populations. The first step in the management
of pneumonia is establishing adequate ventilation and oxygenation.
CLINICAL MANIFESTATIONS  Many cases of pneumonia are pre- Adequate hydration and good pulmonary hygiene (e.g., deep breath-
ceded by a viral upper respiratory tract infection. Individuals then ing, coughing, chest physical therapy) also are important. Antibiotics
develop fever, chills, productive or dry cough, malaise, pleural pain, are used to treat bacterial pneumonia; however, resistant strains of
and sometimes dyspnea and hemoptysis. Physical examination may pneumococci, staphylococci, and gram-negative bacteria are becom-
show signs of pulmonary consolidation, such as dullness to percus- ing more prevalent.56,57 Empiric antibiotics are chosen based on the
sion, inspiratory crackles, increased tactile fremitus, egophony, and likely causative microorganism, although the toxicity of using multiple
whispered pectoriloquy. Individuals also may demonstrate symptoms broad-spectrum antibiotics must be considered.58 Viral pneumonia
and signs of underlying systemic disease or sepsis. is usually treated with supportive therapy alone; however, antivirals
 CHAPTER 26  Alterations of Pulmonary Function 697

These phagocytes engulf the bacilli and begin the process by which the
HEALTH ALERT
body’s defense mechanisms isolate the bacilli, preventing them from
Serum Biomarkers for the Diagnosis of Pneumonia spreading. The neutrophils and macrophages seal off the colonies of
Measurement of serum biomarkers can help to determine the infectious etiol-
bacilli, forming a granulomatous lesion called a tubercle (see Chapter
ogy of pneumonia. The two most widely used biomarkers are procalcitonin
5). Infected tissues within the tubercle die, forming cheeselike material
(PCT) and C-reactive protein (CRP). PCT is produced by the liver, kidneys, and
called caseation necrosis. Collagenous scar tissue then grows around the
monocytes after stimulation by proinflammatory cytokines and by bacterial
tubercle, completing isolation of the bacilli. The immune response is
products. CRP is produced by the liver in response to proinflammatory cyto-
complete after about 10 days, preventing further multiplication of the
kines. In individuals with pneumonia, low levels of PCT (<0.1 mcg/L) or CRP
bacilli.
(<40 mg/L) make bacterial infection unlikely, suggesting either viral, fungal,
Once the bacilli are isolated in tubercles and immunity develops,
or noninfectious causes for the individual’s symptoms. An increase in the lev-
tuberculosis may remain dormant for life. If the immune system is
els of serum PCT (>1.0 mcg/L) or CRP (>200 mg/L) makes bacterial infection
impaired, reactivation with progressive disease occurs and may spread
highly likely. Recent studies suggest that measurement of low procalcitonin
through the blood and lymphatics to other organs. Infection with
levels prevents the inappropriate use of antibiotics for nonbacterial pneumo-
human immunodeficiency virus (HIV) is the single greatest risk factor
nia. Other serum biomarkers, such as interleukin-1β, interleukin-8, proadre-
for reactivation of tuberculosis infection. Cancer, immunosuppressive
nomedullin, pro-atrial natriuretic peptide, pro-vasopressin, and copeptin, are
medications (e.g., corticosteroids), poor nutritional status, and renal
being explored.
failure can also reactivate disease.59

Data from Bellmann-Weiler R et al: Clinical potential of C-reactive CLINICAL MANIFESTATIONS  LTBI is asymptomatic. Symptoms
protein and procalcitonin serum concentrations to guide differential of active disease often develop so gradually that they are not noticed
diagnosis and clinical management of pneumococcal and Legionella until the disease is advanced. Common clinical manifestations include
pneumonia, J Clin Microbiol 48(5):1915–1917, 2010; Brown JS: Bio- fatigue, weight loss, lethargy, anorexia (loss of appetite), and a low-
markers and community-acquired pneumonia, Thorax 64(7):556–558, grade fever that usually occurs in the afternoon. A cough that produces
2009; Conway Morris A et al: Diagnostic importance of pulmonary purulent sputum develops slowly and becomes more frequent over
interleukin-1beta and interleukin-8 in ventilator-associated pneumonia, several weeks or months. Night sweats and general anxiety are often
Thorax 65(3):201–207, 2010; Heppner HJ et al: Procalcitonin: inflam-
present. Dyspnea, chest pain, and hemoptysis may occur as the disease
matory biomarker for assessing the severity of community-acquired
pneumonia—a clinical observation in geriatric patients, Gerontology
progresses. Extrapulmonary TB disease is common in HIV-infected
56(4):385–389, 2010; Kruger S et al: Pro-atrial natriuretic peptide and individuals and may cause neurologic deficits, meningitis symptoms,
pro-vasopressin for predicting short-term and long-term survival in bone pain, and urinary symptoms.
community-acquired pneumonia: results from the German Compe-
tence Network CAPNETZ, Thorax 65(3):208–214, 2010; Torres A, Rello EVALUATION AND TREATMENT  Tuberculosis is diagnosed by a
J: Update in community-acquired and nosocomial pneumonia 2009, positive tuberculin skin test (TST; purified protein derivative [PPD]),
Am J Respir Crit Care Med 181(8):782–787, 2010. sputum culture, immunoassays, and chest radiographs.60 A positive
skin test indicates the need for yearly chest radiographs to detect active
may be needed in severe cases. Infections with opportunistic microor- disease. When active pulmonary disease is present, the tubercle bacil-
ganisms may be polymicrobial and require multiple drugs, including lus can be cultured from the sputum and may be seen with an acid-
antifungals. fast stain. However, sputum culture can take up to 6 weeks to become
positive.
Tuberculosis Treatment consists of antibiotic therapy to control active disease
Tuberculosis (TB) is an infection caused by Mycobacterium tuberculo- or prevent reactivation of LTBI. Recommended treatment includes a
sis, an acid-fast bacillus that usually affects the lungs but may invade combination of as many as four different drugs to which the organ-
other body systems. Tuberculosis is the leading cause of death from a ism is susceptible. Side effects are common and new drugs are being
curable infectious disease in the world. TB cases increased greatly dur- explored.61 Two worrisome treatment categories of TB have become
ing the mid-1990s as a result of acquired immunodeficiency syndrome more prevalent in recent years. “Multidrug-resistant TB” now accounts
(AIDS). Emigration of infected individuals from high-prevalence for approximately 5% of cases worldwide. Even more concerning is the
countries, transmission in crowded institutional settings, homeless- emergence of “extensively drug-resistant TB” for which finding effec-
ness, substance abuse, and lack of access to medical care also have con- tive treatment is even more difficult.62,63
tributed to the spread of TB.
Acute Bronchitis
PATHOPHYSIOLOGY  Tuberculosis is highly contagious and is trans- Acute bronchitis is acute infection or inflammation of the airways
mitted from person to person in airborne droplets.59 In immunocom- or bronchi and is usually self-limiting. In the vast majority of cases,
petent individuals, the microorganism is usually contained by the acute bronchitis is caused by viruses. Bacterial bronchitis is rare in
inflammatory and immune response systems. This results in latent TB healthy adults but is common in individuals with COPD. Although
infection (LTBI) and is associated with no clinical evidence of disease. many of the clinical manifestations are similar to those of pneumonia
Microorganisms lodge in the lung periphery, usually in the upper lobe. (i.e., fever, cough, chills, malaise), chest radiographs show no infil-
Some bacilli migrate through the lymphatics and become lodged in trates. Individuals with viral bronchitis present with a nonproductive
the lymph nodes, where they encounter lymphocytes and initiate the cough that often occurs in paroxysms and is aggravated by cold, dry,
immune response. or dusty air. In some cases, purulent sputum is produced. Chest pain
Once the bacilli are inspired into the lung, they multiply and cause often develops from the effort of coughing. Treatment consists of rest,
localized nonspecific pneumonitis (lung inflammation). Inflammation aspirin, humidity, and a cough suppressant, such as codeine. Bacterial
in the lung causes activation of alveolar macrophages and neutrophils. bronchitis is treated with rest, antipyretics, humidity, and antibiotics.
698 CHAPTER 26  Alterations of Pulmonary Function

Abscess Formation and Cavitation

Venous stasis
An abscess is a circumscribed area of suppuration and destruction of Vessel injury
lung parenchyma. Abscess formation follows consolidation of lung tissue, Hypercoagulability
in which inflammation causes alveoli to fill with fluid, pus, and microor-
ganisms. Aspiration abscess can occur from aspiration of anaerobes, such
as those found in individuals who have pneumonia or who are infected
with Klebsiella or Staphylococcus. Aspiration abscess is usually associated Thrombus formation
with alcohol abuse, seizure disorders, general anesthesia, and swallowing
disorders. Necrosis (death and decay) of consolidated tissue may pro­
gress proximally until it communicates with a bronchus. Cavitation is
Dislodgement of portion of thrombus
the process of the abscess emptying into a bronchus and cavity formation.
Abscess communication with a bronchus causes production of copious
amounts of often foul-smelling sputum, and occasionally hemoptysis.
Other clinical manifestations include fever, cough, chills, and pleural Occlusion of part of pulmonary circulation
pain. The diagnosis is made by chest radiography. Treatment includes
appropriate antibiotics and chest physical therapy (chest percussion and
postural drainage). Bronchoscopy may be performed to drain the abscess.
Hypoxic vasoconstriction
4 QUICK CHECK 26-5
Decreased surfactant
Release of neurohumoral and inflammatory substances
1. Compare pneumococcal and viral pneumonia as to severity of disease.
Pulmonary edema
2. Describe the pathophysiologic features of tuberculosis. Atelectasis
3. How does lung abscess present clinically?

Pulmonary Vascular Disease

Tachypnea
Blood flow through the lungs can be disrupted by disorders that
Dyspnea
occlude the vessels, increase pulmonary vascular resistance, or destroy
Chest pain
the vascular bed. Effects of altered pulmonary blood flow may range
Increased dead space
from insignificant dysfunction to severe and life-threatening changes • •
V/Q imbalances
in ventilation-perfusion ratios. Major disorders include pulmonary
Decreased PaO2
embolism, pulmonary hypertension, and cor pulmonale.
Pulmonary infarction
Pulmonary Embolism Pulmonary hypertension
Decreased cardiac output
Pulmonary embolism (PE) is occlusion of a portion of the pulmonary
Systemic hypotension
vascular bed by an embolus. PE most commonly results from embo-
Shock
lization of a clot from deep venous thrombosis involving the lower
leg (see Chapter 23). Other less common emboli include tissue frag-
FIGURE 26-14  Pathogenesis of Massive Pulmonary Embolism
ments, lipids (fats), a foreign body, or an air bubble. Risk factors for Caused by a Thrombus (Pulmonary Thromboembolism).
PE include conditions and disorders that promote blood clotting as a
result of venous stasis (immobilization, heart failure), hypercoagula-
bility (inherited coagulation disorders, malignancy, hormone replace-
ment therapy, oral contraceptives), and injuries to the endothelial cells Significant obstruction of the pulmonary vasculature leads to
that line the vessels (trauma, caustic intravenous infusions). Genetic increased pulmonary artery pressures (pulmonary hypertension). The
risks include factor V Leiden, antithrombin II, protein S, protein C, pathogenesis of pulmonary embolism caused by a thrombus is sum-
and prothrombin gene mutations. No matter its source, a blood clot marized in Figure 26-14.
becomes an embolus when all or part of it detaches from the site of If the embolus does not cause infarction, the clot is dissolved by
formation and begins to travel in the bloodstream. the fibrinolytic system and pulmonary function returns to normal. If
pulmonary infarction occurs, shrinking and scarring develop in the
PATHOPHYSIOLOGY  The impact or effect of the embolus depends affected area of the lung.
on the extent of pulmonary blood flow obstruction, the size of the
affected vessels, the nature of the embolus, and the secondary effects. CLINICAL MANIFESTATIONS  In most cases, the clinical manifesta-
Pulmonary emboli can occur as any of the following: tions of PE are nonspecific, so evaluation of risk factors and predispos-
1. Embolus with infarction: an embolus that causes infarction (death) ing factors is an important aspect of diagnosis. Although most emboli
of a portion of lung tissue originate from clots in the lower extremities, deep vein thrombosis is
2. Embolus without infarction: an embolus that does not cause perma- often asymptomatic, and clinical examination has low sensitivity for
nent lung injury (perfusion of the affected lung segment is main- the presence of clot, especially in the thigh.
tained by the bronchial circulation) An individual with PE usually presents with the sudden onset of
3. Massive occlusion: an embolus that occludes a major portion of the pleuritic chest pain, dyspnea, tachypnea, tachycardia, and unexplained
pulmonary circulation (i.e., main pulmonary artery embolus) anxiety. Occasionally syncope (fainting) or hemoptysis occurs. With
4. Multiple pulmonary emboli: multiple emboli may be chronic or large emboli, a pleural friction rub, pleural effusion, fever, and leu-
recurrent kocytosis may be noted. Recurrent small emboli may not be detected
 CHAPTER 26  Alterations of Pulmonary Function 699

until progressive incapacitation, precordial pain, anxiety, dyspnea, and COPD

right ventricular enlargement are exhibited. Massive occlusion causes Interstitial fibrosis
severe pulmonary hypertension and shock. Obesity-hypoventilation syndrome

