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Underwood’s
Pathology
SIXTH EDITION
Senior Content Strategist: Jeremy Bowes
Content Development Specialist: Sheila Black
Project Manager: Julie Taylor
Designer Direction: Miles Hitchen
Illustration Manager: Jennifer Rose
Underwood’s
Pathology
a clinical approach
SIXTH EDITION

Edited by
Simon S. Cross MD FRCPath
Professor of Diagnostic Histopathology and Honorary Consultant Histopathologist,
Academic Unit of Pathology, Department of Neuroscience, Faculty of Medicine,
Dentistry & Health, The University of Sheffield, Sheffield, UK

Illustrations and chapter icons by Robert Britton and Antbits Ltd

Edinburgh London New York Oxford Philadelphia St Louis Sydney Toronto 2013
© 2013 Elsevier Ltd. All rights reserved.

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Publisher (other than as may be noted herein).

First edition 1992

Second edition 1996
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Fourth edition 2004
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Sixth edition 2013

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CONTENTS

Preface vi PART 3 SYSTEMATIC PATHOLOGY

Acknowledgements vii
13 Cardiovascular system 246
International Advisers viii
Patrick J. Gallagher, Allard C. van der Wal
Contributors ix
Index of patient symptoms x 14 Respiratory tract 288
William A. H. Wallace
PART 1 BASIC PATHOLOGY
15 Alimentary system 322
1 What is pathology? 3 Heike I. Grabsch
James C. E. Underwood
16 Liver, biliary system and pancreas 360
2 What is disease? 11 Judith I. Wyatt, Beate Haugk
James C. E. Underwood
17 Endocrine system 392
3 What causes disease? 27 Timothy J. Stephenson
James C. E. Underwood, Simon S. Cross
18 Breast 420
Louise J. Jones
PART 2 DISEASE MECHANISMS
19 Female genital tract 442
4 Disorders of growth, differentiation
Michael Wells
and morphogenesis 57
Jonathan P. Bury 20 Urinary and male genital tracts 470
John R. Goepel
5 Responses to cellular injury 79
John R. Goepel, Jonathan P. Bury 21 Kidney diseases 500
Ian S. D. Roberts
6 Disorders of metabolism and
homeostasis 99 22 Lymph nodes and extranodal
Stephen R. Morley lymphoid tissue, spleen and thymus 530
Bridget S. Wilkins
7 Ischaemia, infarction and shock 121
Simon S. Cross 23 Blood and bone marrow 556
Dominic Culligan, Henry G. Watson
8 Immunology and immunopathology 133
W. A. Carrock Sewell 24 Skin 612
Colin Moyes, Karen Blessing
9 Inflammation 165
Timothy J. Stephenson 25 Osteoarticular and connective
tissues 640
10 Carcinogenesis and neoplasia 183
David E. Hughes
Mark J. Arends
26 Central and peripheral nervous
11 Ageing and death 221
systems 674
Emyr W. Benbow
James W. Ironside
12 How do pathologists help patient
care? 233 Glossary 721
Patricia V. Vergani Index 731

v
 PREFACE

Underwood’s Pathology has been written, designed and pro­ (Systematic Pathology) deals in detail with specific diseases,
duced primarily for students of medicine and for those study­ with emphasis on the clinically important aspects.
ing related health science subjects, such as biomedical To assist students in finding the relevant sections of the
scientists. The causes and mechanisms of disease and the book when following a problem-based course we have added
pathology of specific conditions are presented in the contexts a problem-based index at the front of the book and body
of modern cellular and molecular biology and of contempo­ diagrams at the beginning of each systematic pathology
rary clinical practice. chapter which link clinical signs and symptoms to patholo­
Emphasis on problem-based and self-directed learning gies described in that chapter. We must emphasise that the
in medicine continues to grow, often with a concomitant body diagrams and problem-based index are for educational
reduction in didactic teaching and practical pathology purposes rather than for use as a diagnostic aid. Supplemen­
experience. Therefore, the student’s need for a well- tary material is available on the companion website.
illustrated comprehensive source of reliable knowledge Underwood’s Pathology has been praised for its relevance,
about dis­ease has never been greater. Underwood’s Pathology content and clarity. Maintaining this high standard in­
fulfils that need. volves much activity between editions, often in response
Part 1 (Basic Pathology) introduces the student to key to feedback from students and their teachers. We con­
general principles of pathology, both as a medical science tinue to welcome comments and suggestions for further
and as a clinical activity with a vital role in patient care. Part improvements.
2 (Disease Mechanisms) provides fundamental knowledge
about the cellular and molecular processes involved in dis­ SSC Sheffield
eases, providing the rationale for their treatment. Part 3 2012

vi
ACKNOWLEDGEMENTS

This textbook (first titled General and Systematic Pathology) previous editions. I welcome several new contributors to
was conceived by Professor Sir James Underwood when he the book and they have brought great enthusiasm to their
was Professor of Pathology at the University of Sheffield, and revised chapters.
the first edition was published in 1992. It received a warm I have also greatly valued the many comments and sug-
welcome from students and teachers and in the subsequent gestions received from students and their teachers world-
four editions James has refined and improved the textbook. wide. I thank Friyana Dastur-Mackenzie for her assistance
James has now retired to beautiful Cumbria and I am very in compiling the problem-based index for the book. I thank
privileged that he has passed the editorship to me. I hope I the publishing team at Elsevier for continuing the highly
can maintain his very high standards. I am pleased that professional standard of this book’s production. Finally, and
James has still contributed the first three chapters of the most importantly, I would like to thank my wife, Frances,
book, which give an important overview of the scope of for all her support.
pathology. Along with James, a number of other contributors SSC Sheffield
have retired and I thank them for all their hard work on the 2012

vii
 INTERNATIONAL ADVISERS

It is hoped that this textbook will prove a valuable learning

resource internationally. The contribution of the following
international advisors is gratefully recognised.

Professor Y. Collan Professor S. Mori

Department of Pathology Institute of Medical Sciences
University of Turku University of Tokyo
Turku Tokyo
Finland Japan

Dr J. P. Cruse Professor H. K. Muller

King Fahad National Guard Hospital Department of Pathology
Riyadh University of Tasmania
Saudi Arabia Hobart
Australia
Dr I. Damjanov
Department of Pathology Professor I. O. L. Ng
University of Kansas Department of Pathology
Kansas City University of Hong Kong
United States of America Hong Kong

Dr H. Goldman Professor S. Pervez

Harvard Medical School Department of Pathology and Microbiology
Boston Aga Khan University Hospital
United States of America Karachi
Pakistan
Professor Lai-Meng Looi
Department of Pathology Professor K. Ramnarayan
University of Malaya Department of Pathology
Kuala Lumpur Melaka Manipal Medical College
Malaysia Manipal
India
Professor T. L. Miko
Department of Histopathology Dr K. Ramesh Rao
Szent-Györgyi University Medical School Department of Pathology
Szeged Sri Ramachandran Medical College
Hungary Chennai
India
Professor W. J. Mooi
Department of Pathology Professor R. H. Riddell
VU University Medical Centre Department of Pathology and Laboratory Medicine
Amsterdam University of Toronto
The Netherlands Toronto
Canada

viii
CONTRIBUTORS
Mark J. Arends BSc(Hons) MA MBChB(Hons) PhD FRCPath Stephen R. Morley DM LLM MRCP FRCPath MFFLM
Reader and Honorary Consultant, Department of Pathology, Clinical Lead for Clinical Chemistry, Sheffield Teaching
University of Cambridge and Addenbrooke’s Hospital, Hospitals; Consultant Chemical Pathologist and Toxicologist,
Cambridge, UK Northern General Hospital, Sheffield, UK

Emyr W. Benbow BSc MBChB FRCPath Colin Moyes BSc(Hons) MBChB FRCPath
Senior Lecturer in Pathology, Department of Histopathology, Consultant Pathologist, Departments of Pathology,
Manchester Royal Infirmary, Manchester, UK Southern General Hospital, Glasgow, UK

Karen Blessing MD FRCPath Ian S. D. Roberts MBChB FRCPath

Consultant Dermatopathologist, Department of Pathology, Professor of Cellular Pathology, University of Oxford, and
Southern General Hospital, Glasgow, UK Consultant Pathologist, Department of Cellular Pathology,
John Radcliffe Hospital, Oxford, UK
Jonathan P. Bury BMedSci MBChB MPhil FRCPath
Consultant Histopathologist and Honorary Senior Lecturer, W. A. Carrock Sewell MBBS PhD FRCP FRCPath
Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK Consultant Immunologist and Visiting Professor of
Immunology, Path Links Immunology, Scunthorpe General
Simon S. Cross MD FRCPath Hospital, Scunthorpe, UK
Professor of Diagnostic Histopathology and Honorary
Consultant Histopathologist, Academic Unit of Pathology, Timothy J. Stephenson MD MA MBA FRCPath
Department of Neuroscience, Faculty of Medicine, Clinical Director and Honorary Professor, Department of
Dentistry & Health, The University of Sheffield, Sheffield, UK Histopathology, Royal Hallamshire Hospital, Sheffield, UK

Dominic Culligan BSc MBBS MD FRCP FRCPath James C. E. Underwood MD FRCPath FRCP FMedSci
The Aberdeen and North Centre for Haematology, Oncology Emeritus Professor of Pathology, University of Sheffield,
and Radiotherapy (ANCHOR), Aberdeen Royal Infirmary, Sheffield, UK
Aberdeen, UK
Allard C. van der Wal MD PhD
Patrick J. Gallagher MD PhD FRCPath Clinical Pathologist and Professor, Department of Pathology,
Honorary Clinical Senior Lecturer, Centre for Medical Academic Medical Center, University of Amsterdam,
Education, University of Bristol, Bristol, UK Amsterdam, NL

John R. Goepel MBChB FRCPath Patricia V. Vergani MD

Consultant Histopathologist and Honorary Senior Lecturer, Consultant and Honorary Senior Lecturer, Department of
Department of Histopathology, Royal Hallamshire Hospital, Histopathology, Sheffield Teaching Hospitals NHS Foundation
Sheffield, UK Trust, Sheffield, UK

Heike I. Grabsch MD PhD PGCertHealthRes FRCPath William A. H. Wallace BSc(Hon) MBChB(Hon)

Associate Professor in Pathology and Honorary Consultant PhD FRCPE FRCPath
Histopathologist, Section of Pathology and Tumour Biology, Consultant and Honorary Reader in Pathology, Department of
Leeds Institute of Molecular Medicine, University of Leeds, Pathology, Royal Infirmary of Edinburgh, Edinburgh, UK
Leeds, UK
Henry G. Watson MBChB MD FRCP FRCPath
Beate Haugk MD FRCPath Consultant Haematologist, Department of Haematology,
Consultant Histopathologist, Department of Cellular Aberdeen Royal Infirmary, Aberdeen, UK
Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
Michael Wells BSc(Hons) MBChB MD FRCPath FRCOG
David E. Hughes BMedSci PhD MBChB Professor of Gynaecological Pathology and Honorary
Consultant Histopathologist, Department of Histopathology, Consultant Histopathologist, Department of Oncology,
Royal Hallamshire Hospital, Sheffield, UK University of Sheffield Medical School, Sheffield, UK

James W. Ironside CBE BMSc MBChB FRCPath Bridget S. Wilkins BSc MBBChir DM PhD FRCPath
FRCP(Edin), FMedSci FRSE Consultant Histopathologist, Cellular Pathology Department,
Professor of Clinical Neuropathology and Honorary Consultant St Thomas’ Hospital, London, UK and Honorary Senior
Neuropathologist, National CJD Research and Surveillance Lecturer, King’s College London, UK
Unit, Western General Hospital, Edinburgh, UK
Judith I. Wyatt MBChB FRCPath
Louise J. Jones BSc MBChB PhD FRCPath Consultant Histopathologist, Department of Histopathology,
Professor of Breast Pathology; Clinical Senior Lecturer and St James’s University Hospital, Leeds Teaching Hospitals NHS
Honorary Consultant in Pathology, Centre for Tumour Biology, Trust, Leeds, UK ix
Institute of Cancer, Barts and The London School of Medicine
and Dentistry, London, UK
 INDEX OF PATIENT SYMPTOMS

Patient’s symptom Possible pathological causes of this symptom Page number

Abdominal pain, acute Aortic aneurysm 252

Appendicitis 357
Cholecystitis 385
Crohn’s disease 346
Diverticulitis 351
Ectopic pregnancy 468
Gastroenteritis 345
Ischaemic bowel 349
Pancreatitis 387
Peptic ulcer 334
Pyelonephritis 524
Stones in bile duct – biliary colic 361
Stones in ureter – renal colic 472
Ulcerative colitis 348

Abdominal pain, chronic Chronic peptic ulcer 334

Crohn’s disease 346
Diverticular disease 351
Endometriosis 458
Fibroids 457
Gallstones 384
Hydronephrosis 523
Ovarian cysts/tumour 457
Ulcerative colitis 348
Uteric colic 502

Abdominal swelling Aortic aneurysm 253

Colorectal cancer 355
Enlarged bladder due to obstruction 524
Fibroid uterus 457
Gastric cancer 336
Ovarian cyst/tumour 457
Pancreatic cancer 388
Polycystic kidneys 525
Pregnancy 443
Splenomegaly 549

Anorectal pain Anal fissure 358

Anorectal cancer 358
Crohn’s disease 346
Perianal abscess 358
Thrombosed haemorrhoids 358

Arm pain Cervical spondylosis 657

Myocardial ischaemia 267

Back pain Ankylosing spondylitis 661

Bone metastases 655
Duodenal ulcer 333
Myeloma 597
Osteoarthritis 656
Prolapsed intervertebral disc 662
Pyelonephritis 524
Renal stones 472
Vertebral collapse due to osteoporosis 647

x
 INDEX OF PATIENT SYMPTOMS

Patient’s symptom Possible pathological causes of this symptom Page number

Blood in urine Bladder tumour 476

Glomerulonephritis 508
Polycystic kidney disease 525
Prostate cancer 481
Prostatic hyperplasia 479
Renal carcinoma 473
Renal/ureteric stones 472
Urethritis 487
Urinary tract infection 487

Body hair, excess Polycystic ovary syndrome 458

Breast enlargement, men Chronic liver disease 368

Hyperthyroidism 406

Breast lump Abscess 426

Breast cancer 430
Cyst 428
Duct ectasia 426
Fat necrosis 426
Fibroadenoma 429
Fibrocystic disease 426
Lipoma 430

Breast pain Cyclical mastalgia 423

Mastitis/breast abscess 426
Pregnancy 423

Breath, shortness of, acute Acute exacerbation of chronic obstructive 309

pulmonary disease
Acute left ventricular failure 265
Asthma 309
Diabetic ketoacidosis 416
Pneumonia 297
Pneumothorax 320
Pulmonary embolism 125

Breath, shortness of, chronic Anaemia 570

Aortic valve stenosis 275
Asthma 416
Chronic obstructive pulmonary disease 309
Congenital heart disease 280
Congestive cardiac failure 265
Recurrent pulmonary emboli 125

Calf pain Deep vein thrombosis 124

Chest pain Dissecting aortic aneurysm 253

Gastro-oesophageal reflux disease 329
Myocardial infarction 267
Myocardial ischaemia 267
Pleurisy 298
Pulmonary embolism 125

Confusion Cerebral haemorrhage 687

Cerebral infarction 686
Cerebral tumour 705
Diabetic ketoacidosis 416
Hypoglycaemia 696
Hypothyroidism 407
xi
 INDEX OF PATIENT SYMPTOMS

Patient’s symptom Possible pathological causes of this symptom Page number

Consciousness, loss of, episodic Aortic valve stenosis 275

Epilepsy 680
Hypoglycaemia 696
Paroxysmal arrhythmias 272

Constipation Colorectal cancer 355

Diverticular disease 351
Hirschsprung’s disease 341

Cough Asthma 309

Bronchiectasis 301
Chronic bronchitis 297
Left ventricular failure 265
Lung cancer 315
Respiratory tract infection 296
Tuberculosis 300

Coughing up blood Chest infection 296

Lung cancer 315
Mitral valve stenosis 274
Pulmonary embolism 125

Diarrhoea Acute infective gastroenteritis 345

Carcinoid tumour 356
Chronic intestinal infection 343
Coeliac disease 341
Colorectal cancer 355
Crohn’s disease 346
Diverticulitis 351
Drugs, e.g. antibiotics 346
Ulcerative colitis 348

Dizziness Cardiac arrhythmia 272

Hypoglycaemia 696

Epigastric pain Gallstones 384

Gastritis 332
Gastro-oesophageal reflux disease 329
Pancreatitis 387
Peptic ulcer 334

Eye, painful red Acute glaucoma 717

Acute infective conjunctivitis 661
Acute iritis 314
Corneal abrasion 716
Corneal ulcer 716