EVALUATION AND TREATMENT  Routine chest radiographs and

pulmonary function tests are not definitive for pulmonary embolism. Chronic hypoxemia
Arterial blood gas analyses usually demonstrate hypoxemia and hyper- Chronic acidosis
ventilation (respiratory alkalosis). The diagnosis is made by measuring
elevated levels of D-dimer in the blood in combination with scanning
using spiral computed tomography (CT). Serum brain natriuretic pep- Pulmonary artery
vasoconstriction
tide levels are increased in PE and levels are correlated with the severity
of associated hemodynamic complications.64
Prevention of PE depends on elimination of predisposing factors
Increased pulmonary
for individuals at risk. Venous stasis in hospitalized persons is mini- Progression of pulmonary artery pressure
mized by leg elevation, bed exercises, position changes, early postoper- hypertension can be
ative ambulation, and pneumatic calf compression. Clot formation is reversed at this point
also prevented by prophylactic low-dose anticoagulant therapy usually with effective treatment
of primary or underlying
with low-molecular-weight heparin or warfarin. Newer medications disease Intimal fibrosis and hypertrophy
such as the antithrombotics fondaparinux, idraparinux, and ximela- of medial smooth muscle layer
gatran are superior to standard prevention in high-risk individuals of pulmonary arteries
undergoing orthopedic surgery.
Anticoagulant therapy is the primary treatment for pulmonary
embolism. Initial anticoagulant therapy usually includes low-molec- Chronic pulmonary hypertension
ular-weight heparins (e.g., enoxaparin), fondaparinux, or unfraction-
ated heparin.64,65 If a massive life-threatening embolism occurs, a
fibrinolytic agent, such as streptokinase, is sometimes used, and some Cor pulmonale (hypertrophy
individuals will require surgical thrombectomy. After stabilization, and dilation of right ventricle)
coumadin or low-molecular-weight heparin is continued for several
months.
Right heart failure
Pulmonary Hypertension
Pulmonary hypertension is defined as a mean pulmonary artery pres- FIGURE 26-15  Pathogenesis of Pulmonary Hypertension and
Cor Pulmonale.
sure >25 mm Hg. Pulmonary hypertension is classified into several
categories66:
1. Pulmonary arterial hypertension (PAH) that is idiopathic, heri- Pulmonary hypertension associated with lung respiratory disease or
table, drug or toxin induced (weight loss medications, amphet- hypoxia, or both, is a serious complication of many acute and chronic
amines, cocaine), or associated with other conditions, such as HIV pulmonary disorders, such as COPD, fibrosis, and hypoventilation
infection and collagen vascular diseases associated with obesity. These conditions are complicated by hypoxic
2. Pulmonary hypertension associated with left heart diseases (dis- pulmonary vasoconstriction that further increases pulmonary artery
cussed in Chapters 23 and 24) pressures. Acute pulmonary hypertension will resolve if the underlying
3. Pulmonary hypertension associated with lung respiratory disease condition can be reversed quickly. In chronic conditions where hyper-
or hypoxia, or both tension persists, hypertrophy occurs in the medial smooth muscle layer
4. Chronic thromboembolic pulmonary hypertension of the arterioles. The larger arteries stiffen and hypertension progresses,
5. Pulmonary hypertension with unclear and/or multifactorial causing right ventricular hypertrophy and eventually cor pulmonale.
mechanisms The pathogenesis of pulmonary hypertension and cor pulmonale result-
ing from disease of the respiratory system is shown in Figure 26-15.
PATHOPHYSIOLOGY  Idiopathic pulmonary arterial hypertension
(IPAH) is a rare condition and usually occurs in women between the CLINICAL MANIFESTATIONS  Pulmonary hypertension may not be
ages of 20 and 40. IPAH is characterized by endothelial dysfunction detected until it is quite severe. The symptoms are often masked by
with overproduction of vasoconstrictors, such as thromboxane and other forms of pulmonary or cardiovascular disease. The first indica-
endothelin, and decreased production of vasodilators, such as pros- tion of pulmonary hypertension may be an abnormality seen on a chest
tacyclin. Vascular growth factors are released that cause changes in radiograph (enlarged right heart border) or an electrocardiogram that
the vascular smooth wall called remodeling. Angiotensin II, serotonin, shows right ventricular hypertrophy. Manifestations of fatigue, chest
electrolyte transporter mechanisms, and nitric oxide also play a role in discomfort, tachypnea, and dyspnea (particularly with exercise) are
the pathogenesis of this disorder. Together, this results in fibrosis and common. Examination may reveal peripheral edema, jugular venous
thickening of vessel walls (arteriopathy) with luminal narrowing and distention, a precordial heave, and accentuation of the pulmonary
abnormal vasoconstriction.67 These changes cause resistance to pul- component of the second heart sound.
monary artery blood flow, thus increasing the pressure in the pulmo-
nary arteries. As resistance and pressure increase, the workload of the EVALUATION AND TREATMENT  Definitive diagnosis of pulmo-
right ventricle increases and subsequent right ventricular hypertrophy, nary hypertension can be made only with right heart catheterization.
followed by failure, may occur (cor pulmonale). Common diagnostic modalities used to determine the cause include
700 CHAPTER 26  Alterations of Pulmonary Function

chest x-ray, echocardiography, and computed tomography. The diag-

nosis of IPAH is made when all other causes of pulmonary hyperten-
sion have been ruled out. Individuals with IPAH should be advised to
continue physical activity within symptom limits, and oxygen therapy
should be used for advanced stages. Diuretics, anticoagulants, digi-
talis, and calcium channel blockers may be used as general supportive
therapy. Prostacyclin analogs (epoprostenol, beraprost, iloprost) and
endothelin-receptor antagonists (ambrisentan, sitaxsentan, bosentan)
have been shown to reduce pulmonary artery pressures and improve
symptoms.66 Recent studies suggest that hydroxymethylglutaryl-coen-
zyme A (HMG-CoA) reductase inhibitors (statins) may also be help-
ful.67 Those individuals who do not achieve adequate clinical remission FIGURE 26-16  Lip Cancer. Carcinoma of lower lip with central
may require lung transplantation. ulceration and raised, rolled borders. (From del Regato JA, Spjut
The most effective treatment for pulmonary hypertension associ- HJ, Cox JD: Ackerman and del Regato’s cancer, ed 2, St Louis,
ated with lung respiratory disease or hypoxia, or both, is treatment 1985, Mosby.)
of the primary disorder. Supplemental oxygen may be indicated to
reverse hypoxic vasoconstriction.
BOX 26-1 STAGING OF LIP CANCER
Cor Pulmonale Stage I
Cor pulmonale is defined as right ventricular enlargement (hypertrophy, Primary tumor less than 2 cm: no palpable nodes
dilation, or both) caused by pulmonary hypertension (see Figure 26-15).
Stage II
PATHOPHYSIOLOGY  Cor pulmonale develops as pulmonary hyper- Primary tumor 2 to 4 cm; no palpable nodes
tension exerts chronic pressure overload in the right ventricle. Pressure
Stage III
overload increases the work of the right ventricle and causes hyper-
Primary tumor >4 cm; metastasis to lymph nodes
trophy of the normally thin-walled heart muscle. This eventually pro-
gresses to dilation and failure of the ventricle. Stage IV
Large primary tumors; nodes fixed to mandible or distant metastases
CLINICAL MANIFESTATIONS  The clinical manifestations of cor
pulmonale may be obscured by underlying respiratory or cardiac dis-
ease and appear only during exercise testing. The heart may appear PATHOPHYSIOLOGY  The most common form of lower lip cancer is
normal at rest, but with exercise, cardiac output falls. The electrocar- termed exophytic. The lesion usually develops in the outer part of the
diogram may show right ventricular hypertrophy. The pulmonary lip along the vermilion border. The lip becomes thickened and evolves
component of the second heart sound, which represents closure of to an ulcerated center with a raised border (Figure 26-16). Verrucous-
the pulmonic valve, may be accentuated, and a pulmonic valve mur- type lesions are less common. They have an irregular surface, follow
mur also may be present. Tricuspid valve murmur may accompany cracks in the lip, and tend to extend toward the inner surface. Squa-
the development of right ventricular failure. Increased pressures in the mous cell carcinoma is the most common cell type. Basal cell carci-
systemic venous circulation cause jugular venous distention, hepato- noma does not develop unless there is extension from the mucous
splenomegaly, and peripheral edema. membrane or vermilion border of the lip.

EVALUATION AND TREATMENT  Diagnosis is based on physical CLINICAL MANIFESTATIONS  Malignant lesions are often preceded
examination, radiologic examination, electrocardiogram, and echo- by the development of a blister that evolves into a superficial ulceration
cardiography. The goal of treatment for cor pulmonale is to decrease that may bleed. Metastases to the cervical lymph nodes have a low rate
the workload of the right ventricle by lowering pulmonary artery pres- of occurrence (2% to 8%) and are more likely when the primary lesion
sure. Treatment is the same as that for pulmonary hypertension, and is larger and exists for a longer period.
its success depends on reversal of the underlying lung disease.
EVALUATION AND TREATMENT  Diagnosis is commonly made by
4 QUICK CHECK 26-6 clinical history and examination of the lesion. Biopsy confirms the
1. What factors influence the impact of an embolus? presence of malignant cells. The staging for lip cancer is summarized
2. List three causes of pulmonary hypertension. in Box 26-1. Surgical excision is usually effective for smaller lesions.
3. What is cor pulmonale? Larger lesions that require extensive resection may need subsequent
cosmetic surgeries. Interstitial irradiation and radioactive implants
have proven effective for control of primary lesions. The prognosis for
Malignancies of the Respiratory Tract recovery is excellent.
Lip Cancer
Cancer of the lip is more prevalent in men, with 3000 new cases per Laryngeal Cancer
year.68 Long-term exposure to sun, wind, and cold over a period of Cancer of the larynx represents approximately 2% to 3% of all cancers
years results in dryness, chapping, hyperkeratosis, and predisposition in the United States, with more than 12,000 new cases diagnosed in
to malignancy. In addition, immunosuppression, such as that seen in 2010.68 The primary risk factor for laryngeal cancer is tobacco smok-
individuals with renal transplants, increases the risk for lip cancer. The ing; risk is further heightened with the combination of smoking and
lower lip is the most common site. alcohol consumption. The human papillomavirus (HPV) also has been
 CHAPTER 26  Alterations of Pulmonary Function 701

A R L
B
FIGURE 26-17  Laryngeal Cancer. A, Mirror view of carcinoma of the right false cord partially hiding
the true cord. B, Lateral view. (Redrawn from del Regato JA, Spjut HJ, Cox JD: Ackerman and del
Regato’s cancer, ed 2, St Louis, 1985, Mosby.)

linked to both benign and malignant disease of the larynx.69 The high- common cause of cancer death in the United States and is responsible
est incidence is in men between 50 and 75 years of age. for 31% of all cancer deaths in men and 26% of all cancer deaths in
women. Overall 5-year survival remains low at 20%.
PATHOPHYSIOLOGY  Carcinoma of the true vocal cords (glottis) The most common cause of lung cancer is tobacco smoking. Smok-
is more common than that of the supraglottic structures (epiglottis, ers with obstructive lung disease (low FEV1 measurements) are at even
aryepiglottic folds, arytenoids, false cords). Tumors of the subglottic greater risk. Other risk factors for lung cancer include secondhand
area are rare. Squamous cell carcinoma is the most common cell type, (environmental) smoke, occupational exposures to certain workplace
although small cell carcinomas also occur (Figure 26-17). Metastasis toxins, radiation, and air pollution. Genetic risks include polymor-
develops by spread to the draining lymph nodes, and distant metastasis phisms of the genes responsible for growth factor receptors, DNA
is rare. repair, and detoxification of inhaled smoke.71
Types of lung cancer. Primary lung cancers arise from cells that
CLINICAL MANIFESTATIONS  The presenting symptoms of laryn- line the bronchi within the lungs and are therefore called broncho-
geal cancer include hoarseness, dyspnea, and cough. Progressive genic carcinomas. It is now believed that most of these cancers arise
hoarseness can result in voice loss. Dyspnea is rare with supraglottic from mutated epithelial stem cells.72 Although there are many types
tumors but can be severe in subglottic tumors. Cough may follow swal- of lung cancer, they can be divided into two major categories: non–
lowing. Laryngeal pain is likely with supraglottic lesions. small cell lung carcinoma (NSCLC) and neuroendocrine tumors of
the lung. The category of non–small cell lung carcinoma accounts for
EVALUATION AND TREATMENT  Evaluation of the larynx includes 75% to 85% of all lung cancers and can be subdivided into three types
external inspection and palpation of the larynx and the lymph nodes of lung cancer: squamous cell carcinoma, adenocarcinoma, and large
of the neck. Indirect laryngoscopy provides a stereoscopic view of the cell undifferentiated carcinoma. Neuroendocrine tumors of the lung
structure and movement of the larynx. A biopsy also can be obtained arise from the bronchial mucosa and include: small cell carcinoma,
during this procedure. Direct laryngoscopy provides more thorough large cell neuroendocrine carcinoma, typical carcinoid and atypical
visualization of the tumor. Computed tomography facilitates the carcinoid tumors.73 Small cell carcinoma is the most common of these
identification of tumor boundaries and the degree of extension to sur- neuroendocrine tumors, accounting for 15% to 20% of all lung can-
rounding tissue. cers. Characteristics of these tumors, including clinical manifestations,
Combined chemotherapy and radiation can result in cure in are listed in Table 26-3. Many cancers that arise in other organs of the
selected cases; however, sequelae such as swallowing and speech dif- body metastasize to the lungs; however, these are not considered lung
ficulties may result. Endoscopic laser for partial laryngectomies is cancers and are categorized by their primary site of origin.
emerging as the preferred treatment for small supraglottic and sub- Non–small cell lung cancer. Squamous cell carcinoma accounts
glottic malignancies.70 Total laryngectomy is required when lesions for about 30% of bronchogenic carcinomas. These tumors are typi-
are extensive and involve the cartilage. Swallowing and speech therapy cally located near the hila and project into bronchi (Figure 26-18, A).
after treatment can significantly improve recovery. Because of this central location, symptoms of nonproductive cough or
hemoptysis are common. Pneumonia and atelectasis are often associ-
Lung Cancer ated with squamous cell carcinoma (see Figure 26-18, A). Chest pain is
Lung cancers (bronchogenic carcinomas) arise from the epithelium a late symptom associated with large tumors. These tumors are often
of the respiratory tract. Therefore the term lung cancer excludes other fairly well localized and tend not to metastasize until late in the course
pulmonary tumors, including sarcomas, lymphomas, blastomas, of the disease.
hematomas, and mesotheliomas. There were an estimated 222,000 Adenocarcinoma (tumor arising from glands) of the lung consti-
new cases of lung cancer in the United States in 2010.68 It is the most tutes 35% to 40% of all bronchogenic carcinomas (Figure 26-18, B).
702 CHAPTER 26  Alterations of Pulmonary Function

TABLE 26-3 CHARACTERISTICS OF LUNG CANCERS

GROWTH CLINICAL MANIFESTATIONS
TUMOR TYPE RATE METASTASIS MEANS OF DIAGNOSIS AND TREATMENT
Non–Small Cell Carcinoma
Squamous cell carcinoma Slow Late; mostly to hilar Biopsy, sputum analysis, bron- Cough, hemoptysis, sputum production, airway
lymph nodes choscopy, electron microscopy, ­obstruction, hypercalcemia; treated surgically,
immunohistochemistry ­chemotherapy and radiation as adjunctive therapy
Adenocarcinoma Moderate Early; to lymph nodes, Radiography, fiberoptic bronchos- Pleural effusion; treated surgically, chemotherapy as
pleura, bone, adrenal copy, electron microscopy adjunctive therapy
glands, and brain
Large cell carcinoma Rapid Early and widespread Sputum analysis, bronchos- Chest wall pain, pleural effusion, cough, sputum
copy, electron microscopy (by ­production, hemoptysis, airway obstruction resulting
­exclusion of other cell types) in pneumonia; treated surgically

Neuroendocrine Tumors of the Lung

Small cell carcinoma Very rapid Very early; to medias- Radiography, sputum analysis, Cough, chest pain, dyspnea, hemoptysis, localized wheez-
tinum, lymph nodes, bronchoscopy, electron micros- ing, airway obstruction, signs and symptoms of exces-
brain, bone marrow copy, immunohistochemistry sive hormone secretion; treated by chemotherapy and
ionizing radiation to thorax and central nervous system

C
B
FIGURE 26-18  Lung Cancer. A, Squamous cell carcinoma. This hilar tumor originates from the main
bronchus. B, Peripheral adenocarcinoma. The tumor shows prominent black pigmentation, suggestive
of having evolved in an anthracotic scar. C, Small cell carcinoma. The tumor forms confluent nodules.
On cross section, the nodules have an encephaloid appearance. (From Damjanov I, Linder J, editors:
Anderson’s pathology, ed 10, St Louis, 1996, Mosby.)

Pulmonary adenocarcinoma develops in a stepwise fashion through Included in the category of adenocarcinoma is bronchioloalveo-
atypical adenomatous hyperplasia, adenocarcinoma in situ, and lar cell carcinoma. These tumors arise from terminal bronchioles and
minimally invasive adenocarcinoma to invasive carcinoma.74 These alveoli. They are slow-growing tumors with an unpredictable pattern
tumors, which are usually smaller than 4 cm, more commonly arise of metastasis through the pulmonary arterial system and mediastinal
in the peripheral regions of the pulmonary parenchyma. They may be lymph nodes.
asymptomatic and discovered by routine chest roentgenogram in the Large cell carcinomas constitute 10% to 15% of bronchogenic car-
early stages, or the individual may present with pleuritic chest pain and cinomas. This cell type has lost all evidence of differentiation and is
shortness of breath from pleural involvement by the tumor. therefore sometimes referred to as undifferentiated large cell anaplastic
 CHAPTER 26  Alterations of Pulmonary Function 703

cancer. The cells are large and contain darkly stained nuclei. These explored as a means for detecting lung cancer at earlier stages and for
tumors commonly arise centrally and can grow to distort the trachea helping to choose appropriate treatments.76
and cause widening of the carina. For all types of early-stage lung carcinoma, the preferred treat-
Small cell lung cancer. Small cell carcinomas are the most com- ment is surgical resection. Once metastasis has occurred, total surgical
mon type of neuroendocrine lung tumors. Most of these tumors are resection is more difficult and survival rates dramatically decrease. For
central in origin (Figure 26-18, C). Cell sizes range from 6 to 8 μm. individuals with non–small cell carcinoma, adjunctive radiation and
Because these tumors show a rapid rate of growth and tend to metas- chemotherapy may improve outcomes.77 New treatment modalities,
tasize early and widely, small cell carcinomas have the worst progno- such as dose-intensified radiation radiofrequency ablation and micro-
sis. Small cell carcinoma arises from neuroendocrine cells that contain wave ablation, may be available as primary or palliative treatment for
neurosecretory granules; thus small cell carcinoma is often associ- those for whom surgical removal is not an option.78 In advanced dis-
ated with ectopic hormone production. Ectopic hormone production ease, palliative procedures (comfort measures) may be used to relieve
is important to the clinician because resulting signs and symptoms obstructive pneumonitis or prevent recurrence of pleural effusion.
(called paraneoplastic syndromes) may be the first manifestation of the Only about 20% of individuals with small cell lung cancer present
underlying cancer. Small cell carcinomas most commonly produce at an early stage and can be cured of their disease. The outcome for the
antidiuretic hormone, resulting in the syndrome of inappropriate remainder of affected individuals is extremely poor, and treatment is
antidiuretic hormone secretion (SIADH). In other tumors, adreno- usually palliative.79 Chemotherapy and radiation can significantly pro-
corticotropic hormone (ACTH) secretion leads to the development long life and relieve symptoms, but relapse is inevitable.80 Research is
of Cushing syndrome. Signs and symptoms related to this condi- in progress to improve treatment options (see Health Alert: Genetic
tion include muscular weakness, facial edema, hypokalemia, alkalo- and Immunologic Advancements in Lung Cancer Treatment).
sis, hyperglycemia, hypertension, and increased pigmentation. Small
cell lung cancer cells also can produce gastrin-releasing peptide and
calcitonin.
HEALTH ALERT
PATHOPHYSIOLOGY  Tobacco smoke contains more than 30 car- Genetic and Immunologic Advancements
cinogens and is responsible for causing 80% to 90% of lung cancers. in Lung Cancer Treatment
These carcinogens, along with probable inherited genetic predisposi-
tion to cancers, result in multiple genetic abnormalities in bronchial Although new chemotherapeutic agents have improved outcomes slightly
cells including deletions of chromosomes, activation of oncogenes, in the management of lung cancer, overall survival rates remain poor and
and inactivation of tumor-suppressor genes. The most common the toxicities of these regimens limit their use. New understandings of the
genetic abnormality associated with lung cancer is loss of the tumor- genetic and immunologic features of lung cancer cells have led to new treat-
suppressor gene p53.71 Once lung cancer is initiated by these carcino- ment options. Gene therapy is emerging as a way of restoring normal tumor-
gen-induced mutations, further tumor development is promoted by suppressor gene function (e.g., p53) and increasing tumor responsiveness to
growth factors such as epidermal growth factor. chemoradiation through gene transfer, restoring normal DNA methylation
Repetitive exposure of the bronchial mucosa to tobacco smoke patterns, and altering microRNA function. Immunologic therapies include anti-
leads to epithelial cell changes that progress from metaplasia to car- bodies to epidermoid growth factor receptors (erlotinib, gefitinib, and cetux-
cinoma in situ, and finally to invasive carcinoma. Further tumor pro- imab) and antiangiogenesis drugs. The effectiveness of these strategies is still
gression includes invasion of surrounding tissues and finally metastasis being evaluated, but new knowledge is leading to opportunities for innovative
to distant sites including the brain, bone marrow, and liver. treatment.

Data from Kotsakis A, Georgoulias V: Targeting epidermal growth

CLINICAL MANIFESTATIONS  Table 26-3 summarizes the charac- factor receptor in the treatment of non-small-cell lung cancer, Exp
teristic clinical manifestations according to tumor type. By the time Opin Pharmacol 11(14):2363–2389, 2010; Lin PY, Yu SL, Yang PC:
these symptoms are severe enough to motivate the individual to seek MicroRNA in lung cancer, Br J Cancer 103(8):1144–1148, 2010; Mac­
medical advice, the disease is usually advanced. Kinnon AC, Kopatz J, Sethi T: The molecular and cellular biology of lung
cancer: identifying novel therapeutic strategies, Br Med Bull 95:47–61,
EVALUATION AND TREATMENT  Diagnostic tests for the evalu- 2010; Pao W, Chmielecki J: Rational, biologically based treatment of
ation of lung cancer include chest x-ray, sputum cytologic studies, EGFR-mutant non-small-cell lung cancer, Nat Rev Cancer 10(11):760–
774, 2010; Suzuki M, Yoshino I: Aberrant methylation in non-small cell
chest computed tomography, fiberoptic bronchoscopy, and biopsy.
lung cancer, Surg Today 40(7):602–607, 2010; Triano LR, Deshpande
Low-dose helical computed tomography is emerging as a sensitive
H, Gettinger SN: Management of patients with advanced non-small
and specific diagnostic test. Biopsy determines the cell type, and the cell lung cancer: current and emerging options, Drugs 70(2):167–179,
evaluation of lymph nodes and other organ systems is used to deter- 2010; Tufman A, Huber RM: Biological markers in lung cancer: a clini-
mine the stage of the cancer. The histologic cell type and the stage cian’s perspective, Cancer Biomark 6(3–4):123–135, 2010; Vachani A
of the disease are the major factors that influence choice of therapy. et al: Gene therapy for mesothelioma and lung cancer, Am J Respir
The current accepted system for the staging of non–small cell can- Cell Mol Biol 42(4):385–393, 2010.
cer is the TNM classification (T denotes the extent of the primary
tumor, N indicates the nodal involvement, M describes the extent of
metastasis).75
The only proven way of reducing the risk for lung cancer is the
cessation of smoking, although chemopreventative measures are being
4 QUICK CHECK 26-7
1. What are the principal features of lip cancer?
explored. Routine early screening modalities such as chest x-ray and 2. Describe squamous cell carcinoma of the vocal cords.
computed tomography in asymptomatic individuals have not resulted 3. Compare the causes and survival statistics of three types of lung cancer.
in a decrease in lung cancer mortality. Serum biomarkers are being
704 CHAPTER 26  Alterations of Pulmonary Function

DID YOU UNDERSTAND?