Facial swelling Hypothyroidism 645

Facial ulcers and blisters Basal cell carcinoma 625

Herpes simplex virus 325
Impetigo 617
Keratoacanthoma 626

Fever Chronic pyelonephritis 524

Leukaemia 586
Lymphoma 537
Rheumatoid arthritis 657

xii
 INDEX OF PATIENT SYMPTOMS

Patient’s symptom Possible pathological causes of this symptom Page number

Finger clubbing Bronchiectasis 301

Lung cancer 315

Fits Cerebral metastases 709

Primary cerebral tumours 705

Flushing Carcinoid syndrome 462

Hyperglycaemia 416
Hyperthyroidism 406
Hypoglycaemia 696

Foot pain Gout 663

Osteoarthritis 656
Verruca 619

Gait, abnormal Intermittent claudication 252

Multiple sclerosis 694
Osteoarthritis 656
Parkinson’s disease 704
Spinal nerve root pain 683

Haemoptysis Bronchiectasis 301

Lung cancer 315
Pulmonary embolism 125
Respiratory tract infection 296
Tuberculosis 300

Hair loss Alopecia areata 634

Hypoparathyroidism 413
Hypopituitarism 397
Hypothyroidism 407
Male pattern baldness 634
Tinea capitis 619

Hallucinations Cerebral tumour 705

Temporal lobe epilepsy 698

Headache Cerebral metastases 709

Cervical spondylosis 657
Intracerebral haemorrhage 687
Meningitis 689
Primary cerebral tumours 705
Temporal arteritis 669

Incontinence Prostatic hypertrophy 479

Urinary tract infection 487

Infertility Chronic salpingitis 463

Endometriosis 458
Hypopituitarism 397
Uterine fibroids 457

Intercourse, painful Endometriosis 458

Pelvic inflammatory disease 443
Vulvovaginitis 443

xiii
 INDEX OF PATIENT SYMPTOMS

Patient’s symptom Possible pathological causes of this symptom Page number

Itching Head lice 613

Hodgkin’s disease 537
Impetigo 617
Jaundice, typically obstructive 366
Lichen planus 620
Pityriasis rosea 622
Psoriasis 621
Scabies 617
Uraemia of renal failure 507
Urticaria 620

Jaundice Alcoholic cirrhosis 369

Carcinoma of bile duct 381
Carcinoma of head of pancreas 390
Cholangitis 384
Cholestasis of pregnancy 384
Drug-induced cholestasis 384
Gallstones in bile duct 384
Haemolytic anaemia 577
Primary biliary cirrhosis 374
Viral hepatitis 371

Joints, pain, multiple Osteoarthritis 656

Psoriatic arthropathy 641
Rheumatoid arthritis 657

Joints, pain, single Acute exacerbation of osteoarthritis 656

Gout/pseudogout 663

Libido, loss of Hypothyroidism 407

Memory loss Alzheimer’s disease 701

Cerebral infarcts 686
Hypothyroidism 645
Subarachnoid haemorrhage 688
Traumatic head injury 682

Neck, lumps Goitre 407

Lymphoma 537
Prominent normal lymph nodes 534
Reactive lymphadenitis 535
Sebaceous cyst 624

Neck, stiff Ankylosing spondylitis 661

Cervical spondylosis 657
Rheumatoid arthritis 657

Nipple discharge Duct ectasia 426

Duct papilloma 430
Intraduct carcinoma 437
Mastitis/breast abscess 426
Pregnancy 423
Prolactinoma 399

xiv
 INDEX OF PATIENT SYMPTOMS

Patient’s symptom Possible pathological causes of this symptom Page number

Numbness/paraesthesiae Cerebrovascular accident 686

Cervical spondylosis 657
Diabetic neuropathy 91
Multiple sclerosis 694
Peripheral polyneuropathy 710
Prolapsed intervertebral disc 683

Palpitations Hyperthyroidism 406

Ischaemic heart disease 267
Mitral valve disease 274

Pelvic pain Ectopic pregnancy 468

Endometriosis 458
Ovarian cysts/tumours 457
Pelvic inflammatory disease 443
Urinary tract infection 487

Penile pain Balanitis 484

Balanitis xerotica obliterans 484
Herpes simplex 484
Prostatitis 478
Urethritis 487

Penile ulceration Balanitis 484

Balanitis xerotica obliterans 484
Herpes simplex 484

Periods, absence Polycystic ovary syndrome 458

Pregnancy 443

Periods, heavy Cervical polyps 447

Dysfunctional uterine bleeding 443
Endometrial carcinoma 455
Endometrial polyps 454
Endometriosis 458
Fibroids 457

Periods, painful Chronic pelvic inflammatory disease 443

Endometrial polyp 454
Endometriosis 458
Uterine malformation 452

Puberty, delayed Hyperthyroidism 406

Purpura Infective endocarditis 275

Vasculitis 259

Rectal bleeding Anal fissure 358

Bowel ischaemia 350
Colonic angiodysplasia 351
Colorectal adenomas 355
Colorectal cancer 346
Crohn’s disease 346
Diverticular disease 351
Endometriosis 458
Gastroenteritis 345
Haemorrhoids 358
Ulcerative colitis 348

xv
 INDEX OF PATIENT SYMPTOMS

Patient’s symptom Possible pathological causes of this symptom Page number

Rectal pain Anal fissure 358

Anorectal malignancy 358
Perianal abscess 323
Prostatitis 478
Thrombosed haemorrhoids 358

Scrotal swelling Hydrocele 490

Epididymal cyst 708
Epididymo-orchitis 496
Torsion of testes 496

Skin blisters Eczema 615

Herpes simplex 325
Pemphigoid 627
Pemphigus 627
Trauma 626

Skin nodules Basal cell carcinoma 625

Dermatofibroma 636
Lipoma 672
Sebaceous cyst 624
Squamous cell carcinoma 624
Viral warts 619

Skin papules Acne 634

Molluscum contagiosum 619
Scabies 617
Viral warts 619

Skin pustules Acne vulgaris 634

Herpes simplex 325
Impetigo 617

Skin scales/plaques Eczema 615

Psoriasis 621
Seborrhoeic dermatitis 623
Seborrhoeic keratosis 623
Tinea infections 619

Swallowing, difficulty Benign oesophageal stricture 329

Gastro-oesophageal reflux disease 329
Oesophageal cancer 330
Pharyngeal cancer 326

Sweating, excessive Hyperthyroidism 645

Hypoglycaemia 696

Swollen ankles Acute renal failure 519

Chronic renal failure 506
Congestive cardiac failure 265
Nephrotic syndrome 507
Venous insufficiency 247

Swollen glands Leukaemia 586

Lymphoma 537
Rheumatoid arthritis 657

xvi
 INDEX OF PATIENT SYMPTOMS

Patient’s symptom Possible pathological causes of this symptom Page number

Testicular pain Acute epididymo-orchitis 496

Acute orchitis 490
Haematocele 490
Hydrocele 490
Torsion of testes 496
Varicocele 496

Thirst Chronic renal failure 506

Diabetes mellitus 415

Tiredness Anaemia 569

Chronic renal failure 506
Hypothyroidism 645

Tremor Cerebellar tumour 706

Cerebrovascular accident 686
Hyperthyroidism 406
Liver failure 377
Multiple sclerosis 694
Parkinson’s disease 704

Urinary frequency Bladder calculus 476

Prostatic hypertrophy 479
Urinary tract infection 487

Urinary retention Bladder neck obstruction 524

Prostatic hypertrophy 479
Urethral obstruction 487

Urination, excessive Chronic pyelonephritis 524

Chronic renal failure 506
Diabetes mellitus 415

Vaginal bleeding Cervical cancer 450

Cervical polyps 447
Cervicitis 447
Endometrial cancer 455
Endometrial polyps 453
Hydatidiform mole 464
Ovarian cancer 459
Vaginal cancer 447

Vaginal discharge Bacterial vaginosis 443

Candida infection 445
Cervical polyp 447
Cervicitis 447
Trichomonas infection 447

Vertigo Acute viral labyrinthitis 719

Epilepsy 698
Ménière’s disease 719
Vertebrobasilar ischaemia 247

Vision, loss of, acute Acute glaucoma 717

Central retinal artery occlusion 715
Cerebrovascular accident 686
Temporal arteritis 261
Vitreous haemorrhage 675

xvii
 INDEX OF PATIENT SYMPTOMS

Patient’s symptom Possible pathological causes of this symptom Page number

Vision, loss of, gradual Cataract 717

Chronic glaucoma 717
Diabetic retinopathy 716
Hypertensive retinopathy 715
Senile macular degeneration 717

Vomiting Acute viral labyrinthitis 719

Appendicitis 357
Gastroenteritis 345
Hyperglycaemia 416
Hypoglycaemia 696
Perforated peptic ulcer 334
Pyelonephritis 524
Pyloric stenosis 332
Stenosing gastric cancer 334
Ureteric calculus 475

Vomiting blood Acute gastritis 332

Blood dyscrasia, e.g. thrombocytopenia 562
Gastric cancer 336
Gastro-oesophageal reflux 329
Mallory–Weiss tear 328
Oesophageal cancer 330
Oesophageal varices 378
Peptic ulcer 334

Vulval irritation Candida infection 445

Trichomonas vaginalis 447

Vulval swelling Bartholin’s cyst 445

Vulval ulceration Candida infection 445

Herpes simplex 445
Squamous cell carcinoma 446

Weight gain Hypothyroidism 407

Oedema of chronic renal failure 506

Weight loss Hyperthyroidism 406

Untreated type 1 diabetes mellitus 415

xviii
PART 1
BASIC PATHOLOGY
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1
What is pathology?
James C. E. Underwood

History of pathology 4 Building knowledge and understanding

Morbid anatomy Pathology in the problem-oriented integrated medical
Microscopic and cellular pathology curriculum
Molecular pathology
Cellular and molecular alterations in disease Making diagnoses 9
Diagnostic pathology
Scope of pathology 5 Autopsies
Clinical pathology
Pathology and populations 9
Techniques of pathology 5 Causes and agents of disease
The health of a nation
Learning pathology 7 Preventing disability and premature death
Disease mechanisms
Systematic pathology

3
1 What is pathology?

Of all the clinical disciplines, pathology is the one that most

directly reflects the demystification of the human body that Table 1.1 Historical relationship between the hypothetical
causes of disease and the dependence on techniques
has made medicine so effective and so humane. It expresses
for their elucidation
the truth underpinning scientific medicine, the inhuman
truth of the human body, and disperses the mist of evasion
Hypothetical Techniques Period
that characterises folk medicine and everyday thinking cause of disease supporting causal
about sickness and health. hypothesis
From: Hippocratic Oaths by Raymond Tallis
Animism None Primitive, though
Pathology is the scientific study of disease. Pathology comprises the ideas persist
a large body of scientific knowledge and diagnostic methods in some cultures
that are essential, first, for understanding diseases and their
causes and, second, for their effective prevention and treat- Magic None Primitive, though
the ideas persist
ment. Pathology embraces the functional and structural
in some cultures
changes in disease, from the molecular level to the effects
on the individual patient. Pathology is continually changing Humours (excess Early autopsies and c. 500 BC to
and expanding as new research illuminates our knowledge or deficiency) clinical observations c. AD 1500
of disease.
The ultimate goal of pathology is the identification of the Spontaneous Analogies with Prior to AD 1800
causes of disease. This fundamental objective leads to suc- generation decomposing matter
cessful therapy and to disease prevention. Without pathol- (abiogenesis)
ogy, the practice of medicine would still rely on myths and
folklore. Environmental Modern autopsy 1850 to present
Cellular pathology
(e.g. microscopy)
Toxicology
HISTORY OF PATHOLOGY
Microbiology
Evolving concepts about the causes and nature of human Epidemiology
disease reflect prevailing explanations for all worldly events
and also the techniques available for their investigation Genetic Molecular pathology 20th century to
(Table 1.1). Thus, the early dominance of animism, for (e.g. DNA analysis) and present
example in the philosophies of Plato (424–348 bc) and clinical observations on
inherited defects
Pythagoras (c. 580–c. 500 bc), resulted in the belief that
disease was due to the adverse effects of immaterial or
supernatural forces, often as punishment for wrongdoing.
Treatment was often brutal and ineffective.
When many symptoms, signs and post-mortem findings period is regarded as the era of morbid anatomy. A notable
were first believed to have natural explanations, the underly- landmark was the publication in 1761 of De Sedibus et Causis
ing disease was postulated to be due to an imbalance (‘iso- Morborum per Anatomem Indagatis by Giovanni Morgagni
nomia’) of the four humours − phlegm, black bile, yellow (1682–1771). During the 18th and 19th centuries in Europe,
bile and blood − as proposed by Empedocles (490–430 bc) medical science was further advanced by Matthew Baillie
and Hippocrates (c. 460–370 bc). These concepts are now (1761–1823), Carl von Rokitansky (1804–1878) and Ludwig
obsolete. Aschoff (1866–1942); they meticulously performed and
Galen (129–c. 200) built on Hippocrates’ naturalistic ideas documented many thousands of autopsies and, crucially,
about disease by giving them an anatomical and physiologi- correlated their findings with the clinical signs and symp-
cal basis. However, it was probably Ibn Sina (980–1037) − toms of the patients and with the natural history of numer-
commonly known as Avicenna − who, by his Canon of ous diseases.
Medicine, pioneered advances in medicine through scientific
discovery by observation, experimentation and clinical trials.
Microscopic and cellular pathology
Pathology, and indeed medicine as a whole, was revolution-
Morbid anatomy ised by the application of microscopy to the study of diseased
Some of the greatest advances in the scientific study of tissues from about 1800. Previously, it was commonly
disease emerged from internal examination of the body after believed that tissue alterations in disease resulted from a
death. Autopsies (necropsies or post-mortem examinations) process of spontaneous generation; that is, by metamorphosis
have been performed scientifically from about 300 bc and independent of any external cause or other influence. Today,
have thus helped to clarify the nature of many diseases. As this notion seems ridiculous, but 200 years ago nothing was
these examinations were confined initially to the gross known of bacteria, viruses, ionising radiation, carcinogenic
4 (rather than microscopic) examination of the organs, this chemicals, and so on. So Louis Pasteur’s (1822–1895)
 Techniques of pathology 1
demonstration that microorganisms in the environment Approximately 70% of clinical diagnoses are estimated to
could contaminate and impair the quality of wine was a rely on pathology investigations. In the USA, c. 90% of the
major advance in our perception of the environment and our objective data in electronic patient records are derived from
knowledge that pathogens within it, invisible to the naked pathology laboratories.
eye, cause disease.
Rudolf Virchow (1821–1902), a German pathologist and Subdivisions of clinical pathology
ardent advocate of the microscope, recognised that cells Pathology in practice has major subdivisions:
were the smallest viable constituent units of the body and
he formulated a new and lasting set of ideas about disease – • histopathology: the investigation and diagnosis of disease
from the examination of tissues
cellular pathology. The light microscope enabled him to see
changes in diseased tissues at a cellular level. His observa- • cytopathology: the investigation and diagnosis of disease
from the examination of isolated cells
tions, extended further by electron microscopy, have had a
profound and enduring influence. But Virchow’s cell pathol- • haematology: the study of disorders of the cellular and
coagulable components of blood
ogy theory is not complete or immutable: advances in bio-
chemistry have revolutionised our understanding of many • microbiology: the study of infectious diseases and the
organisms responsible for them
diseases at a molecular level.
• immunology: the study of the specific defence mechanisms
of the body
Molecular pathology • chemical pathology: the study and diagnosis of disease from
the chemical changes in tissues and fluids
The impact of molecular pathology is exemplified by advances
in our knowledge of the biochemical basis of congenital • genetics: the study of abnormal chromosomes and genes
disorders and cancer. Techniques with relatively simple prin- • toxicology: the study of the effects of known or suspected
poisons
ciples (less easy in practice) reveal the change of a single
nucleotide in genomic DNA resulting in the synthesis of the • forensic pathology: the use of pathology for legal
purposes (e.g. investigation of death in suspicious
defective gene product that is the fundamental lesion in a
circumstances).
particular disease (Ch. 3).
These subdivisions are more important professionally
(because each requires its own team of trained specialists)
Cellular and molecular alterations in disease than educationally at the undergraduate level. The subject
The application of modern scientific methods have resulted must be taught and learnt in an integrated manner, for the
in a clearer understanding of the ways in which diseases body and diseases make no distinction between these profes-
result from disturbed normal cellular and molecular mecha- sional subdivisions. This book, therefore, adopts a multidis-
nisms (Table 1.2). ciplinary approach to pathology. In the systematic section
(Part 3), the normal structure and function of each organ is
summarised, the pathological basis for clinical signs and
symptoms is described, and the clinical implications of each
SCOPE OF PATHOLOGY disease are emphasised.

Scientific knowledge about human diseases is derived from

observations on patients or, by analogy, from experimental
studies on animals, cell cultures and computer simulations. TECHNIQUES OF PATHOLOGY
The greatest contribution comes from the detailed study of
tissue and body fluids from patients. Pathology also has a Our growing knowledge of the nature and causation
key role in translational research by facilitating the transfer of disease has emerged from applied advances in
of knowledge derived from laboratory investigations into technology.
clinical practice.