Clinical Manifestations of Pulmonary Alterations 7. Pulmonary fibrosis is excessive connective tissue in the lung that dimin-
1. Dyspnea is the feeling of breathlessness and increased respiratory effort. ishes lung compliance; it may be idiopathic or caused by disease.
2. Coughing is a protective reflex that expels secretions and irritants from the 8. Pulmonary edema is excess water in the lung caused by increased capillary
lower airways. hydrostatic pressure, decreased capillary oncotic pressure, or increased
3. Changes in the sputum volume, consistency, or color may indicate underly- capillary permeability. A common cause is left heart failure that increases
ing pulmonary disease. capillary hydrostatic pressure in the pulmonary circulation.
4. Hemoptysis is expectoration of bloody mucus. 9. Acute respiratory distress syndrome (ARDS) results from an acute, diffuse
5. Abnormal breathing patterns are adjustments made by the body to mini- injury to the alveolocapillary membrane and decreased surfactant pro-
mize the work of respiratory muscles. They include Kussmaul, obstructed, duction, which increases membrane permeability and causes edema and
restricted, gasping, Cheyne-Stokes respirations, and sighing. atelectasis.
6. Hypoventilation is decreased alveolar ventilation caused by airway obstruc- 10. Obstructive lung disease is characterized by airway obstruction that
tion, chest wall restriction, or altered neurologic control of breathing and causes difficult expiration. Obstructive disease can be acute or chronic and
results in increased Paco2 (hypercapnia). includes asthma, chronic bronchitis, and emphysema.
7. Hyperventilation is increased alveolar ventilation produced by anxiety, 11. Asthma is an inflammatory disease of the airways resulting from a type
head injury, or severe hypoxemia and causes decreased Paco2 (hypocapnia). I hypersensitivity immune response involving the activity of antigen, IgE,
8. Cyanosis is a bluish discoloration of the skin caused by desaturation of mast cells, eosinophils, and other inflammatory cells and mediators.
hemoglobin, polycythemia, or peripheral vasoconstriction. 12. In asthma, airway obstruction is caused by episodic attacks of broncho-
9. Clubbing of the fingertips is associated with diseases that interfere with spasm, bronchial inflammation, mucosal edema, and increased mucus
oxygenation of the tissues. production.
10. Chest pain can result from inflamed pleurae, trachea, bronchi, or respiratory 13. Chronic obstructive pulmonary disease (COPD) is the coexistence of chronic
muscles. bronchitis and emphysema and is an important cause of hypoxemic and
11. Hypoxemia is a reduced Pao2 caused by (a) decreased oxygen content of hypercapnic respiratory failure.
inspired gas, (b) hypoventilation, (c) diffusion abnormality, (d) ventilation- 14. Chronic bronchitis causes airway obstruction resulting from bronchial
perfusion mismatch, or (e) shunting. smooth muscle hypertrophy and production of thick, tenacious mucus.
15. In emphysema, destruction of the alveolar septa and loss of passive elastic
Disorders of the Chest Wall and Pleura recoil lead to airway collapse and obstruct gas flow during expiration.
1. Chest wall compliance is diminished by obesity and kyphoscoliosis, which 16. Pneumococcal pneumonia is an acute lung infection resulting in an inflam-
compress the lungs, and by neuromuscular diseases that impair chest wall matory response with four phases: (a) consolidation, (b) red hepatization, (c)
muscle function. gray hepatization, and (d) resolution.
2. Flail chest results from rib or sternal fractures that disrupt the mechanics of 17. Viral pneumonia can be severe, but is more often an acute, self-limiting
breathing. lung infection usually caused by the influenza virus.
3. Pneumothorax is the accumulation of air in the pleural space. It can be caused 18. Tuberculosis is a lung infection caused by Mycobacterium tuberculosis
by spontaneous rupture of weakened areas of the pleura or can be secondary (tubercle bacillus). In tuberculosis, the inflammatory response proceeds to
to pleural damage caused by disease, trauma, or mechanical ventilation. isolate colonies of bacilli by enclosing them in tubercles and surrounding
4. Tension pneumothorax is a life-threatening condition caused by trapping of the tubercles with scar tissue.
air in the pleural space. 19. Pulmonary vascular diseases are caused by embolism or hypertension in
5. Pleural effusion is the accumulation of fluid in the pleural space resulting the pulmonary circulation.
from disorders that promote transudation or exudation from capillaries 20. Pulmonary embolism is most often the result of embolism of part of a clot
underlying the pleura or from blockage or injury to lymphatic vessels that from deep venous thrombosis and causes V̇ / Q̇ mismatch, hypoxemia, and
drain into the pleural space. pulmonary hypertension.
6. Empyema is the presence of pus in the pleural space (infected pleural effu- 21. Pulmonary hypertension (pulmonary artery pressure >25 mm Hg) can be
sion) usually from lymphatic drainage from sites of bacterial pneumonia. idiopathic or associated with left heart failure, lung disease, or recurrent
pulmonary emboli.
Pulmonary Disorders
22. Cor pulmonale is right ventricular enlargement or failure caused by pulmo-
1. Atelectasis is the collapse of alveoli resulting from compression of lung tis-
nary hypertension.
sue or absorption of gas from obstructed alveoli.
23. Laryngeal cancer occurs primarily in men and represents 2% to 3% of all
2. Bronchiectasis is abnormal dilation of the bronchi secondary to another pul-
cancers. Squamous cell carcinoma of the true vocal cords is most common
monary disorder, usually infection or inflammation.
and presents with a clinical symptom of progressive hoarseness.
3. Inhalation of noxious gases or prolonged exposure to high concentrations of
24. Lung cancer, the most common cause of cancer death in the United States,
oxygen can damage the bronchial mucosa or alveolocapillary membrane and
is commonly caused by tobacco smoking.
cause inflammation or acute respiratory failure.
25. Lung cancer cell types include non–small cell carcinoma (squamous cell,
4. Pneumoconiosis, which is caused by inhalation of dust particles in the work-
adenocarcinoma, and large cell) and neuroendocrine tumors (small cell car-
place, can cause pulmonary fibrosis, increase susceptibility to lower airway
cinoma, large cell neuroendocrine carcinoma, typical carcinoid and atypical
infection, and initiate tumor formation.
carcinoid tumors). Each type arises in a characteristic site or type of tis-
5. Allergic alveolitis is an allergic or hypersensitivity reaction to many allergens.
sue, causes distinctive clinical manifestations, and differs in likelihood of
6. Bronchiolitis is the inflammatory obstruction of small airways. It is most com-
metastasis and prognosis.
mon in children.
 CHAPTER 26  Alterations of Pulmonary Function 705

 KEY TERMS
•  bscess  698
A •  or pulmonale  700
C • O pen pneumothorax (communicating
• Absorption atelectasis  685 • Cough  679 pneumothorax)  683
• Acute bronchitis  697 • Cyanosis  680 • Orthopnea  679
• Acute lung injury (ALI)  687 • Dyspnea  678 • Oxygen toxicity  686
• Acute respiratory distress syndrome • Emphysema  693 • Paroxysmal nocturnal dyspnea (PND)  679
(ARDS)  687 • Empyema (infected pleural effusion)  684 • Pleural effusion  684
• Adenocarcinoma  701 • Extrinsic allergic alveolitis (hypersensitiv- • Pneumoconiosis  686
• Alveolar dead space  681 ity pneumonitis)  686 • Pneumonia  694
• Aspiration  684 • Exudative effusion  684 • Pneumothorax  682
• Asthma  689 • Flail chest  682 • Pulmonary edema  686
• Atelectasis  685 • Hemoptysis  679 • Pulmonary embolism (PE)  698
• Bronchiectasis  685 • Hypercapnia  680 • Pulmonary fibrosis  686
• Bronchiolitis  685 • Hyperventilation  680 • Pulmonary hypertension  699
• Bronchiolitis obliterans  685 • Hypocapnia  680 • Pulsus paradoxus  690
• Bronchiolitis obliterans organizing pneu- • Hypoventilation  679 • Respiratory failure  682
monia (BOOP)  686 • Hypoxemia  681 • Shunting  681
• Cavitation  698 • Hypoxia  681 • Small cell carcinoma  703
• Cheyne-Stokes respiration  679 • Idiopathic pulmonary fibrosis (IPF)  686 • Squamous cell carcinoma  701
• Chronic bronchitis  693 • Kussmaul respiration (hyperpnea)  679 • Status asthmaticus  691
• Chronic obstructive pulmonary disease • Large cell carcinoma  702 • Surfactant impairment  685
(COPD)  691 • Laryngeal cancer  700 • Tension pneumothorax  684
• Clubbing  680 • Latent TB infection (LTBI)  697 • TNM classification  703
• Compression atelectasis  685 • Lip cancer  700 • Transudative effusion  684
• Consolidation  695 • Lung cancer  701 • Tuberculosis (TB)  697

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nity-onset pneumonia, Lancet Infect Dis 9(6):384–392, 2009. lung cancer, Cancer J 17(1):3–10, 2011.
52. Klevens RM, et al: Invasive methicillin-resistant Staphylococcus aureus 77. Triano LR, Deshpande H, Gettinger SN: Management of patients with
infections in the United States, J Am Med Assoc 298:1763–1771, 2007. advanced non-small cell lung cancer: current and emerging options, Drugs
53. Lieberman D, et al: Respiratory viruses in adults with community- 70(2):167–179, 2010.
acquired pneumonia, Chest 138(4):811–816, 2010. 78. Das M, et al: Alternatives to surgery for early stage non-small cell lung
54. Van der Poll T, Opal SM: Pathogenesis, treatment, and prevention of cancer-ready for prime time? Curr Treat Options Oncol 11(1-2):24–35,
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 CHAPTER

27
Alterations of Pulmonary
Function in Children
Kristi K. Gott and Valentina L. Brashers

http://evolve.elsevier.com/Huether/ •  ey Terms Exercises

K
• Review Questions and Answers • Critical Thinking Questions with Answers
• Animations • Algorithm Completion Exercises
• Quick Check Answers • WebLinks

CHAPTER OUTLINE
Disorders of the Upper Airways, 707 Respiratory Tract Infections, 713
Infections of the Upper Airways, 707 Aspiration Pneumonitis, 716
Aspiration of Foreign Bodies, 709 Bronchiolitis Obliterans, 716
Obstructive Sleep Apnea, 710 Asthma, 716
Disorders of the Lower Airways, 710 Acute Respiratory Distress Syndrome, 718
Respiratory Distress Syndrome of the Newborn, 710 Cystic Fibrosis, 718
Bronchopulmonary Dysplasia, 712 Sudden Infant Death Syndrome (SIDS), 720

Alterations of respiratory function in children are influenced by physi- Croup

ologic maturation, which is determined by age, genetics, and environ- Croup illnesses can be divided into three categories: (1) acute laryn-
mental conditions. Infants, especially premature infants, may present gotracheobronchitis (croup), (2) spasmodic croup, and (3) bacterial
special problems because of incomplete development of the airways, laryngotracheitis.1 Diphtheria can also be considered a croup illness
circulation, chest wall, and immune system. A variety of upper and but is now rare because of vaccinations. Croup illnesses are all charac-
lower airway infections can cause respiratory compromise or play a terized by infection and obstruction of the upper airways.
role in the pathogenesis of more chronic pulmonary disease. Pulmo- Croup is an acute laryngotracheobronchitis and almost always
nary dysfunction can be categorized into disorders of either the upper occurs in children between 6 months and 5 years of age with a peak
or the lower airways. incidence at 2 years of age. In 85% of cases, croup is caused by a virus,
most commonly parainfluenza and in other instances by influenza A,
rhinovirus, or respiratory syncytial virus.2,3 The incidence of croup
DISORDERS OF THE UPPER AIRWAYS is higher in males and is most common during the winter months.
Disorders of the upper airways can cause significant obstruction to Approximately 15% of affected children have a strong family history of
airflow. Common causes of upper airway obstruction in children are croup.2 Spasmodic croup usually occurs in older children. The etiol-
infections, foreign body aspiration, and obstructive sleep apnea. ogy is unknown although association with viruses, allergies, asthma,
and gastroesophageal reflux disease (GERD) is being investigated.2,3
Infections of the Upper Airways Bacterial laryngotracheitis is the most common potentially life-
Table 27-1 compares some of the more common upper airway threatening upper airway infection in children. It is most often caused
infections. by Staphylococcus aureus (S. aureus) (including methicillin-resistant

707
708 CHAPTER 27  Alterations of Pulmonary Function in Children

TABLE 27-1 COMPARISON OF UPPER AIRWAY INFECTIONS

CONDITION AGE ONSET ETIOLOGY PATHOPHYSIOLOGY SYMPTOMS
Acute laryngotracheo- 6 mos to 3 yr Usually gradual Viral Inflammation from larynx Harsh cough; stridor; low-grade fever;
bronchitis to bronchi may have nasal discharge, conjunctivitis
Acute tracheitis 1 to 12 yr Abrupt or following Staphylococcus Inflammation of upper High fever; toxic appearance; harsh
viral illness aureus trachea cough; purulent secretions
Acute epiglottitis 2 to 6 yr Abrupt Haemophilus Inflammation of Severe sore throat; dysphagia; high fever;
influenzae group supraglottic structures toxic appearance; muffled voice; may
A streptococcus drool; dyspnea; sits erect and quietly

Epiglottis

False cords
True cords
Subglottic
tissue
Trachea
Snoring
zone
A B
FIGURE 27-1  The Larynx and Subglottic Trachea. A, Normal tra-
chea. B, Narrowing and obstruction from edema caused by croup.
(From Hockenberry MJ et al: Wong’s nursing care of infants and Inspiratory
Voice stridor
children, ed 9, St Louis, 2010, Mosby.) quality zone
zone
Inflammation and edema
Cough
quality
zone
Upper airway obstruction Expiratory
stridor
zone

Increased resistance to airflow

Increased intrathoracic FIGURE 27-3  Listening Can Help Locate the Site of Airway
negative pressure Obstruction. A loud, gasping snore suggests enlarged tonsils or
adenoids. In inspiratory stridor, the airway is compromised at the
level of the supraglottic larynx, vocal cords, subglottic region, or
Collapse of upper airway upper trachea. Expiratory stridor results from a narrowing or col-
lapse in the trachea or bronchi. Airway noise during both inspira-
tion and expiration often represents a fixed obstruction of the vocal
cords or subglottic space. Hoarseness or a weak cry is a by-product
Respiratory failure of obstruction at the vocal cords. If a cough is croupy, suspect con-
striction below the vocal cords. (Redrawn from Eavey RD: Contemp
FIGURE 27-2  Upper Airway Obstruction With Croup. Ped 3[6]:79, 1986; original illustration by Paul Singh-Roy.)

S. aureus [MRSA] strains), Haemophilus influenzae (H. influenzae), or narrowest point of the airway, making edema in this area critical. Spas-
group A beta-hemolytic Streptococcus (GABHS).1,4 modic croup also causes obstruction but with less inflammation and
edema. As illustrated in Figure 27-2, increased resistance to airflow
PATHOPHYSIOLOGY  The pathophysiology of viral croup is caused leads to increased work of breathing, which generates more negative
primarily by subglottic inflammation and edema from the infection.5 intrathoracic pressure that, in turn, may exacerbate dynamic collapse
The mucous membranes of the larynx are tightly adherent to the of the upper airway. In cases of bacterial laryngotracheitis, the pres-
underlying cartilage, whereas those of the subglottic space are looser ence of airway edema and copious purulent secretions leads to airway
and thus allow accumulation of mucosal and submucosal edema obstruction that can be worsened by the formation of a tracheal pseu-
(Figure 27-1). Furthermore, the cricoid cartilage is structurally the domembrane and mucosal sloughing.1,4
 CHAPTER 27  Alterations of Pulmonary Function in Children 709

CLINICAL MANIFESTATIONS  Typically, the child experiences rhi- Acute Epiglottitis

norrhea, sore throat, and low-grade fever for a few days, and then devel- Historically, acute epiglottitis was caused by H. influenzae type B. Since
ops a harsh (seal-like) barking cough, inspiratory stridor, and hoarse the advent of H. influenzae vaccine, the overall incidence of acute epi-
voice. The quality of voice, cough, and stridor may suggest the loca- glottitis has been reduced by 80% to 90%; however, up to 25% of epi-
tion of the obstruction (Figure 27-3). Most cases resolve spontaneously glottitis cases are still caused by nontypeable strains of H. influenzae.9
within 24 to 48 hours and do not warrant hospital admission. A child Current cases in children usually are related to vaccine failure or are
with severe croup usually displays deep retractions (Figure 27-4), stri- caused by other pathogens, such as GABHS, Streptococcus pneumoniae,
dor, agitation, tachycardia, and sometimes pallor or cyanosis. Candida species, S. aureus, MRSA, or viral pathogens.
Spasmodic croup is characterized by similar hoarseness, barking
cough, and stridor. It is of sudden onset and usually occurs at night PATHOPHYSIOLOGY  The epiglottis arises from the posterior tongue
and without prodromal symptoms. It usually resolves quickly. Chil- base and covers the laryngeal inlet during swallowing. Bacterial inva-
dren with bacterial laryngotracheitis present with high fever, stridor, sion of the mucosa with associated inflammation leads to the rapid
and increased secretions from the mouth and nose that progress over development of edema causing severe, life-threatening obstruction of
hours to days. the upper airway.10

EVALUATION AND TREATMENT  The degree of symptoms deter- CLINICAL MANIFESTATIONS  In the classic form of the disease, a
mines the level of treatment. The most common tool for estimating child between 2 and 7 years of age suddenly develops high fever, irri-
croup severity is the Westley croup score.6 Most children with croup tability, sore throat, inspiratory stridor, and severe respiratory distress.
require no treatment; however, some cases require outpatient treat- The child appears anxious and has a voice that sounds muffled (“hot
ment. These children usually have only mild stridor or retractions and potato” voice). Drooling and dysphagia (inability to swallow) are com-
appear alert, playful, and able to eat. There has been much debate mon. In addition to appearing ill, the child will generally adopt a posi-
about the most effective outpatient treatments for croup. Common tion of leaning forward (tripoding) to try to improve breathing. Death
nonpharmacologic treatments include steam inhalation and ice can occur in a few hours. Nasotracheal intubation or tracheotomy is
masks, although there is no scientific evidence to support their use. mandatory in instances of rapidly increasing obstruction. Pneumonia,
Glucocorticoids—either injected, oral (dexamethasone), or nebulized cervical lymph node inflammation, otitis, and, rarely, meningitis or
(budesonide)—have been shown to improve symptoms. The pres- septic arthritis may occur concomitantly because of bacterial sepsis.
ence of stridor at rest, moderate or severe retractions of the chest,
or agitation suggests more severe disease and does require inpatient EVALUATION AND TREATMENT  Acute epiglottitis is a life-threat-
observation and treatment. For acute respiratory distress, nebulized ening emergency. Efforts should be made to keep the child calm and
epinephrine stimulates α- and β-adrenergic receptors and decreases undisturbed. Examination of the throat should not be attempted
mucosal edema and airway secretions.7 Oxygen should be adminis- because it may trigger laryngospasm and cause respiratory collapse.10
tered. Heliox (helium-oxygen mixture) also can be used in severe cases With severe airway obstruction, the airway may be secured with intu-
although it is not yet considered a mainstay of routine treatment. This bation and antibiotics are administered promptly. Racemic epineph-
works by improving gas flow and thus decreasing the flow resistance rine and corticosteroids may be given until definitive management of
of the narrowed airway.8 In rare cases croup and spasmodic croup the airway can be achieved.10,11 Resolution with treatment is usually
may require placement of an endotracheal tube. Bacterial tracheo- rapid. Postexposure prophylaxis with rifampin is recommended for all
bronchitis is treated with immediate administration of antibiotics and household contacts after a child is diagnosed.
endotracheal intubation to prevent total upper airway obstruction.1
Tonsillar Infections
Tonsillar infections (tonsillitis) are occasionally severe enough to
Suprasternal cause upper airway obstruction. As with other infections of the upper
airway, the incidence of tonsillitis secondary to GABHS (group A beta-
Supraclavicular hemolytic Streptococcus) and MRSA has risen in the past 15 years.
Intercostal Upper airway obstruction because of tonsillitis is a well-known com-
plication of infectious mononucleosis, especially in a young child.
Tonsillitis may be complicated by formation of a tonsillar abscess,
which can further contribute to airway obstruction. The development
Substernal of significant obstruction in tonsillar infections may require the use of
corticosteroids, especially in the case of mononucleosis. The manage-
ment of severe bacterial tonsillitis requires the use of antibiotics. Some
children with recurrent tonsillitis benefit from tonsillectomy.12

Aspiration of Foreign Bodies

Aspiration of foreign bodies (FBs) into the airways usually occurs
in children 1 to 3 years of age. More than 100,000 cases occur each
year.13 Most objects are expelled by the cough reflex, but some objects
may lodge in the larynx, trachea, or bronchi. Large objects (e.g., a
bite of hot dog, nuts, popcorn, grapes, beans, toy pieces, fragments
Subcostal of popped balloons, or coins) may occlude the airway and become
life-threatening. Items of particular concern would be batteries and
FIGURE 27-4  Areas of Chest Muscle Retraction. magnets. The aspiration event commonly is not witnessed or is not
710 CHAPTER 27  Alterations of Pulmonary Function in Children

recognized when it happens because the coughing, choking, or gag- impaired school performance, and poor quality of life.17 Left untreated
ging symptoms may resolve quickly. Foreign bodies lodged in the OSAS also may cause cardiovascular and pulmonary disease, as well as
larynx or upper trachea cause cough, stridor, hoarseness or inability insulin resistance and reduced somatic growth.
to speak, respiratory distress, and agitation or panic; the presentation
is often dramatic and frightening. If the child is acutely hypoxic and EVALUATION AND TREATMENT  All parents should be asked if
unable to move air, immediate action such as sweeping the oral air- their child exhibits snoring, a symptom that is often not sponta-
way or performing abdominal thrusts (formerly called the Heimlich neously reported to the healthcare provider. History and physical
maneuver) may be required to prevent tragedy. Otherwise, broncho- examination are key to diagnosis and a variety of screening tools are
scopic removal should be performed urgently. If an aspirated for- available. Radiographs of the upper airway may be used to rule out
eign body is small enough, it will be transferred to a bronchus before adenoidal hypertrophy.21 The most definitive evaluation is the poly-
becoming lodged. If the foreign body is lodged in the airway for a somnographic sleep study, which documents obstructed breathing
notable period of time, local irritation, granulation, obstruction, and and physiologic impairment. If obstructive sleep apnea is documented
infection will ensue. Thus children may present with cough or wheez- or strongly suspected clinically, children are most often referred for
ing, atelectasis, pneumonia, lung abscess, or blood-streaked sputum. tonsillectomy and adenoidectomy (T & A) on the basis of described
These children are treated by prompt bronchoscopic removal of the symptoms and physical findings, such as enlarged tonsils, adenoidal
object and administration of antibiotics as necessary.14 facies, and mouth breathing.22 For severely affected children who do
not respond to T & A or who have different problems, such as obesity,
Obstructive Sleep Apnea that cannot be remedied rapidly, continuous positive airway pressure
Obstructive sleep apnea syndrome (OSAS) is defined by partial or (CPAP) may be delivered through a tight-fitting nasal mask used dur-
intermittent complete upper airway obstruction during sleep with dis- ing sleep. Treatment is important to minimize associated morbidities.
ruption of normal ventilation and sleep patterns. Childhood OSAS is
quite common, with an estimated prevalence of 2% to 3% of children
12 to 14 years of age and up to 13% of children between 3 and 6 years
4 QUICK CHECK 27-1
1. Compare and contrast pathology, clinical presentations, and severity
of age.15,16 Prevalence is estimated to be two to four times higher in of croup and epiglottitis.
vulnerable populations (blacks, Hispanics, and preterm infants).17 In 2. What symptoms indicate aspiration of a foreign body?
children, unlike adults, OSAS occurs equally among girls and boys. 3. What signs and symptoms suggest obstructive sleep apnea?
Possible influences early in life may include passive smoke inhalation,
socioeconomic status, and snoring together with genetic modifiers that
promote airway inflammation. OSAS also is more likely to occur in
DISORDERS OF THE LOWER AIRWAYS
children who have a history of a clinically significant episode of respi-
ratory syncytial virus (RSV) bronchiolitis in infancy; this is believed to A number of disorders of the lower respiratory tract are specific to
change the neuroimmunomodulatory pathways in the upper airway.18 children, such as newborn respiratory distress syndrome, bronchopul-
monary dysplasia, and congenital malformations. Lower airway infec-
PATHOPHYSIOLOGY  By far the most common predisposing factor tions, such as viral bronchiolitis and bacterial pneumonia, occur fairly
to OSAS in children is adenotonsillar hypertrophy, which causes phys- often in children. Chronic pulmonary conditions, such as asthma and
ical impingement on the nasopharyngeal airway. OSAS also may occur cystic fibrosis, frequently first present clinically in childhood.
in children who are overweight or obese, and in those with craniofacial
anomalies (with structurally small nasopharyngeal airways) or reduced Respiratory Distress Syndrome of the Newborn
motor tone of the upper airways (as may be seen in neurologic disor- Respiratory distress syndrome (RDS) of the newborn (previously
ders, cerebral palsy, and Down syndrome). Allergy and asthma also also called hyaline membrane disease [HMD]) is a significant cause of
may contribute to this condition. Current research links sleep disor- neonatal morbidity and mortality.23 It occurs almost exclusively in
dered breathing (SDB) with airway inflammation and elevated levels of premature infants and the incidence has increased in the United States
C-reactive protein.19 In addition, there are neuroimmunomodulatory over the past 2 decades.24 RDS occurs in 50% to 60% of infants born at
responses that are changed in this condition, such as greater expres- 29 weeks’ gestation and decreases significantly by 36 weeks. Infants of
sion of nerve growth factor (NGF) and neurokinin 1 (NK1) receptor diabetic mothers and those with cesarean delivery (especially elective
mRNA linked with protein concentrations.16,20 Lastly, genetics may C-section) also are more likely to develop RDS. It is more common in
indeed play a role in the neurocognitive dysfunction associated with boys than girls and more common in whites than non-whites. Death
the condition. rates have declined significantly since the introduction of antenatal ste-
roid therapy and postnatal surfactant therapy. Risk factors are summa-
CLINICAL MANIFESTATIONS  There usually is a history of snoring rized in Risk Factors: Respiratory Distress Syndrome of the Newborn.
and labored breathing during sleep, which may be continuous or inter-
mittent. The child may also experience restlessness and sweating. There
may be episodes of increased respiratory effort but no audible airflow,
RISK FACTORS
often terminated by snorting, gasping, repositioning, or arousal. Day-
time sleepiness/napping is occasionally reported, as well as nocturnal Respiratory Distress Syndrome of the Newborn
enuresis. Often the child is a chronic mouth breather and has large ton- • Premature birth
sils. There is no correlation between sleep position and OSAS in chil- • Male gender
dren, except for those children who are notably obese. Obese children • Cesarean delivery without labor
may adopt the prone position to attempt improved ventilation. Sig- • Diabetic mother
nificant morbidity can result from the effects of OSAS, including cog- • Perinatal asphyxia
nitive and neurobehavioral impairment, excessive daytime sleepiness,
 CHAPTER 27  Alterations of Pulmonary Function in Children 711

PATHOPHYSIOLOGY  RDS is caused by surfactant deficiency, which vasoconstriction and increase intrapulmonary resistance and shunt-
decreases the alveolar surface area available for gas exchange. Surfac- ing. This results in hypoperfusion of the lung and a decrease in effec-
tant is a lipoprotein with a detergent-like effect that separates the liquid tive pulmonary blood flow. Increased pulmonary vascular resistance
molecules inside the alveoli, thereby decreasing alveolar surface ten- may even cause a partial return to fetal circulation, with right-to-left
sion. Without surfactant, alveoli collapse at the end of each exhalation. shunting of blood through the ductus arteriosus and foramen ovale.
Surfactant normally is not secreted by the alveolar cells until approxi- Inadequate perfusion of tissues and hypoxemia contribute to meta-
mately 30 weeks’ gestation. In addition to surfactant deficiency, pre- bolic acidosis.
mature infants are born with underdeveloped and small alveoli that are Inadequate alveolar ventilation can be further complicated
difficult to inflate and have thick walls and inadequate capillary blood by increased pulmonary capillary permeability. Many premature
supply such that gas exchange is significantly impaired. Furthermore, infants with RDS will require mechanical ventilation, which dam-
the infant’s chest wall is weak and highly compliant and, thus, the rib ages alveolar epithelium. Together these conditions result in the
cage tends to collapse inward with respiratory effort. The net effect of leakage of plasma proteins into the alveoli. Fibrin deposits in the
all these adverse factors is atelectasis (collapsed alveoli), resulting in airspaces create the appearance of “hyaline membranes,” for which
significant hypoxemia. Atelectasis is difficult for the neonate to over- the disorder was originally named. The plasma proteins leaked into
come because it requires a significant negative inspiratory pressure to the airspace have the additional adverse effect of inactivating any
open the alveoli with each breath. This increased work of breathing surfactant that may be present. The pathogenesis of RDS is summa-
may result in hypercapnia. Hypoxia and hypercapnia cause pulmonary rized in Figure 27-5.