Clinical pathology Gross pathology

Clinical medicine is based on a longitudinal approach to a Before microscopy was applied to medical problems (c.
patient’s illness – the patient’s history, the examination and 1800), observations were confined to those made with the
investigation, the diagnosis, the treatment and follow-up. unaided eye, and thus was accumulated much of our knowl-
Clinical pathology is more concerned with a cross-sectional edge of the morbid anatomy of disease. Gross or macroscopic
analysis at the level of the disease itself, studied in depth – pathology is the modern nomenclature for this approach to
the cause and mechanisms of the disease, and the effects of the study of disease and, especially in the autopsy, it is still
the disease upon the various organs and systems of the body. an important investigative method. The gross pathology of
These two perspectives are complementary and inseparable: many diseases is so characteristic that, when interpreted by
clinical medicine cannot be practised without an under- an experienced pathologist, a fairly confident diagnosis can
standing of pathology; pathology is meaningless if it lacks often be given before further investigation by, for example,
clinical significance. light microscopy. 5
1 What is pathology?

Table 1.2 Examples of the involvement of cellular and extracellular components in disease

Component Normal function Examples of alterations in disease

Cellular

Nucleus Genes encoded in DNA Inherited or spontaneous mutations (e.g. inherited,

metabolic disorders, cancer)
Site of viral replication

Mitochondria Oxidative metabolism Mutations of mitochondrial DNA

Enzyme defects

Lysosomes Enzymic degradation Functional defects cause metabolic storage disorders and
defects in microbial killing

Cell membrane Functional envelope of cell Defects in ion transfer (e.g. cystic fibrosis, hereditary
spherocytosis)

Adhesion molecules Cellular adhesion Increased expression in inflammation

Decreased expression in neoplasia

HLA molecules Immune recognition Aberrant expression associated with autoimmune disease
Some HLA alleles correlate with risk of disease

Receptors Specific recognition Hormone receptors cause cells to respond to physiological

or pathological hormone levels
Lymphocyte receptors enable immune responses to antigens

Secreted products

Collagen Mechanical strength of tissues Replacement of functioning parenchyma by fibrosis

Inherited defects (e.g. osteogenesis imperfecta)

Immunoglobulins Antibody activity in immune reactions Deficiency leads to increased infection risk
Secreted by myeloma cells
Specific antibody activity may be in response to infection or
a marker of autoimmune disease

Nitric oxide Endothelium-derived relaxing factor Increased levels in endotoxic shock and in asthma
causing vasodilatation, inhibition of
platelet aggregation and of proliferation

Hormones Control of specific target cells Excess or deficiency due to disease of endocrine organs

Cytokines Regulation of inflammatory and immune Increased levels in inflammatory, immunological and
responses and of cell proliferation reparative tissue reactions

Free radicals Microbial killing Inappropriate or excessive production causes tissue damage

Light microscopy
plastic. For some purposes (e.g. intraoperative diagnosis),
Advances in optics have yielded much new information sections have to be cut from tissue that has been hardened
about the structure of tissues and cells in health and by rapid freezing. Tissue sections are stained to help distin-
disease. guish between different components (e.g. nuclei, cytoplasm,
Before solid tissues are examined by light microscopy, the collagen).
sample must first be thinly sectioned to permit the transmis- The microscope can also be used to examine cells from
sion of light and to minimise the superimposition of tissue cysts, body cavities, sucked from solid lesions or scraped
6 components. These sections are routinely cut from tissue from body surfaces. This is cytology and is used widely in,
hardened by embedding in wax or, less often, transparent for example, cervical cancer screening.
 Learning pathology 1
Histochemistry Techniques used include direct microscopy of appropriately
Histochemistry is the study of the chemistry of tissues, stained material (e.g. pus), cultures to isolate and grow the
usually by microscopy of tissue sections after they have been organism, and methods to identify correctly the cause of the
treated with specific reagents so that the biochemical fea- infection. In the case of bacterial infections, the most appro-
tures of individual cells can be visualised. priate antibiotic can be selected by determining the sensitiv-
ity of the organism to a variety of agents.
Immunohistochemistry and immunofluorescence
Immunohistochemistry and immunofluorescence use anti- Molecular pathology
bodies (immunoglobulins with antigen specificity) to visu-
alise substances in tissue sections or cell preparations; these Molecular pathology reveals defects in the chemical struc-
techniques use antibodies linked chemically to enzymes or ture of molecules arising from errors in the genome, the
fluorescent dyes, respectively. Immunofluorescence requires sequence of bases that directs amino acid synthesis. Using
a microscope modified for ultraviolet illumination and the in situ hybridisation, specific genes or their messenger RNA
preparations are often not permanent (they fade). For these can be visualised in tissue sections or cell preparations.
reasons, immunohistochemistry is more popular; in this Minute quantities of nucleic acids can be amplified by the
technique, the end product is a deposit of opaque or col- use of the polymerase chain reaction using oligonucleotide
oured material that can be seen with a conventional light primers specific for the genes being studied.
microscope and does not deteriorate. The range of sub- DNA microarrays can be used to determine patterns of gene
stances detectable by these techniques has been enlarged expression (mRNA). This powerful technique can reveal
greatly by the development of monoclonal antibodies. novel diagnostic and prognostic categories, indistinguisha-
ble by other methods.
Electron microscopy Molecular pathology is manifested in various conditions,
for example: abnormal haemoglobin molecules, such as in
Electron microscopy has extended the range of pathology to sickle cell disease (Ch. 23); abnormal collagen molecules in
the study of disorders at an organelle level, and to the dem- osteogenesis imperfecta (Chs 6, 25); and genomic altera-
onstration of viruses in tissue samples from some diseases. tions disturbing the control of cell and tissue growth, playing
The most common diagnostic use is for the interpretation a pivotal role in the development of tumours (Ch. 10).
of renal biopsies.

Biochemical techniques
LEARNING PATHOLOGY
Biochemical techniques applied to the body’s tissues and
fluids in health and disease are now one of the dominant Pathology is best learnt in two stages.
influences on our growing knowledge of pathological proc-
esses. The vital clinical role of biochemistry is exemplified by
the importance of monitoring fluid and electrolyte homeo­
stasis in many disorders. Serum enzyme assays are used
Disease mechanisms
to assess the integrity and vitality of various tissues; for The causation, mechanisms and characteristics of the major
example, raised blood levels of cardiac enzymes and troponin categories of disease are the foundations of pathology. These
indicate damage to cardiac myocytes. aspects are covered in Part 2 of this textbook and many
specific diseases are mentioned by way of illustration.
Haematological techniques Ideally, the principles of disease causation and mechanisms
should be understood before attempting to study systematic
Haematological techniques are used in the diagnosis and
pathology.
study of blood disorders. These techniques range from rela-
tively simple cell counting, which can be performed elec-
tronically, to assays of blood coagulation factors.
Systematic pathology
Cell cultures Systematic pathology is our current knowledge of specific
diseases as they affect individual organs or systems. System-
Cell cultures are widely used in research and diagnosis. They atic pathology comprises Part 3 of this textbook. (‘System-
are an attractive medium for research because of the ease atic’ should not be confused with ‘systemic’. Systemic
with which the cellular environment can be modified and pathology would be characteristic of a disease that pervaded
the responses to it monitored. Diagnostically, cell cultures all body systems!) Each specific disease can usually be attrib-
are used to prepare chromosome spreads for cytogenetic uted to the operation of one or more causes and mechanisms
analysis. featuring in general pathology. Thus, acute appendicitis is
acute inflammation affecting the appendix; carcinoma of the
lung is the result of carcinogenic agents acting upon cells
Medical microbiology
in the lung, and the behaviour of the cancerous cells
Medical microbiology is the study of diseases caused by thus formed follows the pattern established for malignant 7
organisms such as bacteria, fungi, viruses and parasites. tumours; and so on.
1 What is pathology?

Building knowledge and understanding The problem-oriented approach

There are two difficulties commonly facing new students of The problem-oriented approach is the first step in the clini-
pathology: language and process. Pathology, like most branches cal diagnosis of a disease. In many illnesses, symptoms (the
of science and medicine, has its own vocabulary of special patient’s problem) alone suffice for diagnosis. In other ill-
terms. These need to be learnt and understood not just nesses, the diagnosis has to be supported by clinical signs
because they are the language of pathology: they are also a (e.g. abnormal heart sounds). In some cases, the diagnosis
major part of the language of clinical practice. However, can be made conclusively only by special investigations (e.g.
learning the language is not sufficient; learning the mecha- laboratory analysis of blood or tissue samples, imaging
nisms of disease and the effects on individual organs and techniques).
patients is vitally important for clinical practice. In this The links between diseases and the problems they produce
book, each important term will be clearly defined in the are emphasised in the systematic chapters (Part 3) and are
main text or the glossary, or both. exemplified here (Table 1.3).
There is a logical and orderly way of thinking about dis- Justifications for encouraging a problem-oriented
eases and their characteristics. For each disease entity stu- approach are:
dents should be able to list the chief characteristics:
• Patients present with ‘problems’ rather than ‘diagnoses’.
• epidemiology • Some clinical problems have an uncertain pathological
• aetiology basis (this is true particularly of psychiatric conditions
• pathogenesis such as depressive illness).
• pathological and clinical features
• complications and sequelae
• prognosis
• treatment.
Table 1.3 The problem-oriented approach: combinations
Our knowledge about many diseases is still incomplete, but of clinical problems and their pathological basis
at least such a list will prompt the memory and enable stu-
dents to organise their knowledge. Problems Pathological Comment
Pathology is learnt through a variety of media. The bedside, basis (diagnosis)
operating theatre and outpatient clinic provide ample oppor-
tunities for further experience of pathology; hearing a Weight Lung cancer or Can be
diastolic cardiac murmur through a stethoscope should loss and tuberculosis distinguished by
prompt the listening student to consider the pathological haemoptysis finding either
cancer cells or
features of the narrowed mitral valve orifice (mitral steno-
mycobacteria in
sis) responsible for the murmur, and the effects of this
sputum
stenosis on the lungs and the rest of the cardiovascular
system. Dyspnoea and Heart failure Due to, for
ankle swelling example, valvular
disease
Pathology in the problem-oriented integrated
medical curriculum Chest pain and Myocardial Should be
hypotension infarction confirmed by
Although medicine, surgery, pathology and other disciplines ECG and serum
are still taught as separate subjects in some curricula, stu- assay of cardiac
dents must develop an integrated understanding of disease. enzymes,
To encourage this integration, in this textbook the patho- troponin, etc.
logical basis of common clinical signs is frequently empha-
sised so that students can relate their everyday clinical Vomiting and Gastroenteritis Specific microbial
experiences to their knowledge of pathology. There is also diarrhoea cause can be
determined
an index of symptoms and diseases that may cause them
(pp. ix–xvii). Headache, Hypertension May be due to
In general, the development of a clinicopathological impaired vision various causes or,
understanding of disease can be gained by two equally legiti- and microscopic more commonly,
mate and complementary approaches: haematuria without evident
cause
• problem-oriented
• disease-oriented. Headache, Subarachnoid Can be
In learning pathology, the disease-oriented approach is more vomiting and haemorrhage or distinguished
relevant because medical practitioners require knowledge of photophobia meningitis by other clinical
features and
diseases (e.g. pneumonia, cancer, ischaemic heart disease)
examination of
so that correct diagnoses can be made and the most appro- cerebrospinal fluid
8 priate treatment given.
 Pathology and populations 1
• Clinical treatment is often directed towards relieving to do so, a series of samples can be examined to monitor
the patient’s problems rather than curing their disease the course of the disease and response to treatment.
(which may either remit spontaneously or be incurable). The applications of pathology in clinical diagnosis and
patient management are described in Chapter 12.
The disease-oriented approach
The disease-oriented approach is the most appropriate way
Autopsies
of presenting pathological knowledge. It would be possible Autopsy (necropsy and post-mortem examination are syn-
to produce a textbook of pathology in which the chapters onymous) means to ‘see for oneself ’. In other words, rather
were entitled, for example, ‘Cough’, ‘Weight loss’, ‘Head- than relying on clinical signs and symptoms and the results
aches’ and ‘Pain’ (these being problems), but the reader of diagnostic investigations during life, here is an opportu-
would be unlikely to come away with a clear understanding nity to directly inspect and analyse the organs. Autopsies are
of the diseases. This is because one disease may cause a useful for:
variety of problems – for example, cough, weight loss, head-
aches and pain – and may therefore feature in several chap- • determining the cause of death
ters. Consequently, this textbook, like most textbooks of • audit of the accuracy of clinical diagnosis
pathology (and, indeed, of medicine), adopts a disease- • education of undergraduates and postgraduates
oriented approach. • research into the causes and mechanisms of disease
• gathering accurate statistics about disease incidence.
The clinical use of information from autopsies is described
in Chapter 12.
MAKING DIAGNOSES
For the medical undergraduate and postgraduate, the
autopsy is an important medium for the learning of pathol-
Diagnosis is the act of naming a disease in an individual
ogy. It is an unrivalled opportunity to correlate clinical signs
patient. The diagnosis is important: it enables the patient to
with their underlying pathological explanation.
benefit from treatment that is known, or is at least likely, to
be effective, its effects having been observed in other patients
with the same disease.
The process of making diagnoses involves:
PATHOLOGY AND POPULATIONS

• taking a clinical history to document symptoms Although pathology, as practised professionally, is a clinical
• examining the patient for clinical signs discipline focused on the care of individual patients, our
• if necessary, performing investigations guided by the pro- knowledge about the causes of disease, disability and death
visional diagnosis based on signs and symptoms. has wide implications for society.
Although experienced clinicians can diagnose many patients’
diseases quite rapidly (and usually reliably), the student will Causes and agents of disease
find that it is helpful to adopt a formal strategy based on a
There can be controversy about what actually constitutes the
series of logical steps leading to the gradual exclusion of
cause of a disease. Some critics may argue that the science
various possibilities and the emergence of a single diagnosis.
of pathology leads to the identification of merely the agents
For example:
of some diseases rather than their underlying causes. For
• First decide which organ or body system seems to be example, the bacterium Mycobacterium tuberculosis is the
affected by the disease. infective agent resulting in tuberculosis but, because many
• From the signs and symptoms, decide which general people exposed to the bacterium alone do not develop the
category of disease (inflammation, neoplasia, etc.) is disease, social deprivation and malnutrition (both of which
likely to be present. are epidemiologically associated with the risk of tuberculo-
• Then, using other factors (age, gender, previous medical sis) might be regarded by some as the actual causes. Without
history, etc.), infer a diagnosis or a small number of pos- doubt, the marked fall in the incidence of many serious
sibilities for investigation. infectious diseases during the 20th century was achieved at
• Investigations should be performed only if the outcome least as much through improvements in housing, hygiene,
of each one can be expected to resolve the diagnosis, or nutrition and sewage treatment as by specific immunisation
influence management if the diagnosis is already known. and antibiotic treatment directed at the causative organisms.
This distinction between agents and causes is developed
This strategy can be refined and presented in the form of
further in Chapter 3.
decision trees or diagnostic algorithms.

The health of a nation

Diagnostic pathology
Because the methods used in pathology enable reliable diag-
In living patients, we often investigate and diagnose their noses to be made, either during life by biopsy or after death
illness by applying pathological methods to the examination by autopsy, the discipline has an important role in accurately
of tissue biopsies and body fluids. If there are clinical indications documenting the incidence of disease in a population. 9
1 What is pathology?

Cancer registration data are most reliable when based on screened women have their cervix scraped at regular inter-
histologically proven diagnoses; this happens in most cases. vals and the exfoliated cells are examined microscopically to
Epidemiological data derived from death certificates are detect the earliest changes associated with development of
notoriously unreliable unless verified by autopsy. The infor- cancer. Screening for breast cancer is primarily by mammog-
mation thus obtained can be used to determine the true raphy (radiographic imaging of the breast); any abnormali-
incidence of a disease in a population, and the resources for ties are further investigated either by examining cells
its prevention and treatment can be deployed where they aspirated from the suspicious area or by histological exami-
will achieve the greatest benefit. nation of the tissue itself.

Preventing disability and premature death FURTHER READING

Laboratory methods are used increasingly for the detection
of early disease by population screening. The prospects of Porter, R., 1997. The greatest benefit to mankind: a medical history of
humanity from antiquity to the present. HarperCollins, London.
cure are invariably better the earlier a disease is detected. Rosai, J., 1997. Pathology: a historical opportunity. American Journal of
For example, the risk of death from cancer of the cervix Pathology 151, 3–7.
is lowered by screening programmes. In many countries, Tallis, R., 2004. Hippocratic oaths. Atlantic Books, London.