Premature birth

Surfactant deficiency
Structural immaturity of alveoli
Overly compliant chest wall

Atelectasis

Decreased Inactivation
Increased pulmonary
production of of
vascular resistance
surfactant surfactant

Impaired cellular Protein leak Pulmonary

metabolism into airspaces hypoperfusion

Inadequate alveolar ventilation Hypoxemia Hypoxic vasoconstriction

Hypercapnia Right-to-left shunt

Ventilator-induced
epithelial injury

Respiratory acidosis Patent ductus arteriosus

and foramen ovale

Metabolic acidosis

Respiratory failure
FIGURE 27-5  Pathogenesis of Respiratory Distress Syndrome (RDS) of the Newborn.
712 CHAPTER 27  Alterations of Pulmonary Function in Children

CLINICAL MANIFESTATIONS  Signs of RDS appear within minutes

RISK FACTORS
of birth. Some neonates require immediate resuscitation because of
asphyxia or severe respiratory distress. Severity tends to increase over Bronchopulmonary Dysplasia (BPD)
the first 2 days of life. Characteristic signs are tachypnea (respiratory • Premature birth (especially ≤28 weeks)
rate greater than 60 breaths/min), expiratory grunting, intercostal and • Positive-pressure ventilation
subcostal retractions, nasal flaring, and cyanosis. The natural course • Supplemental oxygen administration
is characterized by progressive hypoxemia and dyspnea. Apnea and • Antenatal chorioamnionitis
irregular respirations occur as the infant tires. Severity of hypoxemia • Postnatal sepsis or pneumonia
and difficulty in providing supplemental oxygenation have resulted in • Patent ductus arteriosus
the Vermont Oxford Neonatal Network definition of RDS: a Pao2 less • Nutritional deficiencies
than 50 mm Hg in room air, central cyanosis in room air, or a need • Early adrenal insufficiency
for supplemental oxygen to maintain Pao2 greater than 50 mm Hg,
as well as classic chest film appearance.25 The typical chest radiograph
shows diffuse, fine granular densities within the first 6 hours of life. infants born weighing less than 1500 g on an annual basis. About 20%
This “ground glass” appearance is associated with alveolar flood- to 30% of these infants develop BPD.30 Risk factors for BPD are sum-
ing. Ventilatory support is often required. In most cases the clinical marized in the Risk Factors: Bronchopulmonary Dysplasia (BPD) box.
manifestations reach a peak within 3 days, after which there is gradual In the current era of neonatology, the widespread use of antenatal
improvement. glucocorticoids and postnatal surfactant has lessened the incidence and
severity of RDS, and BPD is occurring primarily in the smallest prema-
EVALUATION AND TREATMENT  Diagnosis is made on the basis of ture infants (23 to 28 weeks’ gestation) who have received mechanical
premature birth or other risk factors, chest radiographs, and, if needed, ventilation. Surprisingly, some of these tiny infants who develop BPD
analysis of amniotic fluid or tracheal aspirates to estimate lung matu- have shown few or no clinical signs of RDS at birth or have initially
rity (lecithin/sphingomyelin ratio [L/S ratio]). The ultimate treat- received only low levels of supplemental oxygen or ventilatory support,
ment for RDS would be prevention of premature birth. For women sometimes for other reasons such as apnea.
in preterm labor, antenatal treatment with glucocorticoids induces a
significant and rapid acceleration of lung maturation and stimulation PATHOPHYSIOLOGY  Classic BPD evolves over several weeks, with
of surfactant production in the fetus. There is extensive evidence that an early exudative inflammatory phase followed by a fibroprolifera-
maternal antenatal corticosteroid therapy significantly reduces the tive phase. However, this severe form, resulting in evidence of marked
incidence of RDS and death, although it is unclear whether repeated airway injury and cyst formation, is no longer common. Instead, the
courses of steroids are safe in this setting.25,26 predominant histopathologic findings in the “new BPD” are those
Current recommendations for infants weighing less than 1000 g of disrupted lung development with poor formation of the alveolar
include prophylaxis beginning within 15 to 30 minutes of birth by architecture. Alveoli are large and fewer in number, thereby present-
administration of exogenous surfactant (either synthetic or natu- ing decreased surface area for gas exchange.31 Furthermore, there is
ral) through nebulizer or nasal continuous positive airway pressure evidence of abnormal vascular endothelial growth factor signaling,
(CPAP) ventilation. Repeat doses are given every 12 hours for the first with resultant abnormal pulmonary capillary development, leading
few days. There is usually a dramatic improvement in oxygenation as to impaired gas exchange, ventilation-perfusion mismatch, and poor
well as a decreased incidence of RDS death, pneumothorax, and pul- capacity to exercise.32 Genetic influences on inflammatory regulation
monary interstitial emphysema.27 For infants weighing more than have been documented in association with the “new BPD.”33 Concen-
1000 g, surfactant replacement is based on clinical need. Surfactant trations of proinflammatory cytokines, such as tumor necrosis factor-
therapy should be considered complementary to antenatal glucocorti- alpha, interleukin-1, interleukin-6, and interleukin-8, are all elevated
coids. The two therapies together appear to have an additive effect on in the amniotic fluid or tracheal aspirates, or both, of preterm infants
improving lung function. who later develop BPD. Inflammation invites neutrophils and macro-
Supportive care includes oxygen administration and often such phages to release reactive oxygen species and proteolytic enzymes.34
measures as mechanical ventilation. Mechanical ventilation can result In more severe cases of BPD, pulmonary hypertension may develop
in a proinflammatory state that may contribute to the development because of abnormal muscularization of the primary vasculature in
of chronic lung disease, such as bronchopulmonary dysplasia (BPD). response to recurrent hypoxemia or inflammatory stimuli. Figure 27-6
Strategies that are lung protective, such as greater reliance on nasal illustrates the pathophysiology of BPD.
CPAP, permissive hypercapnia, lower oxygen saturation targets, mod-
ulation of tidal volume (Vt) settings, and use of high-frequency oscil- CLINICAL MANIFESTATIONS  The current definition of BPD
lation, are being evaluated.28 Inhaled nitric oxide (iNO) resulted in includes need for supplemental oxygen at 36 weeks for at least 28 days
lowered O2 levels and fewer days of ventilation in some trials, although after birth. It also details a graded severity dependent on required
its utility in preterm infants has been questioned.29 Most infants sur- respiratory support at term (mild, moderate, and severe based on
vive RDS and, in many cases, recovery may be complete within 10 to oxygen requirements and ventilatory needs). Clinically, the infant
14 days. However, the incidence of subsequent chronic lung disease is exhibits hypoxemia and hypercapnia caused by ventilation-perfusion
significant among very-low-birthweight infants.24 mismatch and diffusion defects. The work of breathing increases and
the ability to feed may be impaired. Intermittent bronchospasm,
Bronchopulmonary Dysplasia mucus plugging, and pulmonary hypertension characterize the clinical
Bronchopulmonary dysplasia (BPD), also known as chronic lung dis- course. Of the most severely affected infants, dusky spells may occur
ease (CLD) of infancy, is the term used to describe persisting lung disease with agitation, feeding, or gastroesophageal reflux. Infants with mild
following neonatal lung injury, usually associated with premature birth BPD may demonstrate only mild tachypnea and difficulty handling
and perinatal respiratory support. There are approximately 60,000 U.S. respiratory tract infections.
 CHAPTER 27  Alterations of Pulmonary Function in Children 713

Prematurity

Respiratory Infection
insufficiency Patent ductus (chorioamnionitis, sepsis,
arteriosus pneumonia)

Mechanical ventilation
Oxygen therapy Increased pulmonary
blood flow

Decreased lung
compliance

Influx of inflammatory cells

Local cytokine activation
Oxidant damage

Airway injury Disrupted alveolar Disrupted capillary Vascular smooth Increased vascular
Smooth muscle development development muscle hypertrophy permeability
hypertrophy

Increased airway Alveolar Pulmonary Pulmonary edema

resistance hypoplasia hypertension

Decreased lung
Ventilation/perfusion compliance
mismatch

Hypoxemia
Impaired gas exchange
Increased work of breathing

FIGURE 27-6  Pathophysiology of Bronchopulmonary Dysplasia (BPD).

EVALUATION AND TREATMENT  Infants with severe BPD require function abnormalities (significant airflow limitation with broncho-
prolonged assisted ventilation. Prevention of lung damage with dilator responsiveness) may persist for many years.37 Children who
“gentle ventilation” or early nasal CPAP, or both, is used in clinical survive BPD also have increased rates of cognitive, educational, and
situations when permitted. When compared to mechanical ventila- behavioral impairments.38
tion, use of CPAP has resulted in fewer days of oxygen and ventilator
requirement by reducing the amount of lung injury.35 Diuretics are
used to control pulmonary edema. Bronchodilators reduce airway
4 QUICK CHECK 27-2
1. Why are premature infants susceptible to RDS?
resistance. Inhaled corticosteroids improve the rate of extubation 2. Describe the pathologic findings of “new BPD.”
and reduce the time that mechanical ventilation is required.36 Caf-
feine citrate administration, vitamin A supplementation, and careful
nutritional support are routinely used and have resulted in improved
outcomes.30 Respiratory Tract Infections
Death from BPD is usually caused by infection, cor pulmonale, Respiratory tract infections are common in children and are a frequent
or respiratory failure. However, most infants with BPD improve sub- cause for emergency department visits and hospitalizations. Clinical
stantially during the first 2 to 3 years of life. Nevertheless, there is presentation, age of the child, and season of the year can often provide
an increased incidence of asthma during childhood, and pulmonary clues to the etiologic agent, even when the agent cannot be proven.
714 CHAPTER 27  Alterations of Pulmonary Function in Children

Bronchiolitis CLINICAL MANIFESTATIONS  Symptoms usually begin with signifi-

Bronchiolitis is a common, viral lower respiratory tract infection that cant rhinorrhea followed by a tight cough over the next several days,
occurs almost exclusively in infants and young toddlers and is a major along with systemic signs of decreased appetite, lethargy, and fever.
reason for hospitalization of infants and young children.39 It has a sea- Infants typically have tachypnea, variable degrees of respiratory distress,
sonal, yearly incidence, from approximately November to April, and is and abnormal auscultatory findings of the chest. Wheezing is most
the leading cause of hospitalization for infants during the winter sea- common, but rales or rhonchi also may be present. Chest radiographs
son. The most common associated pathogen is respiratory syncytial often reveal hyperexpanded lungs, patchy or peribronchial infiltrates,
virus (RSV), which accounts for up to 75% of cases,39 but bronchi- and, sometimes, atelectasis of the right upper lobe. Very young infants
olitis also may be associated with adenoviruses, influenza, parainflu- may present with severe apnea before lower respiratory tract symptoms
enza, and mycoplasma. Healthy infants usually make a full recovery appear, and these apneas frequently require mechanical ventilation.
from RSV bronchiolitis, but infants who were premature (birthweight Many children also may present with conjunctivitis or otitis media.
<2500 g) or who have underlying BPD or heart disease may have a
much higher risk for a more severe or even deadly course. Bronchi- EVALUATION AND TREATMENT  Diagnosis of bronchiolitis is made
olitis has been linked to an increased risk for asthma later in child- by review of signs and symptoms (e.g., rhinitis, cough, wheezing, chest
hood.40 Associations with rhinovirus and low vitamin D levels also are retractions, tachypnea) and radiologic examination. Nasal washings
being investigated because they appear to correlate with the increased may be tested for specific viral agents, such as RSV. RSV swabs are
likelihood that children develop asthma after they have experienced positive in 70% of these cases.
bronchiolitis.41 Treatment for bronchiolitis is determined by the severity of the
disease and the age of the child. Most cases are mild and require no
PATHOPHYSIOLOGY  Viral infection causes necrosis of the bronchial specific treatment and may be monitored as outpatients. When treat-
epithelium and destruction of ciliated epithelial cells. There is infiltra- ment is indicated, it is primarily supportive in nature. Supplemental
tion with lymphocytes around the bronchioles and a cell-mediated oxygen and increased hydration are commonly used. Inhaled hyper-
hypersensitivity to viral antigens with release of lymphokines causing tonic saline has been found to decrease clinical severity and length of
inflammation, as well as activation of eosinophils, neutrophils, and hospital stay.40,42 Inhaled bronchodilators and steroids benefit infants
monocytes. The submucosa becomes edematous and cellular debris with underlying lung disease, but have not been found to be effective in
and fibrin form plugs within the bronchioles. otherwise healthy infants. Mechanical ventilation is occasionally nec-
Edema of the bronchiolar wall, accumulation of mucus and cellular essary and the use of nasal CPAP and heliox (a mixture of helium and
debris, and, perhaps, bronchospasm narrow many peripheral airways. oxygen) is being explored.43,44 Preventive treatment with RSV-spe-
Other airways become partially or completely occluded. Atelectasis cific monoclonal antibody, provided as a monthly injection through
occurs in some areas of the lung and hyperinflation in others. the RSV season, is recommended for high-risk infants younger than
The mechanics of breathing are disrupted by bronchiolitis. There 2 years who meet specific criteria.
is air trapping, and functional residual capacity (FRC) is greatly
increased. Compliance is decreased because the lungs are already Pneumonia
highly inflated and because airway resistance within the lung is uneven Pneumonia is infection and inflammation in the terminal airways
and increased. The decrease in compliance and the increase in air- and alveoli. It is a major cause of morbidity and mortality, particu-
way resistance result in a substantial increase in the work of breathing. larly in developing countries. The most common agents are viruses,
Serious alterations in gas exchange occur because of airway obstruc- followed by bacteria and atypical microorganisms (e.g., mycoplasma)
tion and patchy atelectasis. Hypoxemia develops because of venti- (Table 27-2). Community-acquired pneumonia (CAP) is one of the
lation-perfusion mismatch (see Chapter 26), and hypercapnia may most common childhood infections and one of the leading causes of
occur in severe cases. hospitalization. Risk factors for developing CAP are age younger than

TABLE 27-2 COMMON TYPES OF PNEUMONIA IN CHILDREN

TYPE CAUSAL AGENT AGE ONSET SIGNS/SYMPTOMS
Viral pneumonia Respiratory syncytial virus Infants for RSV, all Acute or gradual, winter Mild to high fever, cough, rhinorrhea, malaise, rales,
(RSV), influenza, adenovirus, ages for others and early spring rhonchi, or wheezing, apnea, variable radiographic
others pattern
Pneumococcal Pneumococci (Streptococcus Usually 1 to 4 yr Acute, follows an upper High fever, productive cough, pleuritic pain, increased
pneumonia pneumoniae) respiratory tract infection, respiration rate, decreased breath sounds in area of
winter and early spring consolidation; lobar infiltrate or “round pneumonia”
on radiograph
Staphylococcal Staphylococcus aureus 1 wk to 2 yr Acute, winter High fever, cough, respiratory distress, empyema or
pneumonia (including methicillin- pneumatoceles common
resistant strains)
Streptococcal Group A beta-hemolytic All ages Acute, any season High fever, chills, respiratory distress, sepsis, or shock
pneumonia streptococci
Mycoplasmal and Mycoplasma pneumoniae, School-age and Gradual Low-grade fever, cough
chlamydophilal Chlamydophila pneumoniae adolescents
pneumonia
 CHAPTER 27  Alterations of Pulmonary Function in Children 715

2 years, overcrowded living conditions, winter season, recent antibiotic indicators. Auscultation usually shows such abnormalities as crackles
treatment, day-care attendance, and passive smoke exposure. Nutri- or decreased breath sounds. Other less specific findings may include
tional status, age, and underlying disease process influence morbidity malaise, emesis, abdominal pain, and chest pain. Chest film will usu-
and mortality rates related to CAP. ally present with a lobar pattern in older children and adolescents but
Viral pneumonia is more common than bacterial pneumo- may appear patchier with a bronchopneumonic pattern in younger
nia and children are two to three times more likely than adults to children.
acquire these viruses. Mortality in the developed world is rare but Atypical pneumonia (Mycoplasma pneumoniae, Chlamydophila
morbidity is significant. The incidence of viral pneumonia gener- pneumoniae) is the most common cause of community-acquired
ally follows a seasonal pattern. The most common viral pneumonia pneumonia for school-age children and young adults. Chlamydophila
in young children is RSV (respiratory syncytial virus). A number of pneumonia is clinically indistinguishable from and is typically grouped
other viruses are important, including parainfluenza, influenza, and with Mycoplasma as “atypical pneumonia.” Transmission is from per-
adenoviruses. Certain serotypes of adenovirus can cause necrotizing son-to-person with a 2- to 3-week incubation period.
disease, sometimes leading to bronchiolitis obliterans and significant Mycoplasmic microorganisms lack cell walls but have a limiting
lung disability. membrane and a specialized receptor for attaching to ciliated respi-
Acquisition of these viruses is by direct contact, droplet transmis- ratory epithelial cells. Local sloughing of cells occurs. Peribronchial
sion, or aerosol.45 There is initial destruction of ciliated epithelium of lymphocytic infiltration develops, along with neutrophil recruit-
the distal airway with sloughing of cellular material. A mononuclear- ment to the airway lumen. The pattern resembles bronchitis or
predominant inflammatory response occurs, in the interstitium ini- bronchopneumonia.
tially, and later may involve the alveoli as well. Early in the course of Onset is usually gradual, resembling a typical upper respiratory
the disease, it is often difficult to determine whether the pneumonia tract infection but with low-grade fever and prominent cough. Myco-
is viral or bacterial. Differences in the clinical presentation can help plasma can cause a wide spectrum of disease and is more extensive
to determine origin, such as degree of elevation of temperature, abso- as a cause of complications than previously noted. It also is occurring
lute neutrophil counts, and percentage of bands. Ultimately diagno- more frequently in infants and younger children.49 Most cases are not
sis requires laboratory confirmation using immunofluorescence tests. clinically severe and full recovery should be expected. Complications,
Development of safe agents to treat and prevent viral pneumonia con- when they do occur, can include bronchopneumonia, parapneumonic
tinues to be a focus of much research.45 effusions, and necrotizing pneumonitis.
Bacterial pneumonia usually begins with inhalation of microbes
dispersed in ambient air or in secretion droplets (person-to-person EVALUATION AND TREATMENT  Diagnosis of pneumonia is based
spread) or by aspiration of one’s own nasopharyngeal bacteria.46 on clinical and laboratory findings and chest radiograph confirmation;
A preceding viral infection sometimes sets the stage for bacterial the etiologic agent can sometimes be inferred from the age of the child
infection by causing epithelial damage and reduced mucociliary clear- and clinical scenario.50 Guidelines have been developed but often are
ance in the trachea and major bronchi. Once in the alveolar region, very difficult to apply in practice and thus there is lack of consensus
bacteria encounter local host defenses, such as antibodies, comple- regarding their use.51 Although laboratory testing is available, it is
ment, and cytokines, which prepare bacteria for ingestion by alveo- again often difficult to apply with children because they may have an
lar macrophages. Alveolar macrophages recognize bacteria with their overlapping clinical picture (viral versus bacterial). Measurement of
surface receptors and phagocytose them. If these mechanisms fail, serum levels of highly-sensitive C-reactive protein (hs-CRP) may help
macrophages release numerous inflammatory cytokines and neutro- discern between the two entities. Several microbiologic tests are avail-
phils will be recruited into the lung.47 An intense, cytokine-mediated able, such as PCR (polymerase chain reaction) and nucleic acid ampli-
inflammation will ensue. Vascular engorgement, edema, and a fibri- fication tests (NAATs). A bacterial pneumonia will initially produce a
nopurulent exudate occur. Alveolar filling precludes gas exchange patchy infiltration and later cause a segmental or lobar disease. A uni-
and, if extensive, can lead to respiratory failure. If sepsis occurs at the lateral lobar consolidation on a chest x-ray film is often associated with
same time, shock and end-organ hypoperfusion will cause metabolic Streptococcus pneumoniae. The formation of small areas of airway dila-
acidosis. tion (called pneumatoceles) most commonly suggests Staphylococcus
Beyond the neonatal period, infection with streptococci and staph- pneumoniae. Pleural effusions are rarely seen with viral pneumonias or
ylococci microorganisms is most common for this diagnosis. Pneu- atypical pneumonias.
mococcal (Streptococcus pneumoniae) pneumonia is the most common Some pneumonias may be treated on an outpatient basis; however,
cause of community-acquired bacterial pneumonia and presents many children require oxygen supplementation and, occasionally,
acutely and with variable severity.48 In 2000 a polyvariant pneumo- assisted ventilation. This is particularly true with infants who have a
coccal conjugate vaccine (PCV7) was incorporated into routine child- viral interstitial pneumonia, such as RSV. In addition, adequate hydra-
hood immunizations and appears to have lessened the incidence of tion, proper nutrition, and supportive pulmonary therapy are required
pneumococcal pneumonia in children younger than 2 years of age.48 to reduce the duration and severity of illness. Many infants are mark-
Staphylococcal pneumonia and group A streptococcal pneumonia can edly tachypneic and unable to coordinate their breathing with swal-
be particularly fulminant (sudden, severe) and necrotizing (causing lowing; they may require enteral feeding. Aspiration is always a risk
cell death) with a high incidence of accompanying empyema, pneuma- with infants in respiratory distress.
tocele, and sepsis. H. influenzae pneumonia has become rare because Appropriate antibiotic administration for bacterial pneumonias
of widespread immunization. should be instituted.52,53 Local patterns of resistance must be consid-
The clinical presentation of bacterial pneumonia, particularly ered when choosing appropriate antibiotics.54,55 Both pneumococ-
pneumococcal, may include a preceding viral illness followed by fever cal and mycoplasmal pneumonias present some unique treatment
with chills and rigors, shortness of breath, and an increasingly pro- obstacles and often need a multifaceted approach to care, including
ductive cough. Occasionally, there is blood streaking of the sputum. vaccine antigens, antibiotic combinations, and immunoadjuvant
Respiratory rate and oxygen saturation also are important clinical therapies.47,55,56
716 CHAPTER 27  Alterations of Pulmonary Function in Children

Asthma
4 QUICK CHECK 27-3
Asthma is a chronic inflammatory disease characterized by bronchial
1. Describe the typical presentation of RSV bronchiolitis.
hyperreactivity and reversible airflow obstruction, usually in response
2. What clinical features distinguish bacterial pneumonia from atypical
to an allergen (see Chapter 26). It is the most prevalent chronic disease
pneumonia?
in childhood, affecting 10% of U.S. children between 5 and 17 years
of age with boys more often affected than girls.61 Populations most
affected include black and Hispanic children, those living in an urban
setting, ethnic minorities, and those of low socioeconomic status.62
Aspiration Pneumonitis Childhood asthma results from a complex interaction between
Aspiration pneumonitis is caused by a foreign substance, such as genetic susceptibility and environmental factors, including early expo-
food, meconium, secretions (saliva or gastric), or environmental sure to allergens (e.g., air pollution, dust mites, cockroach antigen, cat
compounds, entering the lung and resulting in inflammation of the exposure, and tobacco smoke) and infections, particularly viral respi-
lung tissue. The aspiration of meconium from amniotic fluid can ratory tract infections (e.g., rhinovirus and RSV).63 Vitamin D insuf-
occur at birth. Neurologically compromised children or children ficiency may be a risk factor for wheezing in children.64
with chronic lung disease may have chronic pulmonary aspiration
(CPA), which can cause progressive lung disease, bronchiectasis, and PATHOPHYSIOLOGY  The pathophysiology of asthma in children is
respiratory failure. This is the leading cause of death in children who similar to that for adults and is described in Chapter 26. It is initi-
are neurologically compromised.57 Children undergoing sedation or ated by a type I hypersensitivity reaction (see Chapter 7). The early
anesthesia also may aspirate oral secretions contaminated with anaer- asthmatic response is summarized in Figure 26-9 and Figure 27-7, A).
obic bacteria or acidic stomach contents. The severity of lung injury The late asthmatic response begins 4 to 8 hours after the acute response
after an aspiration incident is determined by the volume and pH of and is summarized in Figure 27-7, B. In chronic asthma, some of these
the material aspirated and the presence of pathogenic bacteria. Very mechanisms may be operational on an ongoing basis.
low pH or extremely high pH will cause a significant inflammatory
response. With hydrocarbon ingestions, lung injury is determined CLINICAL MANIFESTATIONS  In a typical acute asthma attack in
by the volatility and viscosity of the aspirated substance. A low-vis- children, the major complaints are coughing, wheezing, and shortness
cosity substance, such as gasoline or lighter fluid, is the most toxic, of breath. There may or may not have been signs of a preceding upper
and high-viscosity hydrocarbons, such as petroleum jelly or mineral respiratory tract infection, such as rhinorrhea or low-grade fever. In
oil, are much less likely to cause a pneumonitis. Treatment for aspi- children, about 70% to 80% of acute wheezing episodes are associated
ration pneumonitis depends on the material aspirated but generally with viral respiratory tract infections. In infants and toddlers less than
includes broad-spectrum antibiotic coverage. Children with CPA and 2 years old, the most common of these is respiratory syncytial virus
a large amount of upper respiratory tract secretions may benefit from (RSV). In older children and adults, the major viral trigger is rhinovi-
salivary gland injection with botulinum toxin A (BTX-A) to suppress rus (the “common cold” virus).65
secretion.58 On physical examination, there is expiratory wheezing that is often
described as high pitched and musical, and there is prolongation of the
Bronchiolitis Obliterans expiratory phase of the respiratory cycle. Breath sounds may become
Bronchiolitis obliterans (BO) is relatively rare in children. It is char- faint when air movement is poor. The child may speak in clipped sen-
acterized by fibrotic obstruction of the respiratory bronchioles and tences or not at all because of dyspnea. Sometimes hyperinflation (bar-
alveolar ducts secondary to intense inflammation. Two types are rel chest) is visible. Respiratory rate and heart rate are elevated. Nasal
noted in the literature, proliferative and constrictive, with the latter flaring and use of accessory muscles with retractions in the subster-
being the more common form. BO most often occurs as a sequela of nal, subcostal, intercostal, suprasternal, or sternocleidomastoid areas
a severe viral pulmonary infection (e.g., influenza, adenovirus, per- are evident. Infants may appear to be “head bobbing” because of ster-
tussis [whooping cough], or measles). Other cases may be secondary nocleidomastoid muscle use. Pulsus paradoxus (decrease in systolic
to parainfluenza, RSV, human immunodeficiency virus (HIV), or blood pressure of more than 10 mm Hg during inspiration) may be
M. pneumoniae infection. It also may occur after lung, heart-lung, or present. The child may appear anxious or diaphoretic, important signs
bone marrow transplantation, or be associated with collagen vascular of respiratory compromise.
disease, toxic fume inhalation, chronic hypersensitivity pneumonitis, Findings in chronic asthma may include hyperinflation of the tho-
Crohn disease, and Stevens-Johnson syndrome.59 Although the child rax or pectus excavatum. Clubbing should not be seen with asthma
may initially improve after the acute insult, the progression of disease and, if present, should trigger evaluation for other conditions such as
is then reflected by increasing tachypnea, dyspnea, cough, sputum cystic fibrosis. Exercise intolerance may indicate underlying asthma
production, crackles, wheezing, increased chest anteroposterior diam- (see Health Alert: Exercise-Induced Bronchoconstriction).
eter (APD), and hypoxemia.
There is no specific treatment for bronchiolitis obliterans. Some EVALUATION AND TREATMENT  Asthma is often underdiagnosed
children deteriorate rapidly and die within weeks, whereas others fol- and undertreated, especially in preschool-age children because asthma
low a more chronic course. Antiviral agents may assist in blunting the symptoms overlap with other respiratory illnesses, such as bronchitis
initial viral response but otherwise have limited effect on the illness. or upper respiratory tract infections. Diagnosis of asthma is based on
Anti-inflammatory agents are showing promise in reducing airway episodes of wheezing as well as a variety of risk factors including paren-
inflammation and improving pulmonary function. For those chil- tal history of asthma, atopic dermatitis, sensitization to aeroallergens
dren having undergone lung transplantation, increased immunosup- or foods, blood eosinophilia, or wheezing not associated with upper
pressive regimens are sometimes helpful and new research is showing respiratory tract illnesses. The modified Asthma Predictive Index
promise with improved understanding of leukocyte trafficking and (API) can be used to help with asthma diagnosis and is recommended
matrix metalloproteinase-8.60 by the National Institutes of Health (NIH) guidelines.66
 CHAPTER 27  Alterations of Pulmonary Function in Children 717