10
2
What is disease?
James C. E. Underwood

What is disease? 12 Nomenclature of disease 19

Limits of normality
Responses to the environment Principles of disease classification 20
General classification of disease
Characteristics of disease 13 Iatrogenic diseases
Aetiology
Pathogenesis Epidemiology 22
Structural and functional manifestations Epidemiological clues to the causes of disease
Complications and sequelae
Prognosis

11
2 What is disease?

haemoglobin, etc.); failure to do so can result in death from

WHAT IS DISEASE? heart failure. Fair-skinned people get sunburnt from exces-
sive exposure to ultraviolet light from the sun; some adapt
A disease is a condition in which the presence of an abnor- by developing a protective tan; untanned individuals run a
mality of the body causes a loss of normal health. The mere higher risk of skin cancer if they persist in unprotected
presence of an abnormality is insufficient to imply the exposure to the sun. Environmental microorganisms are a
presence of disease unless it is accompanied by ill health, common cause of disease; those individuals who develop
although it may denote an early stage in the development of specific defences against them (e.g. antibodies) can resist
a disease. Therefore, the World Health Organization defines the infection; those who fail to adapt may succumb.
health as ‘a state of complete physical, mental and social well-being
and not merely the absence of disease or infirmity’.
Each separately named disease is characterised by a dis- Disease: failure of adaptation
tinct set of features (cause, signs and symptoms, morpho-
logical and functional changes, etc.). Many diseases share Susceptibility of a species to injurious environmental factors
common features and thereby are grouped in disease results in either its extinction or, over a long period, the
classifications. favoured selection of a new strain of the species better
The abnormalities causing diseases may be structural or adapted to withstand such factors. However, this occurs only
functional, or both. In many diseases the abnormalities are if the injury manifests itself early in life, thus thwarting
obvious and well characterised (e.g. a tumour); in other propagation of the disease susceptibility by reproduction.
instances the patient may be profoundly unwell but the If the injury manifests only in later life, or if a lifetime of
nature of the abnormality is less well defined (e.g. depres- exposure to the injurious agent is necessary to produce the
sive illness). pathological changes, then the agent produces no evolution-
ary pressure for change.
Therefore, disease represents a set of abnormal bodily
Limits of normality responses to agents for which, as yet, there little or no toler-
Normal is not a single discrete state, because there are dif- ance or defence.
ferences between individuals and natural changes during
fetal development, childhood, puberty, pregnancy, ageing, Darwinian medicine
etc. Therefore, ‘normal’ means the most frequent state in a Darwinian medicine is based on belief that diseases not only
population defined by age distribution, gender, etc. have proximate causes and mechanisms (e.g. viruses, bacte-
Most quantifiable biological characteristics are normally ria, mutations) but also have evolutionary causes. Darwinian
distributed, in statistical terms, about an average value. No medicine focuses on the latter aspect and, while it may not
constant numbers can be used to define a normal height, yield cures, it can help us to understand current disease
weight, serum sodium concentration, etc. Normality, when prevalence. Darwinian medicine is also rooted in the belief
quantifiable, is expressed as a normal range, usually encom- that natural selection favours reproductive success rather
passed by two standard deviations (for a ‘normally’ distrib- than health or life-span.
uted feature) either side of the mean (Ch. 12). The probability In Why we get sick: the new science of Darwinian medicine,
that a measurable characteristic is abnormal increases the Randolph Nesse, an evolutionary biologist, and George Wil-
nearer it is to the limits of the normal range, but a value liams, a psychiatrist, explain the application of evolutionary
lying outside the normal range is not necessarily indicative ideas to modern medicine with these examples:
of abnormality – it is just very probably abnormal.
A distinction must also be drawn between what is usual
• Pyrexia and malaise in patients with infections, while
unpleasant, have evolved as a way of compromising the
and what is normal. It is usual to find atheroma (Ch. 13) in metabolism of pathogenic organisms. Thus, antipyretic
an elderly individual – but is it normal? In contrast, atheroma treatments (e.g. paracetamol) that make the patient more
in a teenager is so unusual that it would be regarded as comfortable can prolong the illness.
abnormal and worthy of further investigation.
• Microbes evolve more rapidly than humans, thus explain-
ing the perpetual struggle against infection and its wors-
Responses to the environment ening by the inappropriate use of antibiotics to which
resistance soon develops.
The natural environment of any species contains potentially
injurious agents to which the individual or species will
• Some modern health problems are due to the evolution-
ary legacy of thrifty ‘stone age’ bodies living in a plentiful
either adapt or succumb. modern environment, thus explaining the rising preva-
lence of obesity.
Adaptation • Allergic reactions are due to an immune system that is
biased towards hypersensitivity to innocent agents rather
Adaptation of the individual to an adverse environment is than insufficient reactivity to genuine threats.
well illustrated by the following examples. Healthy moun-
taineers ascending rapidly to the rarefied atmosphere at Ageing and adaptation
high altitudes risk developing ‘mountain sickness’; this One of the main features of ageing is progressive inability
12 can be avoided by allowing the body to adapt (increased to deal with new or worsening environmental threats
 Characteristics of disease 2
(Ch. 11). This is exemplified by the gradual impairment of genetic) and environmental factors. Environmental causes of
immune responses, resulting in: diseases are called pathogens, although this term is used com-
monly only when referring to microbes: bacteria capable of
• re-emergence of dormant infections such as tuberculosis causing disease are pathogenic; those that are harmless are
and herpes zoster
non-pathogenic.
• failure to mount an effective immune response to newly General categories of aetiological agents include:
encountered pathogens.
• genetic abnormalities
Disease predisposition as an adaptive advantage • infective agents, e.g. bacteria, viruses, fungi, parasites
Paradoxically, a disease or disease predisposition can have • chemicals
beneficial effects. A few diseases or disease susceptibilities • radiation
can, in addition to their deleterious effects, confer adaptive • mechanical trauma.
protection against specific environmental pathogens. This
Some diseases have a multifactorial aetiology. They are due to
advantage may explain the high prevalence of a disease in
a combination of causes, such as genetic factors and infective
areas where the specific pathogen for another disease is
agents.
endemic.
Sometimes the aetiology of a disease is unknown, but the
• The sickle cell gene (HbS) and the glucose-6-phosphate disease is observed to occur more commonly in people with
dehydrogenase (G6PD) deficiency gene independently certain constitutional traits, occupations, habits or habitats;
confer protection against malaria by creating a hostile these are regarded as risk factors. These factors may provide
environment for the Plasmodium parasite within red cells. a clue to as yet unidentified aetiological agents. Other risk
• Heterozygosity for the most common mutation (deletion factors may simply have a permissive effect, facilitating the
of phenylalanine at position 508) in the cystic fibrosis development of a disease in that individual; examples include
conductance regulator renders decreased susceptibility to malnutrition, which favours infections.
Salmonella typhi infection. Some agents can cause more than one disease depending
on the circumstances. For example, ionising radiation can
cause rapid deterioration leading to death, scarring of
CHARACTERISTICS OF DISEASE tissues, or tumours.

 Aetiology: the cause of a disease Identification of the causes of disease

 Pathogenesis: the mechanism causing the disease
In terms of causation, diseases may be:
 Pathological and clinical manifestations: the structural
and functional features of the disease • entirely genetic
 Complications and sequelae: the secondary, systemic or
• multifactorial (genetic and environmental)
remote consequences of a disease
 Prognosis: the anticipated course of the disease in terms
• entirely environmental.
of cure, remission, or fate of the patient Most common diseases have entirely environmental causes,
 Epidemiology: the incidence, prevalence and population but genetic influences in disease susceptibility are being
distribution of a disease increasingly discovered, and many diseases with no previ-
ously known cause are being shown to be due to genetic
Characteristic sets of disease features enable them to be abnormalities (Ch. 3). This is the reward of applying the
better understood, categorised and diagnosed. For many principles of clinical genetics and the techniques of molecu-
diseases, however, our knowledge is still incomplete or lar biology to the study of human disease.
subject to controversy. The characteristics of any disease The extent to which a disease is due to genetic or envi-
are (Fig. 2.1): ronmental causes can often be deduced from some of its
main features or its association with host factors. Features
• aetiology (or cause) pointing to a significant genetic contribution include a high
• pathogenesis (or mechanism) incidence in particular families or races, or an association
• morphological, functional and clinical changes with an inherited characteristic (e.g. gender, blood groups,
(or manifestations)
histocompatibility alleles). Diseases associated with particu-
• complications and sequelae (or secondary effects) lar occupations or geographic regions tend to have an envi-
• prognosis (or outcome) ronmental basis; the most abundant environmental causes
• epidemiology (or incidence). of disease are microbes (bacteria, viruses, fungi, etc.).
The aetiology and pathogenesis of a disease may be com-
bined as aetiopathogenesis. Probability of disease
The relationship between the quantity of causal agent and
the probability that disease will result is not always simply
Aetiology
linear (Fig. 2.2). For example, many infections occur only
The aetiology of a disease is its cause: the initiator of the on exposure to a sufficient number of microorganisms; the
subsequent events resulting in the patient’s illness. Diseases body’s defences have to be overcome before disease results.
are caused by a variable interaction between host (e.g. Some agents capable of causing disease, such as alcohol, 13
2 What is disease?

A Skin abscess B Lung cancer C Cirrhosis D Primary hypertension

Aetiology

Staphylococcus Smoking (polycyclic

aureus aromatic hydrocarbons) Hepatitis B virus

Pathogenesis

Acute Genetic alteration Immune reaction to Increased renin

inflammation (mutation) virus-infected cells production from kidneys

Morphological
and functional
features

Skin abscess Lung tumour Cirrhosis High blood pressure

Liver
Complications function
and sequelae

Time
Metastases
Septicaemia (secondary tumours) Liver failure Cerebral haemorrhage

Fig. 2.1 Characteristics of disease. The relationship between aetiology, pathogenesis, morphological and functional manifestations, and
complications and sequelae is illustrated by four diseases. [A] Skin abscess. [B] Lung cancer. [C] Cirrhosis. [D] Primary hypertension.

appear beneficial in small doses; abstention from alcohol Other diseases are the probable consequence of exposure
confers a slightly higher risk of premature death from to causative factors, but they are not inevitable. This is
ischaemic heart disease. exemplified by infections with potentially harmful bacteria:
the outcome can be influenced by various host factors such
Host predisposition to disease as nutritional status, genetic influences and pre-existing
Many diseases are the predictable consequence of exposure to immunity.
the initiating cause; host factors make relatively little con- Some diseases occur more commonly in individuals with
tribution. This is particularly true of physical injury: the a congenital predisposition. For example, ankylosing spondy­
immediate results of mechanical trauma or radiation injury litis (Ch. 25), a disabling inflammatory disease of the spinal
are dose-related; the outcome can be predicted from the joints of unknown aetiology, occurs more commonly in indi-
14 strength of the injurious agent. viduals with the HLA-B27 allele.
 Characteristics of disease 2
A Some diseases predispose to a risk of developing other
diseases. Diseases associated with an increased risk of
cancer are designated premalignant conditions; for example,
hepatic cirrhosis predisposes to hepatocellular carcinoma,
Probability and ulcerative colitis predisposes to carcinoma of the large
of disease
intestine. The histologically identifiable antecedent lesion
from which the cancers directly develop is designated the
premalignant lesion.
Some diseases predispose to others because they have a
permissive effect, allowing environmental agents that are
Amount of physical agent not normally pathogenic to cause disease. This is exempli-
fied by opportunistic infections in patients with impaired
B
defence mechanisms resulting in infection by organisms not
normally harmful (i.e. non-pathogenic) to humans (Ch. 8).
Patients with leukaemia or the acquired immune deficiency
Probability syndrome (AIDS), organ transplant recipients, or other
of disease patients treated with cytotoxic drugs or steroids, are suscep-
tible to infections such as pneumonia due to Aspergillus
fungi, cytomegalovirus or Pneumocystis jirovecii.

Causes and agents of disease

Amount of infecting organism Distinction should be made between the cause and the agent
of a disease. For example, tuberculosis is caused, arguably,
C not by the tubercle bacillus (Mycobacterium tuberculosis) but
by poverty, social deprivation and malnutrition – the tuber-
cle bacillus is ‘merely’ the agent of the disease; the underly-
ing cause is adverse socio-economic factors. There is, in fact,
Probability incontrovertible evidence that the decline in incidence of
of disease
many serious infectious diseases is attributable substantially
to improved hygiene, sanitation and general nutrition rather
than to immunisation programmes or specific antimicrobial
therapy. Such arguments are of relevance here only to
emphasise that the socio-economic status of a country
Amount of allergen or individual may influence the prevalence of the environ-
mental factor or the host susceptibility to it. In practice,
D causes and agents are conveniently embraced by the term
aetiology.

Causal associations
Probability
of disease A causal association is a marker for the risk of developing a
disease, but it is not necessarily the actual cause of the
disease. The stronger the causal association, the more likely
it is to be the aetiology of the disease. Causal associations
become more powerful if:
Amount of alcohol • they are plausible, supported by experimental evidence
Fig. 2.2 Relationships between the amount of a causal agent • the presence of the disease is associated with prior expo-
and the probability of disease. [A] Physical agents. For example,
sure to the putative cause
the risk of traumatic injury to a pedestrian increases in proportion • the risk of the disease is proportional to the level of expo-
to the kinetic energy of the motor vehicle. [B] Infectious agents. sure to the putative cause
Many infectious diseases result only if sufficient numbers of the • removal of the putative cause lessens the risk of the
microorganism (e.g. bacterium, virus) are transmitted; smaller disease.
numbers are capable of being eliminated by the non-immune
and immune defences. [C] Allergens. In sensitised (i.e. allergic) The utility of these statements is illustrated by the associa-
individuals, minute amounts of an allergen will provoke a severe tion between lung cancer and cigarette smoking. Lung
anaphylactic reaction. [D] J-shaped curve. Best exemplified by cancer is more common in smokers than in non-smokers;
alcohol, of which small doses (c. 1–2 units per day) reduce the risk tobacco smoke contains carcinogenic chemicals; the risk of
of premature death from ischaemic heart disease, but larger doses lung cancer is proportional to cigarette consumption; popu-
progressively increase the risk of cirrhosis. lation groups that have reduced their cigarette consumption
(e.g. doctors) show a commensurate reduction in their risk
of lung cancer. 15
2 What is disease?