1 Antigen entry to airway Early Asthmatic Response

2 Mast cell degranulation

Mast cell and release of
Antigen mediators
Mucus plug

Mucus hypersecretion
Goblet cell
Dendritic 3 Mediator
cell Mast cell effects
Vascular
leak of
Airway smooth fluid
muscle constriction
Smooth muscle

A
Late Asthmatic Response

Epithelial
damage/shedding

Vascular
cell adhesion
Th2 cell Eosinophil molecule
Neutrophil
Sensory nerve
activation Airway smooth muscle constriction
B
FIGURE 27-7  Asthmatic Responses. A, In the early asthmatic response, inhaled antigen (1) binds
to preformed IgE on mast cells. Mast cells degranulate (2) and release mediators such as histamine,
leukotrienes, prostaglandin D2, platelet activating factor, and others. Acute inflammation opens inter-
cellular tight junctions, allowing allergen to penetrate and activate submucosal mast cells. Secreted
mediators (3) induce active bronchospasm, edema, and mucus secretion causing airway obstruction.
Inflammatory responses are triggered by chemotactic factors and up-regulation of adhesion molecules
(not shown). At the same time, as shown on the left, antigen may be received by dendritic cells and
later presented, either to regional lymph nodes of naïve (Tho) T lymphocytes or locally to memory Th2
cells in the airway mucosa (see B). B, In the late asthmatic response, there are areas of epithelial
damage and shedding caused at least in part by toxicity of eosinophil products (major basic protein,
eosinophilic cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase). Many inflam-
matory cells are recruited by chemokines and up-regulation of vascular cell adhesion molecules. Local
T lymphocytes display a predominant Th2 cytokine profile. They produce IL-4 and IL-13, which promote
switching of B cells to favor IgE production; and IL-3, IL-5, and granulocyte-macrophage colony-stim-
ulating factor, which encourage eosinophil differentiation and survival. Inflammatory mediators also
activate sensory nerves, further stimulating bronchoconstriction (also see Figure 26-9).
718 CHAPTER 27  Alterations of Pulmonary Function in Children

systemic insult (such as sepsis or multiple trauma), either of which

HEALTH ALERT
activates an inflammatory response that causes alveolocapillary injury.
Exercise-Induced Bronchoconstriction ARDS accounts for approximately 10% of total patient days and one
Exercise-induced bronchoconstriction (EIB) occurs in 90% of children diag- third of all deaths in pediatric intensive care units. Mortality in pediat-
nosed with asthma. It is estimated to occur in 12% of the population without ric ARDS remains high, at approximately 40%.67
diagnosed asthma and is surprisingly common among young, elite athletes. In
the 2008 Olympics, nearly 50% of tested elite athletes had EIB, with swimmers PATHOPHYSIOLOGY  The hallmark of ARDS is lung inflammation.
demonstrating some of the highest prevalence rates. A proposed mechanism Activation of the inflammatory response (see Chapter 26, Figure 26-7)
for EIB is epithelial injury and inflammation from the inhalation of particles includes polymorphonucleocytes, complement, cytokines, arachidonic
and toxins at high flow rates. This results in increased type I hypersensitivity acid metabolites, and reactive oxygen species. Injury to pulmonary
and airway hyperresponsiveness (AHR) in those with asthma and is associated capillary endothelium results in capillary leakage and noncardiogenic
with an increase in leukotriene release. In nonasthmatics, bronchoconstriction pulmonary edema. Edema fluid contains plasma proteins that can
with exercise may be a protective reflex; however, repetitive exposure to high- inactivate surfactant, contributing further to alveolar collapse. During
flow inhaled air has been found to cause AHR and EIB over time. Although the acute phase, the pulmonary microcirculation is compromised by
bronchodilators remain the most commonly used medications for EIB, studies the formation of thrombi composed of fibrin, platelets, and leukocytes.
suggest that inhaled corticosteroids or leukotriene inhibitors are more effec- The early accumulation of edema fluid in the airspaces results in
tive and safer in children. decreased lung compliance, decreased functional residual volume, and
increased dead space. There is ventilation-perfusion mismatching,
Data from Bikov A et al: Exercise increases exhaled breath condensate intrapulmonary shunting, and hypoxemia. In the fibroproliferative
cysteinyl leukotriene concentration in asthmatic patients, J Asthma phase, type II alveolar cells proliferate, and alveolar septal thickening
47(9):1057–1062, 2010; Bougault V, Turmel J, Boulet LP: Bronchial and collagen deposition occur. Interstitial fibrosis can be evident as
challenges and respiratory symptoms in elite swimmers and winter early as 10 days after the initial insult. Similarly, vascular changes may
sport athletes: airway hyperresponsiveness in asthma: its measure- occur, including obliteration of the microcirculation and thickening of
ment and clinical significance, Chest 138(2 suppl):31S–37S, 2010;
the walls of pulmonary arterioles and arteries, which can then lead to
Kersten ET et al: Pilot study: the effect of reducing treatment on exer-
cise induced bronchoconstriction, Pediatr Pulmonol 45(9):927–933,
chronic pulmonary hypertension in survivors.
2010; Randolph C: The challenge of asthma in adolescent athletes:
exercise induced bronchoconstriction (EIB) with and without known CLINICAL MANIFESTATIONS  ARDS develops acutely after the ini-
asthma, Adolesc Med State Art Rev 21(1):44–56, viii, 2010; Szefler SJ: tial insult, usually within 24 hours, though occasionally it is delayed
Advances in pediatric asthma in 2008: where do we go now? J Allergy up to a few days. ARDS is characterized by progressive respiratory
Clin Immunol 123(1):28–34, 2009. distress, severe hypoxemia, decreased pulmonary compliance, and dif-
fuse densities on chest radiograph. Initially, hyperventilation occurs,
Confirmation of the diagnosis of asthma relies on pulmonary func- but CO2 retention may ultimately occur as well because of inadequate
tion testing using spirometry, which can be accomplished only after functional airspace and respiratory muscle fatigue. The severity of the
the child is 5 to 6 years of age. For younger children, an empiric trial of overall picture is modified by comorbid factors, such as the presence of
asthma medications is commonly initiated. sepsis or multiorgan failure, and by the presence or absence of compli-
The goal of asthma therapy is to achieve long-term control by reduc- cations, such as nosocomial pneumonia. Some children who recover
tion in impairment and risk.66 Child/family education and appropriate have residual pulmonary abnormalities.
allergen avoidance techniques should begin immediately. Care pro-
viders need to periodically assess asthma control in children. Key fea- EVALUATION AND TREATMENT  Treatment for ARDS remains
tures for assessment include nighttime awakenings, interference with supportive in nature, and the goals are to maintain adequate tissue
normal activities, use of short-acting β2-agonists, pulmonary function oxygenation, minimize acute lung injury, and avoid iatrogenic pulmo-
testing, and exacerbations requiring steroids. Peak flow meters are nary complications. Most individuals with ARDS require mechanical
often used to help guide treatment. Before therapy is augmented, care ventilation and often relatively high levels of positive end-expiratory
providers need to assess medication administration techniques, envi- pressure (PEEP) to promote alveolar ventilation and stabilization,
ronmental controls, and comorbidities. For reduction in therapy, the and redistribution of alveolar edema fluid into the interstitium.
asthma needs to be under good control for a minimum of 3 months.66 Lung-protective ventilation strategies may include low tidal volume,
The pharmacologic treatment of asthma in children is essentially permissive hypercapnia, prone positioning, and high-frequency oscil-
the same as that for adults and is initiated in a stepwise sequence based lation. Systemic steroids remain a mainstay of treatment to decrease
on asthma severity and response to treatment (see Chapter 26). postextubation stridor and reduce reintubation rates.68 Inhaled nitric
oxide and prostacyclins are under investigation although results have
4 QUICK CHECK 27-4 not been encouraging to date.69,70
1. What are the key features of the early and late asthmatic responses?
Cystic Fibrosis
2. Explain the full progression of blood gas abnormalities in a severe asthma
attack. Cystic fibrosis (CF) is an autosomal recessive inherited disease that
results from defective epithelial chloride ion transport. The CF gene
is located on chromosome 7. There are more than 1500 known muta-
tions of this gene divided into 5 classes.71 These mutations result in
Acute Respiratory Distress Syndrome abnormal expression of the protein cystic fibrosis transmembrane
Acute respiratory distress syndrome (ARDS) is a dramatic, life- conductance regulator (CFTR), which is a chloride channel present
threatening condition resulting from a direct pulmonary insult (such on the surface of many types of epithelial cells including airways, bile
as pneumonia, aspiration, near drowning, or smoke inhalation) or a ducts, pancreas, sweat ducts, and vas deferens.72,73 CF affects primarily
 CHAPTER 27  Alterations of Pulmonary Function in Children 719

whites (approximately 1 in 3500 in North America and Europe). There The CF airway microenvironment favors bacterial colonization.
are approximately 1000 new cases of CF diagnosed each year and the Pseudomonas aeruginosa ultimately colonizes airways in at least 75%
median age at diagnosis is 6 months. The projected life expectancy for of children with CF and Staphylococcus aureus is common. Persistence
those with CF has increased from 31 years to 37 years over the past of these microorganisms incites chronic local inflammation and air-
decade. The estimated carrier frequency is high, 1 in 29 whites in the way damage with microabscess formation, bronchiectasis, patchy con-
United States. Carriers are not affected by the mutation. solidation and pneumonia, peribronchial fibrosis, and cyst formation
(Figure 27-8).71,73 The pathogenesis for these changes is outlined in
PATHOPHYSIOLOGY  Although CF is a multiorgan disease, its most Figure 27-9. Peripheral bullae may develop and pneumothorax may
important effects are on the lungs, and respiratory failure is almost occur. Hemoptysis, sometimes life-threatening, may occur because of
always the cause of death. The typical features of CF lung disease are the erosion of enlarged bronchial arteries. Over time, pulmonary vas-
mucus plugging, chronic inflammation, and chronic infection. The cular remodeling occurs because of localized hypoxia and arteriolar
mucus plugging seen in CF results from both increased production vasoconstriction. Pulmonary hypertension and cor pulmonale may
and altered physicochemical properties of the mucus. Mucus-secreting develop in the late stages of disease.
airway cells (goblet cells and submucosal glands) are increased in num-
ber and size. CF mucus is dehydrated and viscous because of defec- CLINICAL MANIFESTATIONS  The most common presenting symp-
tive chloride secretion and excess sodium absorption. The periciliary toms of CF are respiratory or gastrointestinal (see Chapter 35). Respi-
fluid layer is depleted in volume, impairing the mobility of the cilia ratory symptoms include persistent cough or wheeze and recurrent or
and thereby allowing mucus to adhere to the airway epithelium, along severe pneumonia. Physical signs that develop over time include barrel
with bacteria and injurious by-products from neutrophils.71-73 Neu- chest and digital clubbing. More subtle presentations include chronic
trophils are present in great excess in the airways and release damag- sinusitis and nasal polyps. Newborn screening for CF has expanded
ing oxidants and proteases that cause direct damage to lung structural rapidly throughout the United States and will increase the numbers of
proteins, induce airway cells to produce interleukin-8 (IL-8) (which early, presymptomatic diagnosis (see Health Alert: Newborn Screening
attracts more neutrophils and stimulates mucus secretion), and destroy for Cystic Fibrosis).74
immunoglobulin G (IgG) and complement components important for
opsonization and phagocytosis of pathogens.71 EVALUATION AND TREATMENT  The standard method of diagnosis
is the sweat test, which reveals sweat chloride concentration in excess
of 60 mEq/L. Genotyping for CFTR mutations is available as an alter-
native or supplemental method.72,73 Treatment is primarily focused on
nutrition (see Chapter 35) and pulmonary health.

CFTR defect

Dehydrated mucus

Impaired mucus
clearance Mucus
hypersecretion

↑ DNA, F-actin
content in Chronic bacterial
Reduced
mucus infection
opsonophagocytosis
↑ IL-8

Chronic neutrophilic ↑ Neutrophil

inflammation elastase

FIGURE 27-8  Pathology of the Lung in End-Stage Cystic Fibro- Degradation of

sis. Key features are widespread mucus impaction of airways and structural proteins
bronchiectasis (especially from the upper lobe [U]), with hemor- Bronchiectasis
rhagic pneumonia in the lower lobe (L). Small cysts (C) are present
at the apex of the lung. (From Kleinerman J, Vauthy P: Pathology of FIGURE 27-9  Pathogenesis of Cystic Fibrosis Lung Disease.
the lung in cystic fibrosis, Atlanta, 1976, Cystic Fibrosis Foundation.) CFTR, Cystic fibrosis transmembrane conductance regulator.
720 CHAPTER 27  Alterations of Pulmonary Function in Children

HEALTH ALERT HEALTH ALERT

Newborn Screening for Cystic Fibrosis Gene Therapies for Cystic Fibrosis
Unfortunately, the diagnosis of cystic fibrosis (CF) is still frequently missed After sequencing the cystic fibrosis (CF) gene in 1989, hopes were voiced for
or significantly delayed, and only made after hospitalization for unexplained a gene therapy “cure” within 5 years. Ideally, the normal cystic fibrosis trans-
recurrent respiratory symptoms and failure to thrive. Neonatal screening membrane conductance regulator (CFTR) gene could be inhaled or sprayed into
results in early diagnosis for CF and is based on measuring the amount of the lungs and thereby halt disease progression. The task has proven more for-
immunoreactive trypsinogen (IRT)