Causal associations may be neither exclusive nor absolute. • degeneration: a deterioration of cells or tissues in
For example, because some heavy cigarette smokers never response to, or failure of adaptation to, a variety of agents
develop lung cancer, smoking cannot alone be regarded as • carcinogenesis: the mechanism by which cancer-causing
a sufficient cause; other factors are required. Conversely, agents result in the development of tumours
because some non-smokers develop lung cancer, smoking • immune reactions: undesirable effects of the body’s
cannot be regarded as a necessary cause; other causative immune system.
factors must exist.
These and other disease mechanisms are described in Part
Causal associations tend to be strongest with infections.
2 of this textbook.
For example, syphilis, a venereal disease, is always due to
infection by the spirochaete Treponema pallidum; there is no
other possible cause for syphilis; syphilis is the only disease Latent intervals and incubation periods
caused by Treponema pallidum.
Few aetiological agents cause signs and symptoms immedi-
Koch’s postulates ately after exposure. Usually, some time elapses. In the
An infective (e.g. bacterial, viral) cause for a disease is not context of carcinogenesis, this time period is referred to as
usually regarded as proven until it satisfies the criteria enun- the latent interval – often two or three decades. In infectious
ciated by Robert Koch (1843–1910), a German bacteriologist disorders (due to bacteria, viruses, etc.), the period between
and Nobel Prize winner in 1905: exposure and the development of disease is called the incuba-
tion period; it is often measured in days or weeks, and each
• The organism must be sufficiently abundant in every case infectious agent is usually associated with a characteristic
to account for the disease. incubation period.
• The organism associated with the disease can be culti- The reason for discussing these time intervals here is that
vated artificially in pure culture. it is during these periods that the pathogenesis of the disease
• The cultivated organism produces the disease upon inoc- is being enacted, culminating in the development of symp-
ulation into another member of the same species. tomatic pathological and clinical manifestations that cause
• Antibodies to the organism appear during the course of the patient to seek medical help.
the disease.
The last point was added subsequently to Koch’s list.
Although Koch’s postulates have lost their novelty, their Structural and functional manifestations
relevance is undiminished. However, each postulate merits The aetiological agent (cause) acts through a pathogenetic
further comment because there are notable exceptions: pathway (mechanism) to produce the manifestations of
disease, giving rise to clinical signs and symptoms (e.g.
• In some diseases the causative organism is very sparse. weight loss, shortness of breath) and the abnormal features
A good example is tuberculosis, where the destructive
lesions contain very few mycobacteria; in this instance, or lesions (e.g. carcinoma of the lung) to which the clinical
the destruction is caused by an immunological reaction signs and symptoms can be attributed. The pathological
triggered by the presence of the organism. manifestations may require biochemical methods for their
detection and, therefore, should not be thought of as only
• Cultivation of some organisms is remarkably difficult, yet
those visible to the unaided eye or by microscopy. The bio-
their role in the aetiology of disease is undisputed.
chemical changes in the tissues and the blood are, in some
• Ethics prohibit wilful transmission of a disease from one
instances, more important than the structural changes,
person to another, but animals have been used success-
fully as surrogates for human transmission. many of which may appear relatively late in the course of
the disease.
• Immunosuppression may lessen the antibody response
Although each separately named disease has its own dis-
and also render the host extremely susceptible to the
disease. In addition, if an antibody is detected it should tinctive and diagnostic features, some common structural
be further classified to confirm that it is an IgM class and functional abnormalities, alone or combined, result in
antibody, denoting recent infection, rather than an IgG ill health.
antibody, denoting long-lasting immunity due to previ-
ous exposure to the organism.
Structural abnormalities
Common structural abnormalities causing ill health are:
Pathogenesis
The pathogenesis of a disease is the mechanism through • space-occupying lesions (e.g. cysts, tumours) destroying,
displacing or compressing adjacent healthy tissues
which the aetiology (cause) operates to produce the patho-
logical and clinical manifestations. Groups of aetiological • deposition of an excessive or abnormal material in an
organ (e.g. fat, amyloid)
agents often cause disease by acting through the same
common pathway of events. • abnormally sited tissue (e.g. tumours, heterotopias) as
a result of invasion, metastasis or developmental
Examples of disease pathogenesis include:
abnormality
• inflammation: a response to many microorganisms and • loss of healthy tissue from a surface (e.g. ulceration) or
16 other harmful agents causing tissue injury from within a solid organ (e.g. infarction)
 Characteristics of disease 2
• obstruction to normal flow within a tube (e.g. asthma, there is no prospect of recovery (e.g. disseminated cancer).
vascular occlusion) Examples of known mediators of symptoms are listed in
• distension or rupture of a hollow structure (e.g. aneu- Table 2.1.
rysm, intestinal perforation).
Other structural abnormalities visible only by microscopy Lesions
are very common and, even though they do not directly
A lesion is the structural or functional abnormality respon-
cause clinical signs or symptoms, they are nevertheless diag-
sible for ill health. Thus, in a patient with myocardial
nostically useful and often specific manifestations of disease.
infarction, the infarct or patch of dead heart muscle is the
For this reason, the morphological examination of diseased
lesion; this lesion is in turn a consequence of another lesion
tissues is fruitful for clinical diagnosis and research. At an
– occlusion of the supplying coronary artery by a thrombus
ultrastructural level (electron microscopy), one might see
(coronary artery thrombosis). A lesion may be purely
alien particles such as viruses in the affected tissue; there
biochemical, such as a defect in haemoglobin synthesis in a
could be abnormalities in the number, shape, internal struc-
patient with a haemoglobinopathy.
ture or size of tissue components such as intracellular
Some diseases have no overtly visible lesions, despite pro-
organelles or extracellular material. By light microscopy,
found consequences for the patient; for example, schizo-
abnormalities in cellular morphology or tissue architecture
phrenia and depressive illness yield nothing visibly abnormal
can be discerned. Immunohistochemistry (Ch. 12) can be
in the brain if examined using conventional methods.
used to make visible otherwise invisible, but important,
alterations in cells and tissues. With the unaided eye,
changes in the size, shape or texture of whole organs can be Pathognomonic abnormalities
discerned either by direct inspection or by indirect means
Pathognomonic features denote a single disease, or disease
such as radiology.
category, and without them the diagnosis is impossible or
uncertain. For example, Reed–Sternberg cells are said to be
Functional abnormalities pathognomonic of Hodgkin’s disease; they are exceptionally
Examples of functional abnormalities causing ill health rare in any other condition. Similarly, the presence of Myco-
include: bacterium tuberculosis, in the appropriate context, is pathog-
nomonic of tuberculosis.
• excessive secretion of a cell product (e.g. nasal mucus in Pathognomonic abnormalities are extremely useful clini-
the common cold, hormones having remote effects) cally, because they are absolutely diagnostic. Their presence
• insufficient secretion of a cell product (e.g. insulin lack leaves no doubt about the diagnosis. Unfortunately, some
in type 1 diabetes mellitus) diseases are characterised only by a combination of abnor-
• impaired nerve conduction malities, none of which on its own is absolutely diagnostic;
• impaired contractility of a muscular structure. only the particular combination is diagnostic. Some diseases
characterised by multiple abnormalities are called syndromes
What makes patients feel ill? (p. 20).
The ‘feeling’ of illness is usually due to one or a combination
of common symptoms:
Complications and sequelae
• pain
Diseases may have prolonged, secondary or distant effects.
• fever
Examples include the spread of an infective organism from
• nausea
the original site of infection, where it had provoked an
• malaise.
inflammatory reaction, to another part of the body, where a
Each of these common symptoms has a pathological basis similar reaction will occur. Similarly, malignant tumours
and, in those conditions that remit spontaneously, treatment arise initially in one organ as primary tumours, but tumour
for symptomatic relief may be sufficient. cells eventually permeate lymphatics and blood vessels and
In addition to the general symptoms of disease, there are thereby spread to other organs to produce secondary tumours
other specific expressions of illness that help to focus atten- or metastases. The course of a disease may be prolonged and
tion, diagnostically and therapeutically, on a particular organ complicated if the body’s capacity for defence, repair or
or body system. Examples include: regeneration is deficient.

• altered bowel habit (diarrhoea or constipation)

• abnormal swellings Prognosis
• shortness of breath The prognosis forecasts the course of the disease and, there-
• skin rash (which may or may not itch). fore, the fate of the patient. When we say that the 5-year
The symptoms of disease (the patient’s presenting com- survival prospects for carcinoma of the lung are about 5%,
plaints) invariably have an identifiable scientific basis. this is the prognosis for that condition. Sometimes we can
This is important to know because often nothing more be very specific because the information available about an
than symptomatic treatment is required because either the individual patient and their disease may enable an accurate
disease will remit spontaneously (e.g. the common cold) or forecast; for example, a patient who presents with a 17
2 What is disease?

Table 2.1 Examples of the known mediators of the symptoms of disease

Symptom Mediators Comment

Pain Free nerve endings stimulated by mechanical, May signify irritation of a surface (e.g.
thermal or chemical agents (e.g. bradykinin, peritoneum), distension of a viscus (e.g. bladder),
5-HT, histamine; prostaglandins enhance ischaemia (e.g. angina), erosion
sensitivity) of a tissue (e.g. by tumour) or inflammation

Swelling Increased cell number or size, or abnormal Common manifestation of inflammation and
accumulation of fluid or gas of tumours

Shortness of breath Increased blood CO2 or, to a lesser extent, Usually due to lung disease, heart failure
(dyspnoea) decreased blood O2 concentration or severe anaemia

Fever (pyrexia) lnterleukin-1 (IL-1) released by leucocytes acts IL-1 release frequently induced by bacterial
on thermoregulatory centre in hypothalamus, endotoxins
mediated by prostaglandins (PG)
Aspirin reduces fever by blocking PG synthesis

Weight loss Inadequate food intake or catabolic state Common manifestation of cancer, not necessarily
mediated by humoral factors from tumours of the alimentary tract or disseminated

Bleeding Weakness or rupture of blood vessel wall Coagulation defects lead to spontaneous bruising
or coagulation defect or prolonged bleeding after injury

Diarrhoea Malabsorption of food results in osmotic Most commonly due to infective causes not
retention of water in stools requiring specific treatment other than fluid
replacement
Decreased transit time, possibly due to humoral
effects
Damage to mucosa impairing absorption and
exuding fluid

Itching (pruritus) Mast cell degranulation and release of Manifestation of, for example, allergy
histamine

Cough Neuropeptide release in response, usually, Common manifestation of respiratory tract

to irritation of respiratory mucosa disease

Vomiting Stimulation of vomiting centre in medulla, Usually denotes upper gastrointestinal disease
usually by afferent vagal impulses (e.g. gastroenteritis), but may be due to
CNS lesions

Cyanosis Reduced oxygen content of arterial Due to respiratory disease, cardiac failure or
haemoglobin congenital shunting

Remission and relapse

carcinoma of the lung that has already spread to the liver,
bones and the brain very probably (and unfortunately) has Not all chronic diseases pursue a relentless course. Some
a 6-month survival prospect of nil. are punctuated by periods of quiescence when the patient
The prognosis for any disease may be influenced by enjoys relatively good health. Remission is the process of
medical or surgical intervention; indeed that is the objective. conversion from active disease to quiescence. Later, the
So one must distinguish between the prognosis for a disease signs and symptoms may reappear; this is the process of
that is allowed to follow its natural course and the prognosis relapse. Some diseases may oscillate through several cycles
for the same disease in a group of patients receiving appro- of remission and relapse before the patient is cured of or
priate therapy. succumbs to the disease. Diseases characterised by a ten-
In assessing the long-term prognosis for a chronic disease, dency to remit and relapse include chronic inflammatory
it is important to compare the survival of a group of patients bowel disease (Crohn’s disease and ulcerative colitis) and
with actuarial data for comparable populations without the treated acute leukaemia (particularly in childhood).
disease. The survival data for the group with the disease The tendency of some diseases to go through cycles of
should be corrected to allow for deaths that are likely to remission and relapse can make it difficult to be certain
18 occur from other diseases. about prognosis in an individual case.
 Nomenclature of disease 2
Morbidity and mortality terms, prefixes and suffixes used in the nomenclature of
The morbidity of a disease is the sum of the effects upon the diseases and their pathological features. Until the 19th
patient. The morbidity of a disease may or may not result in century, many diseases and causes of death were recorded
disability of the patient. For example, a non-fatal myocardial in a narrative form, often based on symptoms. The early
infarct (heart attack) leaves an area of scarring of the myo- medical statisticians, William Farr (1807–1883) and Jacques
cardium, impairing its contractility and predisposing to Bertillon (1851–1922), pioneered a systematic and uniform
heart failure: this is the morbidity of the disease in that approach to disease classification, thereby laying the founda-
particular patient. The heart failure manifests itself with tions of modern disease nomenclature.
breathlessness, restricting the patient’s activities: this is the
patient’s disability.
The mortality of a disease is the probability that death will Primary and secondary
be the end result. Mortality is expressed usually as a percent- The words primary and secondary are used in two different
age of all those patients presenting with the disease. For ways in the nomenclature of disease:
example, the mortality rate of myocardial infarction could
be stated as 50% in defined circumstances. 1. They may be used to describe the causation of a disease.
Primary in this context means that the disease is without
evident antecedent cause. Other words with the same
Disability and disease meaning are essential, idiopathic, spontaneous and cryp-
Many diseases result in only transient disability; for example, togenic. Thus, primary hypertension is defined as abnor-
influenza or a bad cold may necessitate time off work for an mally high blood pressure without apparent cause. The
employed person. Some diseases, however, are associated precise cause awaits discovery.
with a significant risk of permanent disability; in such cases, Secondary means that the disease represents a com-
treatment is intended to minimise the risk of disability. plication or manifestation of some underlying lesion.
Some investigations and treatments carry a small risk of Thus, secondary hypertension is defined as abnormally
harm, often permanent, and the risk of disability must be high blood pressure as a consequence of some other
outweighed by the potential benefit to the patient. lesion (e.g. renal artery stenosis).
Generally, the earlier a disease is diagnosed, the smaller 2. The words primary and secondary may be used to distin-
the risk of disability either from the disease itself or from guish between the initial and subsequent stages of a
its treatment. This is one of the main objectives of screening disease, most commonly in cancer. The primary tumour
programmes for various conditions (e.g. for cancers of the is the initial tumour from which cancer cells disseminate
cervix and breast). The objective assessment, preferably to cause secondary tumours elsewhere in the body.
measurement, of disability is important in the evaluation of
the impact of a disease or the adverse effects of its treatment.
There is, for example, a balance between the longevity of Acute and chronic
survival from a disease and the quality of life during the Acute and chronic are terms used to describe the dynamics
period of survival after diagnosis: a treatment that prolongs of a disease. Acute conditions have rapid onset, often but
life may be unacceptable because it prolongs suffering; treat- not always followed by rapid resolution. Chronic conditions
ment that makes a patient more comfortable, but does not may follow an acute initial episode, but often are of insidious
prolong life and may actually shorten it, may be more accept- onset, and have a prolonged course lasting months or years.
able. Measures that take account of the duration and quality Subacute, a term now rarely used, is intermediate between
of survival are QALYs (quality-adjusted life years) and DALYS acute and chronic. These terms are most often used to
(disability-adjusted life years); they enable scientifically based qualify the nature of an inflammatory process. However,
judgements about the impact of diseases, treatments and they can be used to describe the dynamics of any disease.
preventive measures. The words may be used differently by patients to describe
some symptoms, such as an ‘acute’ pain being sharp or
severe.
NOMENCLATURE OF DISEASE

Benign and malignant

 Uniform nomenclature helps communication and enables
accurate epidemiological studies Benign and malignant are emotive terms used to classify
 Many standard rules are used to derive names of certain diseases according to their likely outcome. Thus,
diseases benign tumours remain localised to the tissue of origin and
 Eponymous names commemorate, for example, the are very rarely fatal unless they compress some vital struc-
discoverer or signify ignorance of cause or mechanism ture (e.g. brain), whereas malignant tumours invade and
 Syndromes are defined by the aggregate of signs and spread from their origin and are commonly fatal. Benign
symptoms hypertension is relatively mild elevation of blood pressure
that develops gradually and causes insidious injury to the
Before proceeding to a detailed discussion of disease it is organs of the body. This situation contrasts with malignant
important to clarify the meaning of some of the common hypertension, in which the blood pressure rises rapidly and 19
2 What is disease?

causes severe symptoms and tissue injury (e.g. headaches, recognised or diagnosed. Syndromes often have eponymous
blindness, renal failure, cerebral haemorrhage). titles. Examples include:

• Cushing’s syndrome: hyperactivity of the adrenal cortex

Prefixes resulting in obesity, hirsutism, hypertension, etc.
(Cushing’s disease is this syndrome resulting specifically
Commonly used prefixes and their usual meanings are:
from a pituitary tumour secreting ACTH)
• ana-, meaning absence (e.g. anaphylaxis) • nephrotic syndrome: albuminuria, hypoalbuminaemia
• dys-, meaning disordered (e.g. dysplasia) and oedema; this syndrome can result from a variety of
• hyper-, meaning an excess over normal glomerular and other renal disorders.
(e.g. hyperthyroidism)
• hypo-, meaning a deficiency below normal Numerical disease coding systems
(e.g. hypothyroidism)
• meta-, meaning a change from one state to another Standard numerical codes, rather than names, are often used
(e.g. metaplasia) for disease registration and in epidemiological studies. Each
• neo-, meaning new (e.g. neoplasia). disease or disease group is designated a specific number. The
most widely used systems are ICD (International Classifica-
tion of Diseases, a World Health Organization System) and
Suffixes SNOMED (Systematized Nomenclature of Medicine).
Commonly used suffixes and their usual meanings are:

• -itis, meaning an inflammatory process (e.g. appendicitis) PRINCIPLES OF DISEASE CLASSIFICATION

• -oma, meaning a tumour (e.g. carcinoma)
• -osis, meaning state or condition, not necessarily patho-
logical (e.g. osteoarthrosis)  Classifications aid diagnosis and learning
• -oid, meaning resembling (e.g. rheumatoid disease)  May change with advances in medical knowledge
• -penia, meaning lack of (e.g. thrombocytopenia)  Diseases may be classified by a variety of complementary

• -cytosis, meaning increased number of cells, usually in methods

blood (e.g. leucocytosis)
• -ectasis, meaning dilatation (e.g. bronchiectasis)
• -plasia, meaning a disorder of growth (e.g. hyperplasia) Diseases do not occur to conform to any classification.
• -opathy, meaning an abnormal state lacking specific char- Disease classifications are creations of medical science and
are justified only by their utility. Classifications are useful
acteristics (e.g. lymphadenopathy).
in diagnosis to enable a name (disease or disease category)
to be assigned to a particular illness.
Eponymous names Disease classification at a relatively coarse level of catego-
An eponymous disease or lesion is named after a person or risation is unlikely to change quickly. However, the more
place associated with it. Eponymous names are used com- detailed the level of classification, the more likely it is to
monly either when the nature or cause of the disease or change as medical science progresses. The general classifica-
lesion is unknown, or when long-term usage has resulted in tion of disease into categories such as inflammatory and
the name entering the language of medicine, or to com- neoplastic (see below) is long established.
memorate the person who first described the condition.
Examples include: General classification of disease
• Graves’ disease: primary thyrotoxicosis The most widely used general classification of disease is that
• Paget’s disease of the nipple: infiltration of the skin of based on pathogenesis or disease mechanisms (Fig. 2.3).
the nipple by cells from a cancer in the underlying breast Most diseases can be assigned a place in the following
tissue classification:
• Crohn’s disease: a chronic inflammatory disease of the
gut affecting most commonly the terminal ileum and • congenital
causing narrowing of the lumen — genetic (inherited or sporadic mutations)
• Hodgkin’s disease: a neoplasm of lymph nodes charac- — non-genetic
terised by the presence of Reed–Sternberg cells • acquired
• Reed–Sternberg cells: large cells with bilobed nuclei and — inflammatory
— haemodynamic
prominent nucleoli which are virtually diagnostic of
Hodgkin’s disease. — growth disorders
— injury and disordered repair
— disordered immunity
Syndromes — metabolic and degenerative disorders.
A syndrome is an aggregate of signs and symptoms or a Two important points must be made here. First, the above
20 combination of lesions without which the disease cannot be classification is not the only possible classification of disease.
 Principles of disease classification 2
Mode of acquisition Pathogenetic classification Subclassification Examples

Inherited Cystic fibrosis

Genetic
Spontaneous Down’s syndrome
Congenital
Environmental Rubella-associated malformations
Non-genetic
Accidental Cerebral palsy due to hypoxia at birth

Acute Acute appendicitis

Inflammation
Chronic Tuberculosis

Neoplastic Lung cancer

Growth disorders
Non-neoplastic Benign prostatic hyperplasia

Kinetic energy Bone fracture

Injury and disordered repair
Chemical, etc. Aspirin-induced gastric ulcers
Acquired
Shock Haemorrhagic shock
Haemodynamic
Occlusive lesions Ischaemic heart disease

Immunodeficiency AIDS
Disordered immunity
Autoimmune, allergy, etc. Graves’ thyroiditis

Diabetes mellitus
Metabolic and
degenerative
Osteoarthritis

Fig. 2.3 A general classification of disease. The most widely used general classification of disease is based on the mode of acquisition of
the disease (i.e. congenital or acquired) and the principal disease mechanism (e.g. genetic, vascular). The main pathogenetic classes are divided
into two or more subclasses. There is, however, significant overlap and many acquired diseases are more common in those with a genetic
predisposition.

Second, many diseases share characteristics of more than • malformations in 3.5%

one of the above categories. • single gene defects in 1%
Patients might prefer the following disease classification: • chromosome aberrations in 0.5%.
• recovery likely Common malformations include congenital heart defects,
— with residual disability spina bifida and limb deformities. Single gene defects include
— without residual disability conditions such as phenylketonuria and cystic fibrosis.
• recovery unlikely Chromosomal aberrations include Turner’s syndrome (XO
— with pain sex chromosomes) and Down’s syndrome (trisomy 21 –
— without pain. three copies of chromosome 21). The risk of chromosomal
abnormalities increases with maternal age: for example, the
This classification is perfectly legitimate and may be fore-
risk of a child being born with Down’s syndrome, the com-
most in the patient’s mind, but it is not particularly useful
monest chromosome abnormality, is estimated at 1 in 1500
either as a diagnostic aid or for categorisation according to
for a 25-year-old mother, rising to 1 in 30 at the age of
the underlying pathology.
45 years.
Congenital diseases are initiated before or during birth,
but some may not cause clinical signs and symptoms until
adult life. Congenital diseases may be due to genetic defects,
Congenital diseases
either inherited from the parents or genetic mutations before
Congenital abnormalities (genetic/chromosome disorders birth, or to external interference with normal embryonic and
and malformations) occur in approximately 5% of births in fetal development. An example of a genetic defect is cystic
the UK. They comprise: fibrosis, a disorder of cell membrane transport inherited 21
2 What is disease?

as an autosomal recessive abnormality. Examples of non- Growth disorders

genetic defects include congenital diseases such as deafness Diseases characterised by abnormal growth include adapta-
and cardiac abnormalities resulting from fetal infection by tion to changing circumstances. For example, the heart
maternal rubella (German measles) during pregnancy. enlarges (by hypertrophy) in patients with high blood pres-
A common natural consequence of an abnormal preg- sure, and the adrenal glands shrink (by atrophy) if a disease
nancy is a miscarriage or spontaneous abortion. However, of the pituitary gland causes loss of ACTH production. The
some abnormal pregnancies escape natural elimination and most serious group of diseases characterised by disordered
may survive to full-term gestation unless there is medical growth is neoplasia or new growth formation, leading to
intervention. the formation of solid tumours (Ch. 10) and leukaemias
(Ch. 23).
Fetal origins of adult disease The suffix ‘-oma’ usually signifies that the abnormality
Some diseases occurring in late adult life, such as ischaemic is a solid tumour. Exceptions include ‘granuloma’, ‘hae-
heart disease, are more common in individuals who had a matoma’ and ‘atheroma’; these are not tumours.
low weight at birth. This is postulated to be due to subtle
abnormalities of morphogenesis associated with nutritional Injury and repair
deprivation in utero (the ‘Barker hypothesis’). Mechanical injury or trauma leads directly to disease, the
precise characteristics of which depend upon the nature and
extent of the injury. The progress of disease is influenced by
Acquired diseases the body’s reaction to it. In particular, repair mechanisms
Acquired diseases are due to environmental causes. Most may be defective due to old age, malnutrition, excessive
diseases in adults are acquired. mobility, presence of foreign bodies, and infection. This
Acquired diseases can be further classified according to subject is discussed in detail in Chapter 5.
their pathogenesis.
Metabolic and degenerative disorders
Inflammatory diseases Metabolic and degenerative disorders are numerous and
Inflammation (Ch. 9) is a physiological response of living heterogeneous. Some metabolic disorders are congenital
tissues to injury. Diseases in which an inflammatory reac- (inborn errors of metabolism) and due to defective parental
tion is a major component are classified accordingly. They genes. Other metabolic disorders are mainly acquired (e.g.
are usually named from the organ affected followed by the diabetes mellitus, gout), although there may be a degree of
suffix ‘-itis’. Thus the following are all examples of inflam- genetic predisposition, and some are abnormalities second-
matory diseases: ary to disease (e.g. hypercalcaemia due to hyperparathy-
roidism). Degenerative disorders are characterised by a loss
• encephalitis (brain) of the specialised structure and function of a tissue; as such,
• appendicitis (appendix) this category could include almost every disease, but the
• dermatitis (skin) designation is reserved for those conditions in which degen-
• arthritis (joints). eration appears to be the primary or dominant feature and
There are, however, potentially confusing exceptions to the the cause is poorly understood. These disorders are dis-
nomenclature. For example, tuberculosis, leprosy and syphi- cussed in detail in Chapter 6.
lis are infections characterised by an inflammatory reaction.
Pneumonia and pleurisy refer to inflammation of the lung Iatrogenic diseases
and pleura, respectively.
Iatrogenic disease is illness induced by a medical treatment
Each separate inflammatory disease has special features
or investigation. All medical interventions are associated
determined by:
with some risk to the patient. The probability that harm
• cause (microbial, chemical, etc.) might result should be outweighed by the potential benefit.
• precise character of the body’s response (suppurative, The scope of iatrogenic diseases is very wide (Table 2.2).
granulomatous, etc.) Adverse drug reactions constitute a major category of iatro-
• organ affected (lungs, liver, etc.). genic disease and surveillance arrangements are in force in
many countries: for example the ‘Yellow Card’ system of
Vascular disorders reporting to the Medicines and Healthcare products Regula-
Vascular disorders (Chs 7 and 13) are those resulting from tory Agency in the UK.
abnormal blood flow to, from or within an organ. Blood
vessels are vital conduits. Any reduction in flow through a
vessel leads to ischaemia of the tissue it supplies. If ischaemia EPIDEMIOLOGY
is sustained, death of the tissue or infarction results. Exam-
ples include:  Epidemiology is the pathology of populations

• myocardial infarction (‘heart attack’)  Scope includes the incidence, prevalence, remission and

• cerebral infarction or haemorrhage (‘stroke’) mortality rates of a disease

 Variations may provide clues to aetiology and guide
• limb gangrene
optimal use of healthcare resources
22 • shock and circulatory failure.
 Epidemiology 2
Population
Table 2.2 Examples of iatrogenic diseases sample

Causative agent Resulting disease A

or abnormality
B
Radiation (therapeutic) Skin erythema C
Fibrosis D

Neoplasia E
F
Radiation (diagnostic) Neoplasia
G
Fetal malformations
H
Blood transfusion and blood Hepatitis (due to viruses) I
products (e.g. clotting J
Haemolysis (if mismatched
factor concentrates)
blood)
1950 1960 1970 1980 1990 2000 2010
AIDS (due to HIV)
Year
Penicillin Allergy
Disease X Disease Y
Aspirin and other Gastritis and gastric erosions Fig. 2.4 Disease incidence and prevalence. A population sample
non-steroidal of 10 individuals (A to J), all born in 1950, is followed for 60 years
anti-inflammatory drugs to determine the relative incidence and prevalence of two diseases.
Disease X is an acute illness with no long-term effects; it has a very
Aminoglycoside antibiotics Deafness high incidence (affecting 90% in this sample), but a low prevalence
because at any one time the number of cases to be found is very
Chlorpromazine Cholestatic jaundice low. Disease Y is a chronic illness; it has a lower incidence (affecting
only 30% in this sample) but a relatively high prevalence (from 1990
Steroid therapy Cushing’s syndrome onwards in this sample) because of the accumulation of cases in the
population.
Epidemiology is the study of disease in populations. Knowl-
edge about the population characteristics of a disease is
important for: • the incidence rate is the number of new cases of the disease
occurring in a population of defined size during a defined
• providing aetiological clues period
• planning preventive measures • the prevalence rate is the number of cases of the disease
• provision of adequate medical facilities to be found in a defined population at a stated time
• population screening for early diagnosis. • the remission rate is the proportion of cases of the disease
that recover
Epidemiological clues to the causes of disease • the mortality rate is the number or percentage of deaths
from a disease in a defined population.
Epidemiology often provides important clues to the causes From these four measures one can deduce much about the
of a disease. If, for example, in a particular geographical behaviour of a disease (Fig. 2.4). Chronic (long-lasting)
region or group of individuals the actual incidence of a diseases have a high prevalence: although new cases might
disease exceeds the expected incidence, this suggests that be infrequent, the total number of cases in the population
the disease may be due to: accumulates. Diseases with relatively acute manifestations
• a genetic predisposition more prevalent in that popula- may have a high incidence but a low prevalence, because
cases have either high remission rates (e.g. chickenpox) or
tion, or
• an environmental cause more prevalent in that geograph- high mortality rates (e.g. lung cancer).
Migrant populations are especially useful to epidemiolo-
ical region or group of individuals, or
• combination of genetic and environmental factors.
a gists, enabling them to separate the effects of genetic (racial)
factors and the environment (e.g. diet) (Ch. 3).
Epidemiologically derived clues about the causes of a disease The net effect of disease and nutritional deprivation on a
invariably require direct confirmation by laboratory testing. population can be illustrated as age pyramids, the profiles
often revealing striking contrasts between countries
Disease incidence, prevalence, remission and (Fig. 2.5).
mortality rates
Incidence, prevalence, remission and mortality rates
Geographic variations
are numerical data about the impact of a disease on a Although many diseases occur worldwide, there are many
population: geographic variations, even within one country. There are 23
2 What is disease?

Nigeria: 2000 12
Male Female Cancers
80+
75–79 10 Ischaemic
70–74 heart disease

Projected gobal deaths (millions)

65–69
60–64 8 Stroke
55–59
50–54 HIV/AIDS
6
45–49
40–44
35–39 4 Tuberculosis
30–34 Malaria Other infectious
diseases
25–29
2 Road traffic
20–24 accidents
15–19
10–14 0
5–9 2000 2010 2020 2030
0–4 Year
25 20 15 10 5 0 0 5 10 15 20 25 Fig. 2.6 Projected global causes of death, 2002–2030. Other
Population (millions) than HIV/AIDS, there is an anticipated decline in mortality from
infectious diseases contrasting with the steady increase in deaths
from cancer and cardiovascular conditions due to ageing of the
United Kingdom: 2000 global population. (Based on World Health Statistics 2007, World
Male Female
100+ Health Organization)
95–99
90–94
85–89 Historical changes in disease incidence
80–84 and mortality
75–79
70–74 Changes in disease incidence with time (Fig. 2.6) reflect
65–69 variation in the degree of exposure to the cause, or preven-
60–64 tive measures such as immunisation. Changes in mortality
55–59 additionally reflect the success of treatment.
50–54 The reduced incidence or elimination of serious infections
45–49 (e.g. typhoid, cholera, tuberculosis, smallpox) is the result
40–44
of improved sanitation and, in some instances, the effective-
35–39
30–34
ness of immunisation programmes. Indeed, it is likely that
25–29 sanitation, particularly sewerage and the provision of fresh
20–24 water supplies, has had a much greater impact on the inci-
15–19 dence of these diseases than have advances in medical
10–14 science. Mortality from bacterial infections is also much
5–9 reduced due to the advent of antibiotic therapy. Many viral
0–4 infections elude specific treatment, but mass immunisation
2.5 2.0 1.5 1.0 0.5 0.0 0.0 0.5 1.0 1.5 2.0 2.5 has considerably reduced their incidence.
Population (millions) During the 19th and 20th centuries, the declining inci-
Fig. 2.5 National health revealed by age pyramids. In dence in many serious infections was accompanied by an
Nigeria, among other African countries, disease and nutritional increasing incidence of other conditions, notably cardiovas-
problems severely curtail life expectancy. In the United Kingdom, cular disorders (e.g. hypertension, atherosclerosis) and their
among other ‘developed countries’, a high proportion of the complications (e.g. ischaemic heart disease, strokes). The
population survives into old age, albeit often accompanied by apparent increase is partly due to the fact that the average
chronic ill health. (Data from US Census Bureau, International age of the population in most developed countries is increas-
Data Base)
ing; cardiovascular disorders are more common with increas-
ing age, unlike infections which afflict all ages. Nevertheless,
irrespective of this age-related trend, there is a genuine
increased incidence of these disorders. This increase is due
considerable differences between so-called developed and to changes in diet (e.g. fat content) and lifestyle (e.g.
developing countries; for example, cardiovascular disorders, smoking, lack of exercise) and the consequent obesity. Inter-
psychiatric illness and some cancers predominate in coun- vention by reducing dietary and behavioural risk factors has
tries such as the USA and the UK, but these conditions are begun to yield a beneficial reduction in the risk of developing
less common in most of Africa and Asia. In developing the complications of cardiovascular disorders.
countries, the major health problems are due to infections Historical changes in the incidence of neoplastic diseases
24 and malnutrition. (i.e. tumours) provide vital clues to their aetiology. For
 Epidemiology 2
example, a dramatic increase in the incidence of a formerly • coal-worker’s pneumoconiosis due to coal dust
uncommon tumour may be the result of exposure to a new inhalation
environmental hazard. Historical changes led to the discov- • asbestosis due to asbestos dust inhalation
ery of the association between ionising radiation and many • dermatitis due to formaldehyde, organic solvents, etc.
types of cancer, and between smoking and lung cancer.
It is important to identify occupational hazards so that
risks can be minimised. Furthermore, in many countries,
Socio-economic factors
Socio-economic factors undoubtedly influence the incidence
of certain diseases and the host response to them. Over-
USA
crowding encourages the spread of infections, leading to
the rapid development of epidemics. Economic hardship United Kingdom
is commonly accompanied by malnutrition (Ch. 6), a condi-
tion causing ill health directly and also predisposing Japan
to infections. India
A particularly sensitive and widely used indicator of the
socio-economically related health of a population is the China
infant mortality rate. This rate varies considerably between
Nigeria
countries, but in general the rate is lower in countries
regarded as being developed (Fig. 2.7). Chad
Within a developed country, such as the UK, less affluent
individuals have a higher incidence of cervical cancer, ischae- Angola
mic heart disease and respiratory infections, among many 0 20 40 60 80 100 120 140 160
other conditions. Infant mortality per 1000 live births
Fig. 2.7 International variations in infant mortality rates.
Occupational factors Infant (age less than 1 year) mortality rates are important and
sensitive indicators of a nation’s health and health service provision.
The association of a disease with a particular occupation Common causes of infant death in countries with high infant
can reveal the specific cause. Well-documented associations mortality rates are diarrhoeal diseases and pneumonia. (Data derived
include: from World Health Statistics 2007, World Health Organization)

A Developing countries B Developed countries

Ischaemic heart
HIV/AIDS disease
Lower respiratory Depressive illness
infections
Cerebrovascular
Diarrhoeal diseases disease

Childhood disorders Alcohol use disorders

Low birth weight Dementia, etc.

Malaria Deafness

Bronchitis and
Depressive illness emphysema

Ischaemic heart Road traffic injury

disease
Tuberculosis Osteoarthritis

Road traffic injury Lung cancer

0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
% DALYs % DALYs
Fig. 2.8 The top ten major burdens of disease in ‘developing’ and ‘developed’ countries (2000). Based on the The World Health
Report 2002 (World Health Organization), the burden of disease is estimated in disability-adjusted life years (DALYs). [A] In developing
countries, infections such as HIV/AIDS account for much ill health and death. [B] In contrast, in developed countries, cardiovascular conditions
are among the leading causes. 25
2 What is disease?

patients disabled by occupational diseases may be entitled of serious illness supervenes, the accumulated deterioration
to compensation. of the body reduces its viability until it reaches the point
where death supervenes. In almost every case, however,
there is a final event that tips the balance and is registered
Hospital and community contrasts
as the immediate cause of death. In younger individuals
Medical students often develop a biased impression of the dying prematurely, death is usually more clearly attributable
true incidence of diseases because much of their training to a single fatal condition in an otherwise reasonably healthy
occurs in hospitals. The patients and diseases they see are individual.
selected rather than representative; only those cases requir- In developed countries, such as the USA and in Europe,
ing hospital investigation or treatment are sent there. For diseases of the cardiovascular system account for much ill
most diseases, even in countries with well-developed health health (Fig. 2.8). A newborn infant in these countries has a
services, patients remain in the community. Patients seen 1 in 3 chance of ultimately dying in adult life from ischaemic
by a community medical practitioner are most likely to heart disease, and a 1 in 5 chance of ultimately dying from
have psychiatric illness, upper respiratory tract infections cancer. In some famine-ridden countries, newborn infants
and musculoskeletal problems. The general hospital cases have similar probabilities of dying from diarrhoeal diseases
are more likely to be patients with cardiovascular diseases, and malnutrition in childhood.
proven or suspected cancer, drug overdoses, severe trauma,
etc.
FURTHER READING
Age and disease
Lopez, A.D., Mathers, C.D., Ezzati, M., et al., 2006. Global burden of
Many diseases become more prevalent with increasing age. disease and risk factors. The World Bank and Oxford University Press,
Indeed, the occurrence of these diseases, often together in New York (http://files.dcp2.org/pdf/GBD/GBD.pdf ).
the same patient, is a key feature of elderly populations and Nesse, R.M., Williams, G.C., 2004. Why we get sick: the new science of
Darwinian medicine. Vintage, New York.
an important determinant of healthcare planning.
Stearns, S.C., Koella, J.C., 2007. Evolution in health and disease. Oxford
University Press, Oxford.
US Census Bureau. International Data Base. http://www.census.gov/ipc/
Common causes of mortality and morbidity www/idb/index.html.
Death is inevitable. In many people, death may be preceded Webb, P., Bain, C., Pirozzo, S., 2005. Essential epidemiology: an
introduction for students and health professionals. Cambridge University
by a variable period of senility, during which there is cumula- Press, Cambridge.
tive deterioration of the structure and function of many World Health Organization. World health statistics, 2007. WHO, Geneva.
organs and body systems (Ch. 11). Unless an acute episode World Health Organization website. http://www.who.int.

26
3
What causes disease?
James C. E. Underwood, Simon S. Cross

Causes of disease 28 Environmental factors 40

Predisposing factors and precursors of disease Chemical agents causing disease
Prenatal factors Physical agents causing disease
Aetiology and age of disease onset
Multifactorial aetiology of disease Infective agents 42
Evidence for genetic and environmental factors Bacteria
Viruses
Genetic abnormalities in disease 32 Yeasts and fungi
Gene structure and function Parasites
Techniques for studying genetic disorders Prions
Diseases due to genetic defects

27
3 What causes disease?

Predisposing factors and precursors

CAUSES OF DISEASE of disease
Many diseases are the predictable consequence of exposure to
 Diseases are due to genetic, environmental or
the initiating cause; host (i.e. genetic) factors make rela-
multifactorial causes tively little contribution to the outcome. This is particularly
 Role of genetic and environmental factors can be true of physical injury: the results of mechanical trauma and
distinguished by epidemiological observations, family radiation injury are largely dose related; the effect is directly
studies or laboratory investigations proportional to the physical force.
 Some diseases with a genetic basis may not appear until Other diseases are the probable consequence of exposure
adult life to causative factors, but they are not absolutely inevitable.
 Some diseases with environmental causes may have their For example, infectious diseases result from exposure to
effects during embryogenesis
potentially harmful environmental agents (e.g. bacteria,
viruses), but the outcome is often influenced by various
host factors such as age, nutritional status and genetic
In terms of causation, diseases may be:
variables.
• entirely genetic – either inherited or prenatally acquired Some diseases predispose to others; for example, ulcerative
defects of genes colitis predisposes to carcinoma of the colon, and hepatic
• multifactorial – interaction of genetic and environmental cirrhosis predisposes to hepatocellular carcinoma. Diseases
factors predisposing to tumours are called pre-neoplastic conditions;
• entirely environmental – no genetic component to risk of lesions from which tumours can develop are called pre-
disease. neoplastic lesions. Some diseases occur most commonly in
those individuals with a congenital predisposition. For
Features pointing to a significant genetic contribution to the
example, ankylosing spondylitis, a disabling inflammatory
cause of a disease include a high incidence in particular
disease of the spinal joints of unknown aetiology, is much
families or races, or an association with a known inherited
more common in people with the HLA-B27 haplotype
feature (e.g. gender, blood groups, histocompatibility haplo-
(Ch. 25).
types). Environmental factors are suggested by disease asso-
Some diseases predispose to others because they have a
ciations with occupations or geography. Ultimately, however,
permissive effect, allowing environmental agents that are not
only laboratory investigation can provide irrefutable identi-
normally pathogenic to cause disease. For example, opportun-
fication of the cause of a disease. The extent to which a
istic infections occur in those patients with impaired defence
disease is due to genetic or environmental causes can often
mechanisms, allowing infection by normally non-pathogenic
be deduced from some of its main features (Table 3.1).
organisms (Ch. 8).

Prenatal factors
Table 3.1 Clues to a disease being caused by either
genetic or environmental factors Prenatal factors, other than genetic abnormalities, contribut-
ing to disease risk are:
Disease Genetic cause Environmental
• transplacental transmission of environmental agents
characteristic cause
• nutritional deprivation.
Age of Usually early Any age Diseases due to transplacental transfer of environmental
onset (often in agents from the mother to the fetus include fetal alcohol
childhood) syndrome and congenital malformations due to maternal
rubella infection. Fetal alcohol syndrome is still a serious
Familial Common Unusual (unless family
problem, but malformations due to rubella are much less
incidence exposed to same
environmental agent)
common now that immunisation is widespread.
The notion that disease risk in adult life could be due
Remission No (except by Often (when to fetal nutritional deprivation has gained support from
gene therapy) environmental cause the work of David Barker. The Barker hypothesis is that an
can be eliminated) adult’s risk of, for example, ischaemic heart disease and
hypertension is programmed partly by nutritional depriva-
Incidence Relatively Common tion in utero. This is plausible; nutritional deprivation could
uncommon have profound effects during critical periods of fetal
morphogenesis.
Clustering In families Temporal or spatial or
both
Aetiology and age of disease onset
Linkage to Common Relatively rare
Do not assume that all diseases manifest at birth have an
inherited
factors inherited or genetic basis; as noted previously (Ch. 2), dis-
28 eases present at birth are classified into those with a genetic
 Causes of disease 3
basis and those without a genetic basis. Conversely, although Evidence for genetic and environmental
most adult diseases have an entirely environmental cause, factors
genetic influences to disease susceptibility and vulnerability
Genetic contributions to disease incidence are exposed when
to environmental agents are being increasingly discovered.
any putative environmental factors are either widely preva-
The incidence of many diseases rises with age because:
lent (most individuals are exposed) or non-existent (no
• Probability of contact with an environmental cause known environmental agents). The epidemiologist Geoffrey
increases with duration of exposure risk. Rose exemplified this by suggesting that, if every individual
• The disease may depend on the cumulative effects of one smoked 40 cigarettes a day, we would never discover that
or more environmental agents. smoking was responsible for the high incidence of lung
• Impaired immunity with ageing increases susceptibility cancer; however, any individual (especially familial) varia-
to some infections. tion in susceptibility to lung cancer would have to be attrib-
• The latent interval between the exposure to cause and uted to genetic differences. An environmental cause, such
the appearance of symptoms may be decades long. as smoking, is easier to identify when there are significant
individual variations in exposure which can be correlated
with disease incidence; indeed, this enabled Doll and Hill in
Multifactorial aetiology of disease the 1950s to demonstrate a strong aetiological link to lung
cancer risk.
Many diseases with no previously known cause are being
shown to be due to an interplay of environmental factors
and genetic susceptibility (Fig. 3.1). These discoveries are Family studies
the rewards of detailed family studies and, in particular,
application of the new techniques of molecular genetics. Strong evidence for the genetic cause of a disease, with little
Diseases of adults in which there appears to be a significant or no environmental contribution, comes from observations
genetic component include: of its higher than expected incidence in families, particularly
if they are affected by a disease that is otherwise very rare
• breast cancer in the general population. Such diseases are said to ‘run in
• Alzheimer’s disease families’.
• diabetes mellitus Having identified the abnormality in a family, it is then
• osteoporosis important to provide genetic counselling so that parents can
• coronary atherosclerosis. make informed decisions about future pregnancies. The
One of the reasons why there may be only slow progress in precise mode of inheritance will determine the proportion
characterising the genetic component of the diseases listed of family members (i.e. children) likely to be affected.
above and others is that two or more genes, as well as envi- Because inherited genetic disorders are either sex-linked, or
ronmental factors, may be involved. Pursuing the genetic autosomally dominant or autosomally recessive, not all indi-
basis of these polygenic disorders requires complex analyses. viduals in one family may be affected even if the disease has
no environmental component.

Studies on twins
Genetic factors Environmental factors
Observations on the incidence of disease in monozygotic
(identical) twins are particularly useful in disentangling the
relative influences of ‘nature and nurture’; of greatest value
in this respect are identical twins who, through unfortunate
Cystic fibrosis
family circumstances, are reared in separate environments.
Uncommon diseases occurring in both twins are more likely
to have a genetic component to their aetiology, especially if
Diabetes
the twins have been brought up and lived in different
environments.

Breast cancer
Studies on migrants
Traumatic head The unusually high incidence of a particular disease in a
injury country or region could be due either to the higher preva-
lence of a genetic predisposition in the racial or ethnic
group(s) in that country or to some environmental factor
such as diet or climatic conditions. Compelling evidence of
Fig. 3.1 Proportionate risk of disease due to genetic or
environmental factors. Some conditions are due solely to genetic the relative contributions of genetic and environmental
(e.g. cystic fibrosis) or environmental (e.g. traumatic head injury) factors in the aetiology and pathogenesis of a disease can be
factors. An increasing number of other diseases (e.g. diabetes, breast obtained by observations on disease incidence in migrant
cancer) are being shown to have a genetic component to their risk, populations (Fig. 3.2). For example, if a racial group with a
particularly in cases diagnosed at a relatively young age. low incidence of a particular disease migrates to another 29
3 What causes disease?

Incidence of disease The polymorphisms of greatest relevance to disease sus-

in migrants
ceptibility are:
High incidence in
indigenous population • HLA types
• blood groups
• cytokine genes.
HLA types
Clinical and experimental observations on the fate of organ
Due to unavoidable
environmental transplants led to the discovery of genes known as the major
factors Due to potentially histocompatibility complex (MHC). In humans, the MHC
avoidable factors
genes reside on chromosome 6 and are designated HLA genes
(human leucocyte antigen genes). HLA genes are expressed
on cell surfaces as substances referred to as ‘antigens’, not
Due to genetic
factors because they normally behave as antigens in the host that
bears them, but because of their involvement in graft rejec-
Years after migration tion (Ch. 8). The body does not normally react to these
substances, because it is immunologically tolerant of them
Fig. 3.2 Clues to genetic and environmental causes from
and they are recognised as ‘self ’ antigens.
disease incidence in migrants. When people with a low incidence
of a disease migrate to a country in which the indigenous population
HLA types are grouped into classes, principally:
has a high incidence, any change in the incidence of the disease in
the migrants provides important clues to the role of genetic and
• Class I are expressed on the surface of all nucleated cells.
In all diploid cells there are pairs of allelic genes at each
environmental factors in causing the disease. A rapid rise in
of three loci: these genes are known as A, B and C. The
incidence would attribute the disease to unavoidable environmental
factors such as climate or widely prevalent microorganisms. A more
normal role of class I types is to enable cytotoxic T lym-
gradual rise would be due to factors such as diet, over which there phocytes to recognise and eliminate virus-infected cells.
may be some initial cultural resistance to change. No change in • Class II are expressed on the surface of those cells that
disease incidence attributes the high incidence to genetic factors in interact with T lymphocytes by physical contact, such as
the indigenous population. The distinctions are rarely as clear-cut as antigen-presenting cells (e.g. Langerhans cells). The
in this graphic example. pairs of allelic genes at each of three loci are known as
DP, DQ and DR. The normal role of class II types is the
initiation of immune responses.
country in which the disease is significantly more common, Diseases may be associated with HLA types because:
there are two possible outcomes leading to different
conclusions: • Some infective microorganisms bear antigens similar to
those of the patient’s HLA substances and thereby escape
1. If the incidence of the disease in the migrant racial group immune recognition and elimination
rises, it is likely that environmental factors (e.g. diet) are • The immune response to an antigen on an infective
responsible for the high incidence in the indigenous microorganism cross-reacts with one of the patient’s
population. HLA substances, thus causing tissue damage
2. If the incidence of the disease in the migrant racial group • The gene predisposing to a disease is closely linked
remains low, it is more likely that the higher incidence in (genetic linkage; p. 36) to a particular HLA gene.
the indigenous population is due to genetic factors.
Diseases associated with HLA types are listed in Table 3.2.
Most observations on disease incidence in migrant popula- They are all chronic inflammatory or immunological disor-
tions have been made on neoplastic disorders (cancer). This ders. In some instances the association is so strong that
is because cancer is a major illness, likely to be reliably HLA testing is important diagnostically: the best example
diagnosed by biopsy, and, in many countries, documented is the association of HLA-B27 with ankylosing spondylitis
in cancer registries. (Ch. 25).
Autoimmune diseases (diseases in which the body’s
immunity destroys its own cells) are most frequently associ-
Association with gene polymorphisms
ated with specific HLA types. The combination of HLA-DR3
Within the population there are many normal genetic vari- and HLA-B8 is particularly strong in this regard, but it must
ations or polymorphisms. The effect of some of these poly- be emphasised that it is present in only a minority of patients
morphisms is obvious: examples are skin, hair and eye with autoimmune disease. Autoimmune diseases also illus-
colour, body habitus, etc. When possessed by large groups trate a separate feature of the association between HLA
of people of common ancestry, a cluster of polymorphic vari- types and disease. Normally, class II types are not expressed
ants constitutes racial characteristics. In other instances the on epithelial cells. However, in organs affected by autoim-
polymorphism has no visible effects: examples are blood mune disease, the target cells for immune destruction are
groups and HLA types (see below); these are evident only often found to express class II types. This expression enables
30 by laboratory testing. their immune recognition and facilitates their destruction.
 Causes of disease 3
Gender and disease
Table 3.2 Examples of disease associated with HLA types
Gender, like any other genetic feature of an individual, may
Disease HLA type(s) Comments be directly or indirectly associated with disease. An example
of a direct association, other than the absurdly simple (e.g.
Allergic disorders A23 Requires carcinoma of the uterus and being female), is haemophilia.
(e.g. eczema, environmental Haemophilia is an inherited X-linked recessive disorder of
asthma) allergen
blood coagulation. It is transmitted by females to their male
children. Haemophilia is rare in females because they have
Ankylosing B27 Associated in c.
spondylitis 90% of cases two X chromosomes, only one of which is likely to be defec-
tive. Males always inherit their single X chromosome from
Coeliac disease DR3, B8 Gluten sensitivity their mother; if the mother is a haemophilia carrier, half of
her male children are likely to have inherited the disease.
Graves’ disease DR3, B8 Due to thyroid- Some diseases show a predilection for one of the sexes.
(primary stimulating For example, autoimmune diseases (e.g. rheumatoid disease,
thyrotoxicosis) immunoglobulin systemic lupus erythematosus) are generally more common
in females than in males; the reason for this is unclear.
Hashimoto’s DR5 Aberrant HLA class
Atheroma and its consequences (e.g. ischaemic heart
thyroiditis II expression on
disease) tend to affect males earlier than females, but after
thyroid epithelium
the menopause the female incidence approaches that in
Insulin-dependent DR3, DR4, Immune injury males. Females are more prone to osteoporosis, a common
(juvenile onset) B8 to beta-cells in cause of bone weakening, particularly after the menopause.
diabetes mellitus pancreatic islets In some instances the sex differences in disease incidence
are due to social or behavioural factors. The higher incidence
Rheumatoid DR4 Autoimmune of carcinoma of the lung in males is due to the fact that they
disease disease smoke more cigarettes than do women.

Racial differences
Blood groups Racial differences in disease incidence may be genetically
Blood group expression is directly involved in the pathogen- determined or attributable to behavioural or environmental
esis of a disease only rarely; the best example is haemolytic factors. Racial differences may also reflect adaptational
disease of the newborn due to rhesus antibodies (Ch. 23). responses to the threat of disease. A good example is
A few diseases show a weaker and indirect association with provided by malignant melanoma (Ch. 24). Very strong
blood groups. This association may be due to genetic linkage; evidence implicates ultraviolet light in the causation of
the blood group determinant gene may lie close to the gene malignant melanoma of the skin; the highest incidence is in
directly involved in the pathogenesis of the disease. Caucasians living in parts of the world with high ambient
Examples of blood group-associated diseases include: levels of sunlight, such as Australia. The tumour is, however,
relatively uncommon in Africa, despite its high sunlight
• duodenal ulceration and group O levels, because the indigenous population has evolved with
• gastric carcinoma and group A. an abundance of melanin in the skin.
Some abnormal genes are more prevalent in certain races.
Cytokine genes For example, the cystic fibrosis gene is carried by 1 in 20
There is evidence linking the incidence or severity of chronic Caucasians, whereas this gene is rare in Africans and Asians.
inflammatory diseases to polymorphisms within or adjacent Conversely, the gene causing sickle cell anaemia is more
to cytokine genes. Cytokines are important mediators and common in blacks than in any other race. These associations
regulators of inflammatory and immunological reactions. may be explained by a heterozygote advantage conferring pro-
It is logical, therefore, to explore the possibility that tection against an environmental pathogen (Table 3.3).
enhanced or abnormal expression of cytokine genes may Other diseases in different races may be due to socio-
be relevant. economic factors. Perinatal mortality rates are often used as
Associations have been found between a tumour necrosis an indicator of the socio-economic welfare of a population.
factor (TNF) gene polymorphism and Graves’ disease of the Regrettably, the perinatal mortality rate is much higher in
thyroid (Ch. 17) and systemic lupus erythematosus (Ch. certain racial groups, but this outcome is due almost entirely
25). The TNF gene resides on chromosome 6 between the to their social circumstances and is, therefore, theoretically
HLA classes I and II loci, linkage with which may explain an capable of improvement.
indirect association between TNF gene polymorphism and Parasitic infestations are more common in tropical cli-
disease. There are also associations between interleukin-1 mates, not because the races predominantly dwelling there
gene cluster (chromosome 2) polymorphisms and chronic are more susceptible, but often because the parasites cannot
inflammatory diseases. The associations seem to be stronger complete their life cycles without other hosts that live only
with disease severity than with susceptibility. in the prevailing environmental conditions. 31
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reunions from time to time, lectures (seanchus),
followed by discussions on Irish subjects, concerts
(sgoruidheacht), with choirs, Irish dances and songs,
and ceilidhe, informal meetings on the lines of ancient
village gatherings, where serious conversation—in
Irish—alternates with music or a ‘recital,’ that is to say, a
story or a piece of news, told, according to popular custom,
by the author or a raconteur. Every year the Gaelic and
National Festival, that of St. Patrick, is celebrated
throughout Ireland, but notably in Dublin. … A start—the first
and greatest difficulty—has been made, and now the League is a
power in Ireland. It sells annually 20,000 Gaelic books and
pamphlets, in which are included editiones principes of
the poets of the eighteenth century, and new Irish
publications, tales, and novels. Its financial resources are
moderate. They represent, however, the spontaneous obol of the
poor; and a large part of the annual subscription to the
Language Fund, during St. Patrick’s week, is made up of pence
and of half-pence. From the start the League has had the good
sense officially to declare that it was both necessary and
desirable that it should stand apart from all political and
religious struggles; such has been its line of conduct, and
now within it are found representatives of every party, from
the strongest Orangemen to the fiercest separatists."

L. Paul-Dubois,
Contemporary Ireland,
part 3, chapter 2
(Maunsel & Co. Dublin, 1908).

Public meetings have been held in Ireland during the past year
(1909) to support the demand of the Gaelic League "that the
Irish language, both oral and written, and Irish history be
made essential subjects for matriculation in the new national
University, and that proper provision be made for the teaching
of Irish in all its colleges."
IRELAND: A. D. 1901 (March).
Census

"4,456,546 Persons (2,197,739 Males and 2,258,807 Females)

were returned in the Enumerators’ Summaries as constituting
the population of Ireland on the night of Sunday, the 31st of
last March—thus showing a decrease since 1891 of 248,204
persons, or 5.3 per cent.—the decrease in the number of males
was equal to 5.2 per cent., and in the number of females to
5.3 per cent.

"There was during the decade a decrease of 41,297 persons, or

3.5 per cent. in the Province of Leinster; 98,568, or 8.4 per
cent. in the Province of Munster; 38,463, or 2.4 per cent. in
the Province of Ulster; and 69,876, or 9.7 percent, in the
Province of Connaught."

In 1841 the population enumerated in Ireland as a whole had

been 8,196,597; in 1851 it had been 6,574,278; in 1861,
5,798,967; in 1871, 5,412,377; in 1881, 5,174,836; in 1891,
4,704,750. Excepting in 1861 the showing is a steady decrease,
and this latest census finds the island almost half
depopulated.

"According to the Summaries furnished by the Enumerators,

3,310,028 persons returned themselves as Roman Catholics, this
number being 237,279 or 6.7 per cent under the number so
returned in 1891; 579,385 were returned under the head of
‘Protestant Episcopalians,’ being a decrease of 20,718, or 3.5
percent., compared with the number tabulated under that head
in 1891; 443,494 were returned as Presbyterians, being a
decrease of 1,480 or 0.3 per cent. compared with 1891; the
number of Methodists returned on the present occasion amounts
to 61,255, being an increase of 5,745 or 10.4 per cent, on the
number returned on the Census Forms in 1891."

In Dublin City, as extended under the Dublin Corporation Act

 of 1900, the population enumerated in 1901 was 289,108, being
a gain of 20,521 since 1891. With the Urban Districts of
Rathmines and Rathcar, Pembroke, Blackrock and Kingstown
added, the total population of Dublin and suburbs was
373,179,—an increase in the decade of 27,220.

The following table shows the population of the 14 towns in

which more than 10,000 inhabitants were found: compared with
the enumeration of 1891.

Towns. 1891. 1901.

Belfast 273,079 348,965

Cork 75,345 75,978
Limerick 37,155 38,085
Londonderry 33,200 39,873
Waterford 26,203 26,743
Galway 13,800 13,414
Drogheda 13,708 12,765
Newry 12,961 12,587
Dundalk 12,449 13,067
Lisburn 12,250 11,459
Wexford 11,545 11,154
Lurgan 11,429 11,777
Kilkenny 11,048 10,493
Sligo 10,862 10,862

Total 554,446 637,222

IRELAND: A. D. 1902 (February).

Lord Rosebery and Sir Henry Campbell-Bannerman at issue on
the Home Rule question.

In a speech delivered at Liverpool in February Lord Rosebery

pronounced a most positive funeral oration on what he assumed
 to be the death and burial of the Irish Home Rule question in
British politics. A few days later Sir Henry
Campbell-Bannerman, speaking at the annual meeting of the
General Committee of the National Liberal Federation, took
occasion to resurrect the supposedly buried issue and take it
under his protection, as one of the responsibilities of the
Liberal Party.
{333}
Home Rule, he said, was often spoken of as if it were "a
strange, fantastic, almost whimsical and mad-cap policy,
rashly adopted in a random way, to secure the Irish vote. It
is to be easily and lightly dropped at any moment when an
equal amount of support can be obtained from any other
quarter! Not a very noble view of the case! Not, in truth, a
very creditable or even a decent view of the case, but
intelligible enough if there were in the way no principles and
no facts." One such fact he found in the "fixed constitutional
demand of the Irish people"; and Sir Henry concluded that the
"old policy" remains "the sole remedy for the condition of
Ireland, which is the most serious weakness in the whole
British Empire and the most grave blot upon its fame."

By these two sharply opposed utterances the Liberals of the

United Kingdom were called to decide which leading they would
follow—that of Lord Rosebery or that of Sir Henry. Not being
in power, however, nor measurably within reach of it, decision
of the party did not need to be made in haste.

IRELAND: A. D. 1902-1908.
Conditions in the matter of Disorder and Crime.

In the course of a debate in the British Parliament on

conditions in Ireland, which took place on the 24th of
February, 1909, Lord Percy, charging the Liberal Government
with responsibility for an increase of disorder and crime
since it came into power, brought statistics in evidence as
follows: "Take the indictable offences against property and
firing into houses. In 1906 the total number of these offences
was 20; in 1907, 29; in 1908, 80. Outrages on the person by
the use of firearms, agrarian and non-agrarian, were:—In the
first 11 months of 1906, 20 agrarian and 36 non-agrarian; in
1907, 56 agrarian and 53 non-agrarian; in 1908, 128 agrarian
and 65 non-agrarian. In addition to these open outrages there
was the system of boycotting and intimidation. In
cattle-driving—a new offence unheard of before the days of the
Chief Secretary—there were 390 cases in 1907 and 681 in 1908.
The number of persons under police protection on January 31,
1907, was 196; in 1908, 270; and in 1909, 335. The cases of
boycotting had risen from 162 on November 30, 1905, to 874 on
January 31, 1908. An impression prevailed that the cases of
boycotting were ‘minor cases,’ and of no great importance; but
the Lord Chief Justice, at the Clare Spring Assizes on one
occasion, referring to these so-called minor cases, pointed
out that no one dealt with or spoke to the boycotted person,
and that he had to go 20 miles to Limerick for the necessaries
of life. People also had to go to mass and to weddings
protected by police; and he asserted that the Government could
not point to a civilized country in Europe in which the
Government would tolerate a large section of its population
living daily and hourly under the shadow of a terror like
this."

The Chief Secretary for Ireland, Mr. Birrell, retorted with

the following: "For the purpose of making a comparison between
the condition of Ireland to-day and as it was when the
Government was led by the right honourable gentleman the
leader of the Opposition, when they introduced and made
permanent their Crimes Act, we must consider what was the
state of things in 1886 as compared with what it is now. I
will give the House the figures. Murders in 1886, seven; in
1908, one; manslaughter in 1886, three; now, none; firing at
the person, 16; now, 15; firing into dwellings—and here is a
most formidable addition, I admit—43; now, 66; incendiary
fires and arson, 103; now, 54; killing, cutting, and maiming
 cattle—a horrible and brutal crime—73; now, 22—far too many;
riots and affrays, nine; now, 13; threatening letters or
notices, 434; now, 233; intimidation, 92; now, 57; injury to
property, 150; now, 89; other offences, 136; now, 26; showing
in 1886 a total of 1,056, and now a total of 576. On January
1, 1886, there were 175 persons wholly boycotted, and 716
partially boycotted—a total of 891. In those days, I admit,
the police made no distinction between partial and minor
boycotting. In 1887 there were 145 persons wholly boycotted,
and 763 partially boycotted, making a total of 908. On January
1, 1909, there were 15 wholly boycotted, 10 partially
boycotted, and 172 cases of minor boycotting, making in all
197. Persons under constant police protection on December 31,
1887, numbered 252, and those under protection by patrol,
704—a total of 956. On December 31, 1908, there were 74
persons under constant protection, 270 under protection by
patrol, a total of 344 against the total of 956. I leave the
House to draw their own inference from those figures."

An official return to Parliament, from the Royal Irish

Constabulary Office, Dublin Castle, of the number of cases of
boycotting and of persons boycotted throughout Ireland on the
31st day of January, 1908, and on various days in several
preceding years, showed 5 cases of entire boycotting,
affecting 26 persons, and 9 cases of partial boycotting,
affecting 39 people, on the date mentioned in 1908; 4 cases of
entire boycotting, affecting 20, with seven cases of the
partial boycott, affecting 35, on the 31st of July, 1907. On
the 31st of July, 1903, there had been 4 cases of entire and
21 cases of partial boycotting affecting 25 and 131 persons
respectively; while the cases on the 31st of March, 1902, of
entire boycotting had numbered 5, the partial cases 46, and
they were directed in the first instance against 26 people,
and against 275 in the second.

IRELAND: A. D. 1905.
Defective working of the Land Purchase Act of 1903.
 Inadequacy of its financial provisions.
Baffled in the Western Counties by cupidity of landlords.

The first two years of the working of the Irish Land Purchase
Act of 1903 sufficed to show that the splendid promise of that
measure could not be realized satisfactorily without
fundamental changes in its plan. By that time the agreements
effected between landlords and tenants for transfers of land
from the former to the latter called for purchase payments far
in excess of the sums which the Act had provided for supplying
at so early a stage of the operation. The process of transfer
was checked and the feelings that helped it on were chilled by
increasing delays in the completion of transactions when
begun.

But this was not the worst disappointment in the working of

the Act. Another more serious is charged to the cupidity of
landlords in the poorer counties of the west. In the article
by Mr. Thomas W. Russell from which a quotation is given above
he explains it as follows:

{334}

"It was quite impossible to apply the same rule to Connaught

and to other similar areas as to Ulster, Leinster, and
Munster. In the west the holdings are small and hopelessly
uneconomic in their character. Parliament felt, and rightly
so, that to make the occupier of a five-acre bog holding an
owner was to do him no good. Such a feat in statesmanship
merely freed the western landlord from a risky security and
transferred the risk to the state. It was, therefore, enacted
that the large grass holdings which abound in that region,—and
which are held by graziers on a tenure of eleven months, the
object of the term being to avoid the creation of a tenancy,
—should be bought and wherever possible should be distributed
among the small holders, thus rendering a decent living
possible. And in several cases this has been successfully done
by the congested districts board, with the very best results.
… The landlords as a whole professed at the land conference
and in Parliament their entire willingness to sell, provided
they received a price equivalent when securely invested to
their second-term net income. To enable this to be done the
bonus of £12,000,000 was sanctioned by Parliament. The whole
thing was a bargain—a clear case of contract. And what the
western landlords have been guilty of is a simple breach of
faith. They are quite ready to sell the bog holdings, the
barren mountain tracts out of which a decent living cannot be
had, demanding for this wretched land in many cases more than
is being asked in Antrim and Down for the best land in these
counties. But the grass ranches they refuse to part with. And
so the whole plan of the act,—the whole scheme for the
re-settling of the land, and raising the station of the small
holder,—has been brought to naught.

"In this connection another difficulty has arisen. When the

western sections of the act were being passed, Mr.
Wyndham,—who was in grim earnest about these poor
people,—provided for the sale of congested estates to the
estates commissioners or to the congested districts board.
Special inducements were given to sales under these sections.
The cost of sale was borne almost entirely by the state, and
the commissioners were authorized in such cases to spend money
upon the improvement of the holdings. The policy was
excellent. But the landlords have ruined it. They quickly
discovered that if they sold to the estates commissioners the
land would be inspected by an expert valuer, and its price
would depend upon its value. This was not their idea of how
things should be done. They preferred to sell to the tenant
direct, against whom they could use the screw of arrears of
rent, and from whom they could exact a higher price. Hardly a
case of sale to the estates commissioners has taken place
under these well-meant sections. And for the reasons stated. …
The fact is, compulsory powers of purchase in all such cases
ought to have been frankly given. But to mention the word
 compulsion to the then chief secretary was to send him into a
fury. He would not hear of it."

T. W. Russell,
Workings of the Irish Land Purchase Act
(American Review of Reviews, November, 1905).

IRELAND: A. D. 1905.
Formation of the Sinn Fein Party.

"While the outside world was looking to the Irish

Parliamentary Party as the guardian of the national conscience
of Ireland, a Young Ireland Party, determined, virile,
thoughtful, idealistic and, strange though it may seem,
practical, was gradually forming, becoming a power, sweeping
away outworn ideas, preaching new and putting them into
practice, and working wonders in the revival of a genuine
national spirit throughout the country. … Naturally, and very
gradually, the various units gravitated toward one another;
and, less than two years ago, under the guidance of a Dublin
boy named Arthur Griffith, they elected a National Council,
and formed themselves into a party known as the ‘Sinn Fein
Party,’ which included probably three-fourths of the national
thinkers in Ireland. Since its inception, the Sinn Fein Party
has been rapidly gaining power, raising itself upon the ruins
of a fast crumbling Parliamentary agitation, and eventually
leaping into greater popular prestige when, recently, the
ludicrous Irish Councils Bill was submitted to the nation as
the fruits of a generation of Parliamentary agitation.

"'Sinn Fein' is Gaelic for 'Ourselves.' The doctrine of

the Sinn Fein Party is that the salvation of a nation is to be
wrought out by the people and upon the soil of that nation,
and it holds that ‘God helps those who help themselves.’ It
asks Ireland to cultivate, what for a long time it neglected,
self-reliance, and aims at regenerating the Irish nation, not
merely politically, but also linguistically, industrially,
 educationally, morally and socially. Almost all preceding
national movements made the grave mistake of considering
politics coincident with patriotism; the Sinn Fein policy
provides for all-round upbuilding of the nation, and is
successfully working along many lines on which no political
movement touched before."

Seumas MacManus,
Sinn Fein
(North American Review, August, 1907).

IRELAND: A. D. 1905 (December).

Change of Government.

On the change of government which took place in the United

Kingdom in December, Mr. Balfour resigning the Premiership and
Sir Henry Campbell-Bannerman forming a Liberal Ministry, the
Earl of Aberdeen was appointed Lord Lieutenant and Mr. James
Bryce Chief Secretary for Ireland.

IRELAND: A. D. 1907.
Effects of the Land Purchase Act as seen by
a revisiting Irishman.

Notwithstanding the defects in the working of the Land

Purchase Act, as described above, Mr. T. P. O’Connor, the
well-known Irish journalist in London, on returning from a
visit to Ireland in the spring of 1907 after a somewhat
protracted absence, wrote enthusiastically to the New York
Tribune of the happy wakening he had found in the country to a
new life. "You are seeing in Ireland," said a lady to him,
"not merely a revolution but a renaissance," and he found her
characterization to be true. He concludes, too, that there was
no exaggeration in her further remark, that "so much is going
on in Ireland now that you dare n’t leave it even for a
month." "Everybody," writes Mr. O’Connor, "seemed to be doing
something and something new for Ireland"; with Catholics and